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Epidemiology of pediatric hiv infection, hiv: pathogen and pathogenesis, preventing hiv infection in infants, children, and youth, recognizing hiv infection in infants, children, and adolescents: routine testing and clinical presentations, indications for routine hiv testing, adolescents, clinical presentations that warrant hiv testing, pretest counseling and consent for testing, hiv testing assays in infants, children, and adolescents, management of hiv-exposed infants, neonatal arv prophylaxis, routine hiv virologic testing schedule for hiv-exposed infants, pcp prophylaxis and immunizations, importance of primary care visits, long-term concerns for hiv-exposed uninfected infants, management of hiv infection in infants, children, and adolescents, baseline evaluation, art: goals and principles, prophylaxis and immunizations for hiv-infected infants, children, and adolescents, complications of hiv infection in the cart era, counseling and support, coping with the diagnosis and prognosis, disclosure of hiv infection status, adherence to care and treatment, school and sports participation, transition to adult health care, preventing and managing hiv infection in infants, children, and adolescents in the united states.

AUTHOR DISCLOSURE

Dr Siberry has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

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George K. Siberry; Preventing and Managing HIV Infection in Infants, Children, and Adolescents in the United States. Pediatr Rev July 2014; 35 (7): 268–286. https://doi.org/10.1542/pir.35-7-268

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• Ris (Zotero)
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Effective prevention strategies have reduced the risk of perinatal transmission of human immunodeficiency virus (HIV) infection to less than 1% to 2% in the United States, but failures to fully implement these strategies result in continued preventable infant HIV infections. In addition, the increasing number of sexually acquired HIV infections in adolescents underscores the important role of the pediatrician in preventing and diagnosing HIV infection in youth.

After completing this article, readers should be able to:

Recognize the important role that the pediatrician plays in the prevention, detection, and care of patients infected with and affected by human immunodeficiency virus (HIV).

Understand the epidemiology of HIV infection in infants, children, and adolescents.

Select the proper HIV diagnostic testing plan for infants, children, and adolescents.

Plan the comprehensive management of HIV-exposed infants.

Recognize the clinical conditions suggestive of HIV infection, including the major opportunistic infections seen in patients with HIV/AIDS.

Understand the principles, monitoring, and complications of HIV treatment in infants, children, and adolescents.

Since the first description of infants with human immunodeficiency virus (HIV) infection in the early 1980s, ( 1 )( 2 ) tremendous advances have been made in the understanding, prevention, and treatment of HIV infection. Effective prevention strategies have reduced the risk of perinatal transmission, or maternal-to-child transmission (MTCT), of HIV infection to less than 1% to 2% in the United States, and the World Health Organization has made global elimination of new infant HIV infections a realistic target by 2015. ( 3 ) For those children who have HIV infection, the development of potent antiretroviral (ARV) drugs has transformed a once progressive and often fatal infection for children into a chronic condition with markedly reduced morbidity and expectations for long and productive lives.

Worldwide, an estimated 34 million people are living with HIV infection; 3.4 million (approximately 10%) are younger than 15 years. ( 4 ) Nearly all (95%) children younger than 15 years acquired HIV infection perinatally; in fact, a substantial number of the 2 million adolescents (ages 10-19 years) with HIV infection worldwide are thought to be long-term survivors of perinatal HIV infection, but data have not been collected in a way to distinguish perinatal (vertical) and behavioral (horizontal) routes of HIV transmission in this age group. ( 5 )

As of 2011, in the United States, 4500 children (ages <15 years) had perinatal HIV infection, but this number represents approximately half of all perinatally infected HIV-infected people in the United States because diminishing numbers of new infant infections and markedly improved long-term survival of children with perinatal HIV infection have meant that most perinatally infected children are now adolescents and young adults. ( 5 )( 6 )( 7 )

The predominant route of HIV infection in children is MTCT, including intrauterine, intrapartum, and postnatal (through breastfeeding) transmission. In the absence of ARV preventive interventions, in nonbreastfeeding populations, 25% to 30% of infants born to HIV-infected women will become infected; the risk increases to as high as 50% for infants with prolonged breastfeeding. Sexual transmission is an important mode of transmission for adolescents, especially for adolescent girls in settings with generalized HIV epidemics and for young men who have sex with men (MSM). Less common routes of transmission include transfusion with blood products tainted with HIV (before routine screening of blood products for HIV was established), percutaneous exposure, and, rarely, HIV-infected caretakers chewing or warming food in their mouths and then feeding it to infants and children. ( 8 )

HIV-1 and HIV-2 are enveloped, single-strand RNA retroviruses. HIV-1 is overwhelmingly responsible for HIV infections worldwide, including the United States. HIV-2 causes infection predominantly in people from parts of West Africa, but it is less transmissible and generally associated with lower levels of viral replication and less severe disease. ( 9 )

The principal targets of HIV are cells expressing the CD4 + molecule: CD4 + T lymphocytes (CD4 T cells) and monocytes or macrophages. HIV binds the CD4 target with a cellular coreceptor (CCR5 or CXCR4), resulting in virus envelope fusion with the host cell wall that permits viral entry into the cell. CD4 + cells in the gut are a major target, and the virus disseminates widely soon after infection, including to the central nervous system. CD4 T-cell infection is followed by viral replication, release of HIV virions, and CD4 T-cell death, leading over time to progressive CD4 T-cell depletion and impairment of cellular immunity, the hallmark of HIV-related immunodeficiency.

In a small proportion of CD4 T cells, HIV entry instead leads to integration of the HIV genome (HIV RNA reverse transcribed to a DNA sequence) into the cellular genome of a CD4 T cell that enters a quiescent phase as a memory CD4 T cell, harboring its latent HIV infection for activation months or years later. Such latent infection of long-lived memory T cells underlies a main barrier to sterilizing cure of HIV infection. ( 10 )

The most important strategies to prevent MTCT in the United States have been administering ARV drugs to HIV-infected mothers and their infants, elective caesarean section for HIV-infected women who reach term without achieving plasma HIV virologic suppression, and providing replacement feeding instead of breast milk to infants of HIV-infected mothers. In settings outside the United States where infant replacement feeding confers an unacceptably high risk of HIV-unrelated morbidity and mortality (including in many sub-Saharan African countries), the additional strategy of administering ARV drugs to mothers or infants during breastfeeding has become an effective means to allow breastfeeding while reducing the risk of HIV transmission. In the United States, however, all HIV-infected women are still advised against breastfeeding, regardless of ARV use and maternal plasma HIV suppression, because neither maternal nor infant ARV prophylaxis completely eliminates breast milk HIV transmission (residual transmission can be as high as 5%) and safe and affordable replacement feeding is available. ( 11 )( 12 )

The ability of ARV drugs to prevent MTCT was first found in the landmark AIDS Clinical Trials Group 076 trial, which found that zidovudine administered during pregnancy, intrapartum, and (to the infant) after birth could cut transmission from 26% to 8% in the absence of breastfeeding. ( 13 ) Subsequent studies found even greater efficacy for combination ARV therapy (cART), which was generally composed of at least 3 ARV drugs from at least 2 different classes. Routine use of cART for pregnant women in the United States has resulted in MTCT risk less than 1% to 2% and estimated annual new infant infections numbering about 200 nationwide. ( 14 ) In fact, pregnant women who achieve consistent plasma HIV virologic suppression during pregnancy are at such low risk of MTCT that neither elective caesarean section nor intrapartum ARV therapy (intravenous zidovudine) is recommended to further reduce transmission risk. ( 11 ) However, failure to identify HIV infection in pregnant women, barriers that prevent HIV-infected women from receiving cART during pregnancy, and incident HIV infection in pregnant and breastfeeding women remain important problems that contribute to residual infant infections in the United States. ( 14 )( 15 )

The latest recommendations by the US Department of Health and Human Services for preventing MTCT in the United States can be found at http://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines . The comprehensive prevention approach is multipronged: routine testing for HIV in pregnant women, administering ARV drugs to HIV-infected pregnant women and their infants, supporting women’s retention in care and adherence to cART, offering elective cesarean section to women who have not achieved HIV plasma viral RNA concentration (viral load) less than 1000 copies/mL by the end of pregnancy, minimizing invasive obstetric procedures (eg, fetal scalp electrode), avoidance of breastfeeding, primary prevention of HIV infection in women of reproductive age, and ensuring access to family planning services for HIV-infected women.

HIV testing is recommended as early as possible in each pregnancy, including for women who tested HIV negative during a prior pregnancy. Retesting in late pregnancy should be considered for all HIV-seronegative women and is recommended for pregnant women who are at high risk of HIV infection, such as women with a known HIV-infected partner, history of injection drug use, or sexually transmitted infection (STI) diagnosis signs or symptoms of acute HIV infection; women who reside in jurisdictions with elevated HIV incidence among women of childbearing age (≥17 HIV cases per 100,000 person-years); and women receiving health care in facilities with at least 1 diagnosed HIV case per 1,000 pregnant women per year. ( 16 )( 17 ) Women presenting in labor who have not received appropriate HIV testing in pregnancy should undergo rapid HIV antibody testing. If the results are positive, a confirmatory HIV test should be performed as soon as possible, and maternal and infant ARV therapy should be initiated, pending the confirmatory test result. If the confirmatory HIV test result is positive, infant ARV therapy should be continued; if the test result is negative, then infant ARV therapy should be stopped.

Newborn nurseries should have procedures in place to alert nursery staff when an HIV-exposed infant is born because neonatal ARV prophylaxis should be initiated as soon after birth as possible, ideally within 6 to 12 hours (see the Management of HIV-Exposed Infant section). On admission to the newborn nursery and at the first newborn outpatient visit, documented maternal HIV testing results should be confirmed. For a newborn whose mother did not receive appropriate HIV testing in pregnancy, HIV exposure status should be confirmed by performing rapid HIV antibody testing on the mother; if maternal testing cannot be performed, infant antibody testing should be performed to assess potential HIV exposure. If a rapid maternal or infant antibody test result is positive, the infant should initiate ARV therapy immediately, pending confirmatory testing, as for women with positive rapid antibody test results during labor and delivery (see above).

HIV infection should be suspected in patients who present with typical clinical findings, but many children and youth have their conditions diagnosed before clinical manifestations develop because of several routine indications for HIV testing.

All infants born to women with HIV infection should undergo a scheduled series of HIV virologic tests that will lead to confirmation or exclusion of perinatal HIV infection (see the Management of HIV-Exposed Infant section). If the maternal HIV status has not been determined, maternal HIV antibody testing (or, if the mother is not available, infant HIV antibody testing) should be requested to determine whether the infant is HIV exposed.

Many new US cases of HIV infection are diagnosed in infants and children born outside the United States, especially in high HIV prevalence settings, such as sub-Saharan Africa. ( 18 ) Some of these children have come to the United States with their mothers or families, whereas others have been adopted. HIV antibody testing should be offered to foreign-born children (particularly from settings of moderate or high HIV prevalence) to evaluate for infection (in those age ≥18 months) or for perinatal exposure (in those age <18 months); those younger than 18 months who are HIV antibody positive will require additional HIV virologic testing, as for HIV-exposed newborns, to assess whether they are HIV infected (see the HIV Testing in Infants, Children, and Adolescents section).

Clinicians caring for infants and children with HIV exposure or infection should ensure that the siblings of these patients have also been evaluated for HIV infection. For instance, when managing an HIV-exposed infant, the clinician should recommend to the mother that she have her other children tested for HIV infection, even if they appear healthy, unless there is documentation that she did not have HIV infection at the time she was pregnant with or breastfeeding those older children. Although unusual, some undiagnosed (and thus untreated) perinatally HIV-infected children have survived into their teens without serious illness, so there is no upper age limit for siblings to be considered for HIV testing.

The Centers for Disease Control and Prevention (CDC) recommends performing an HIV test routinely beginning at age 13 years, the US Preventive Services Task Force guidelines recommend routine screening beginning at age 15 years, and the American Academy of Pediatrics recommends HIV testing at least once by age 16 to 18 years in patient populations with HIV prevalence of 0.1% or higher. ( 16 )( 19 )( 20 ) Thus, routine HIV screening is recommended for nearly all adolescents at least once, even in the absence of specific risk factors. The indications for and intervals between subsequent HIV testing are determined by level of risk. Those at very high risk should be offered HIV testing at least annually, whereas an interval of 3 to 5 years is reasonable for those at elevated but lesser degree of risk. ( 16 ) Important indicators of very high risk include young MSM and intravenous drug users. Other adolescents at increased risk of HIV infection include those whose sexual partners are MSM, intravenous drug users, or HIV infected; those who report unprotected anal or vaginal sexual intercourse; those who have STIs; and sexually active youth who live in an area of increased HIV prevalence (defined by the CDC as a community with an HIV seroprevalence of at least 1%).

Many infants and children with HIV infection may have prolonged periods without severe illnesses or clinical manifestations of HIV infection. However, perinatally infected infants (especially those infected in utero) are at high risk of rapid progression to severe illness and death. Although full implementation of prevention of MTCT policies should prevent nearly all infant HIV infections and identify early those few infections that occur despite appropriate interventions, there are still infants and children whose perinatal HIV exposure and resulting infection have escaped detection; it is therefore important for clinicians to recognize specific infections and clinical presentations that may be a sign of unrecognized HIV infection (or other immunodeficiency). Table 1 summarizes the clinical manifestations of untreated HIV infection.

Relative Frequency of Clinical Conditions in Untreated Human Immunodeficiency Virus Infection

HPV=human papillomavirus, MAC= Mycobacterium avium complex, PCP =Pneumocystis jiroveci pneumonia.

Some conditions belong to more than one category.

Adapted from Simpkins et al. ( 21 )

Pneumocystis pneumonia (PCP), caused by the fungus Pneumocystis jirovecii (formerly carinii) , was among the most common and deadly presentations of HIV infection in infants early in the epidemic. ( 22 ) Rare in the first month of life, this condition peaks at ages 3 to 6 months. Infants present with progressive cough, poor feeding, dyspnea, and often fever. Onset can be gradual or abrupt, but progression to hypoxia, respiratory failure, and death will occur without prompt recognition and treatment. ( 22 )

Mucosal candidiasis is a common and early sign of HIV infection in untreated infants. Although an episode of oral thrush can occur in infants without immunodeficiency, oral candidiasis that is severe, persistent, or recurrent is an important manifestation of the cellular immune dysfunction caused by HIV infection and other diseases that cause immunodeficiency.

Recurrent bacterial pneumonia and other bacterial infections (sinusitis and otitis) were common in HIV-infected infants and children before cART and may be the first clue to unrecognized HIV infection. Although these infections generally have similar presentations and pathogens (especially pneumococcus) in HIV-infected and uninfected children, their increased frequency and recurrence are typical in children with HIV infection.

The constellation of persistent parotid gland swelling, lymphadenopathy, and chronic interstitial lung disease (lymphocytic interstitial pneumonitis) was a typical pattern in pediatric HIV infection, often in those untreated children who were spared more serious infections in the first few years of life.

Growth monitoring and neurodevelopmental screening, essential aspects of standard pediatric primary care, may reveal failure to thrive, stunting, or abnormal motor and cognitive development that may be important clues to untreated HIV infection in infants and children.

All children with tuberculosis disease should be tested for HIV infection. Adults with HIV infection are more likely to develop contagious tuberculosis disease, increasing the risk of tuberculosis infection in children in their households. HIV-infected children who acquire tuberculosis infection are then more likely to develop tuberculosis disease because of their HIV-related immunologic impairments.

Herpes zoster (shingles) is uncommon in children, but most children who develop it probably do not have an immunodeficiency disorder. Children with untreated HIV infection, however, frequently develop zoster. In the United States, where unrecognized HIV infection in children is fortunately rare, an episode of zoster may not warrant automatic HIV testing. However, an episode of zoster in a child merits thorough review of the child’s history of other illnesses, careful physical examination, and ascertainment of health status of mother and siblings to determine whether HIV testing is warranted. Clinicians should have a low threshold for performing HIV testing in children with zoster that is severe or recurrent.

In adolescents, the diagnosis of a new STI should prompt HIV testing. HIV infection does not directly increase the risk of contracting STIs, but an incident STI is a marker of the same sexual risk behavior that increases the risk of HIV transmission.

Those who care for adolescents, including pregnant and breastfeeding women, should be able to recognize presentations of primary HIV infection several days to weeks after incident HIV infection when HIV viremia (and potential for transmission to others) is high and HIV antibodies have not yet appeared. Most episodes (50%-90%) of primary HIV infection are symptomatic, but the variable severity and nonspecific flulike or mononucleosis-like nature of acute retroviral syndrome often result in patients not seeking medical care for their illness and/or clinicians not recognizing it as possible primary HIV infection. ( 23 ) The most common features include fever, vomiting, diarrhea, headache, myalgias, lymphadenopathy, and rash ( Table 2 ). Sexually active patients with lymphadenopathy, maculopapular rash, and shallow, sharp ulcers of the oral and/or anogenital mucosae should be evaluated for acute HIV infection. Because this early phase of HIV infection precedes the full antibody response, patients with suspected acute HIV infection should be tested with a fourth-generation combined antigen-antibody test or a plasma HIV RNA test (see the HIV Testing Assays section). Patients diagnosed as having acute HIV infection should be counseled about their high risk of transmitting HIV through unprotected sexual contact with others; HIV specialists should be consulted promptly for recommendations regarding HIV treatment. Because of the high risk of MTCT after acute HIV infection in pregnancy or during breastfeeding, pregnant women with acute HIV infection should be urgently referred for comprehensive care and ARV therapy initiation, and breastfeeding women with acute infection should be counseled to stop breastfeeding immediately, be referred for their own care, and have their infants undergo evaluation for HIV infection.

Presentation of Acute Human Immunodeficiency Virus Infection

Adapted with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health: Richey LE, Alperin J. Acute human immunodeficiency virus infection. Am J Med Sci. 2013:345(2):136–142. ( 24 )

Promotional and commercial use of the material in print, digital or mobile device format is prohibited without permission from the publisher, Lippincott Williams & Wilkins. Please contact [email protected] for further information.

Patients who meet criteria for routine HIV screening (eg, pregnant women and initial testing for adolescents) should be notified that HIV testing is recommended but given the option to decline testing. ( 16 ) HIV testing provides an important opportunity to educate patients about HIV and to counsel them about sexual practices and other behaviors that may elevate their risk of HIV infection. However, mandatory HIV prevention counseling and separate written consent for HIV testing can be barriers to HIV testing and are not recommended by the CDC. Clinicians should be familiar with their local laws and regulations because some jurisdictions and institutions continue to require such counseling and/or written consent to proceed with testing. ( 25 ) The clinician should make a clear plan with the patient for delivering the test results, including timing (if not using rapid testing), location (usually best to discuss results in person), who else (eg, parents, partners, friends) should or should not be present for discussion of results, and what additional confirmatory testing will be needed if initial test results are positive.

In most cases, the plan for HIV testing of perinatally exposed newborns has been discussed with the mother (and often other caretakers) even before the infant’s birth. However, each clinical encounter with the infant and family is an opportunity to review the HIV testing plans and the interpretation of available results.

In older children for whom HIV testing is indicated (usually those who escaped detection in infancy), the discussion of the purpose and plan for testing will depend on the age of the child and must take into account how to respect the (HIV-infected) mother’s feelings about discussing her own HIV diagnosis with the child and other family members. This process is best handled by an interdisciplinary team (eg, physician, nurse, and social worker) experienced with such situations.

Several assays are available for diagnostic HIV testing ( Table 3 ); assay selection depends on availability, desired turnaround time, age, and suspicion of acute HIV infection.

Diagnostic Assays Used for HIV Testing

EIA=enzyme immunoassay; HIV=human immunodeficiency virus; IFA=immunofluorescent assay; PCR=polymerase chain reaction; WB=Western blot.

See Centers for Disease Control and Prevention ( 26 ) for additional information.

The current standard HIV diagnostic testing for children (age ≥18 months), adolescents, and adults (including pregnant women) relies on detection of HIV antibody in a blood specimen in 2 steps: a screening enzyme-linked immunoassay (EIA) is performed first, and if the result is reactive, a confirmatory HIV antibody test, such as a Western blot, is then performed. Both tests must be positive to meet the criteria for HIV infection. Rapid, point-of-care EIAs are available for detecting HIV antibodies in blood and saliva specimens; negative results reliably exclude established HIV infection and standard EIA tests (none is sensitive for detecting acute HIV infection), but positive test results need to be confirmed with standard HIV diagnostic assays.

Newer fourth-generation HIV testing assays that detect the HIV p24 antigen and both IgM and IgG antibodies to p24 antigen have higher sensitivity, especially for identification of recent HIV infections. ( 26 ) The CDC is anticipated to update their guidelines to recommend use of these fourth-generation assays as the preferred initial test to screen for HIV infection (for those at least age 18 months), and most experts prefer this assay to traditional antibody assays when acute HIV infection is suspected.

Virologic testing includes assays that detect HIV antigens (including the fourth-generation combined antigen-antibody assays discussed above) and those that detect HIV DNA (by polymerase chain reaction [PCR]) or HIV RNA (by PCR and other methods). These assays are important diagnostically for recent or primary HIV infection, when viremia is present but antibody is not, and in infants (up to age 18 months), in whom the presence of passively transferred maternal HIV antibodies requires virologic detection to identify those infants who are infected. The DNA PCR detects intracellular proviral DNA, the result of viral reverse transcriptase transcribing HIV RNA to DNA in the host cell. The HIV DNA PCR test is used almost exclusively for infant diagnosis, although the DNA PCR or RNA assays are equally acceptable for this purpose. Combined antigen-antibody assays should not be used for infant diagnosis. HIV RNA assays and combined antigen-antibody assays are both appropriate for detecting primary HIV infection (beyond age 18 months). Quantitative HIV RNA assays are also routinely used for monitoring of response to ART in HIV-infected people and may be more widely available than the DNA PCR assays.

Primary medical care practitioners for infants should know how to manage the HIV-exposed infant. The components of special care for such infants include ARV prophylaxis, HIV diagnostic testing, evaluation for the need for PCP prophylaxis, routine immunizations, monitoring for manifestations of HIV infection, and reinforcing education and counseling for the mother and family. Detailed, regularly updated guidelines for managing HIV-exposed infants are available at http://www.aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0 .

All HIV-exposed infants should receive zidovudine prophylaxis, started as soon after birth as possible and preferably within 6 to 12 hours of delivery. The usual dose (gestational age ≥35 weeks) is 4 mg/kg orally twice daily and should be given for 6 weeks. Zidovudine dosing is different for preterm infants (gestational age <35 weeks) ( Table 4 ). Zidovudine can also be given intravenously (at a different dose) for newborns initially unable to tolerate oral medications. In addition to zidovudine, newborns at high risk of perinatal infection (those whose mothers did not receive ARV drugs during pregnancy) should be given 3 oral doses of nevirapine beginning as soon as possible after birth (within 48 hours) ( Table 4 ). These drugs are generally well tolerated by infants; anemia and neutropenia related to zidovudine are the most common adverse effects, and these conditions usually resolve within several weeks after discontinuation of zidovudine therapy. Complete blood cell count with differential should be measured at baseline; hematologic parameters should be reassessed at approximately age 4 weeks in infants with hematologic risk factors (such as prematurity or anemia at baseline) or clinical suspicion of anemia. Early discontinuation of infant ARV prophylaxis because of hematologic toxic effects should be undertaken in consultation with a pediatric HIV expert.

Neonatal ARV Drug Dosing for Prevention of Mother-to-Child Transmission of HIV

ARV=antiretroviral; HIV=human immunodeficiency virus.

Adapted from AIDS Info. ( 11 )

Nevirapine dosing given as actual doses not as milligram per kilogram dosing.

In 2013, researchers described an infant with well-documented perinatal HIV infection who received an ART treatment (not prophylaxis) regimen beginning at age 30 hours until shortly after age 1 year who had no evidence of HIV infection after the family discontinued her treatment. This case of apparent resolution of infection after early, intensive ARV treatment has sparked a great deal of interest in the potential for early, multidrug therapy for high-risk newborns to result in functional cure. Until more evidence is available, this approach should be considered experimental, and deviation from standard neonatal prophylaxis regimens should only be undertaken under the guidance of a pediatric HIV expert. The Perinatal HIV Hotline can also be helpful for providing guidance ( http://www.nccc.ucsf.edu/ ).

Virologic testing (HIV DNA PCR or HIV RNA assays) should be performed within the first 14 to 21 days of life, at age 1 to 2 months, and then at age 4 to 6 months for all HIV-exposed infants. Many experts also perform a test in the newborn nursery, especially for high-risk infants (eg, whose mothers did not achieve virologic suppression by the time of delivery). Testing should never be performed on cord blood. HIV can be presumptively excluded (in nonbreastfed infants) on the basis of 2 negative results on virologic tests performed no earlier than age 14 days and at least 1 performed no earlier than age 1 month or based on 1 negative result on a virologic test performed no earlier than age 8 weeks. HIV can be definitively excluded on the basis of 2 negative results on virologic tests both performed no earlier than age 1 month and at least 1 performed no earlier than age 4 months.

For infants whose mothers were diagnosed as having HIV infection during breastfeeding, the recommended infant virologic testing schedule is baseline and then intervals of 4 to 6 weeks, 3 months, and 6 months after recognition of maternal infection and interruption of breastfeeding.

If, at any time, a virologic test result is positive, the infant should be promptly recalled for confirmatory testing and assessment.

All infants with known or possible HIV infection, regardless of CD4 cell count or percentage, should be prescribed PCP prophylaxis beginning at age 6 weeks. The preferred agent for prophylaxis is 2.5 to 5 mg/kg of cotrimoxazole (based on trimethoprim component) per dose given twice daily, usually on 3 days (consecutive or alternating) per week. Infants in whom HIV has been presumptively or definitively excluded by age 6 weeks do not need to start PCP prophylaxis; for infants who do not have virologic test results available by age 6 weeks, PCP prophylaxis should be started and then can be discontinued as soon as virologic testing results demonstrate presumptive or definitive absence of HIV infection.

HIV-exposed infants should receive all of standard immunizations in the first few months of life. ( 23 ) In fact, these infants may have lower levels of protective antibodies passively transferred from their HIV-infected mothers, putting them at higher risk of pneumococcal and other vaccine preventable diseases. ( 27 )( 28 ) Although there is some theoretical concern about administering live rotavirus vaccine to infants with possible HIV infection, this vaccine is still generally recommended based on low likelihood that infants in the United States will be HIV infected and limited data demonstrating it is well tolerated in HIV-infected infants. ( 29 )

Routine health maintenance visits for HIV-exposed infants offer the opportunity to detect growth faltering, abnormal neurodevelopment, and physical examination findings (eg, candidiasis) that may signal the presence of HIV infection. These visits also permit clinicians to assess social support needs for mothers and families, review with parents and caretakers the testing and prophylaxis results and plans for the infant, and reinforce safe infant feeding recommendations. Feeding counseling messages should include complete avoidance of breastfeeding and advice that all HIV-infected adult caretakers should avoid prewarming or prechewing food in their mouths before feeding it to their infants. ( 30 )

As a result of the use of ARV drugs and other prevention strategies, most of the approximately 9,000 infants born annually in the United States to HIV-infected mothers ( 31 ) will escape HIV infection. Most ARV drugs have been used extensively enough in pregnancy to conclude there is little or no increased risk of congenital defects (although the potential teratogenicity of efavirenz continues to be debated). ( 32 ) However, surveillance remains important because new ARV drugs and combinations will be used by pregnant women. ( 33 ) There is also evidence that use of combination ARV regimens in pregnancy, especially those that include protease inhibitors, may increase the risk of preterm birth and lower birth weight. ( 34 ) Longitudinal studies of perinatally ARV-exposed, HIV-uninfected children have been largely reassuring but have raised some concerns about subtle ARV effects on hematologic measures, immune function, growth, language, and neurocognitive outcomes, and effects in many organ systems. ( 35 )( 36 )( 37 )( 38 ) In addition, children may experience long-term adverse effects of problems that are more common in HIV-affected families in the United States (eg, poverty, mental illness, and substance abuse) and of their mothers managing their HIV infection. Clinicians can assist mothers in deciding how and when to disclose their HIV infection to their older children and can encourage mothers to have advance care plans in place in case of sudden, severe illness.

Patients who have positive HIV test results should be referred promptly to an HIV specialist for comprehensive evaluation ( Table 5 ) so the clinical and immunologic stage of disease can be assessed and treatment recommended. The specialist group should be contacted as soon as the positive result is known because immediate initiation of ART may be indicated, especially for infected infants and patients with advanced disease.

Clinical and Laboratory Monitoring of Children Before and After Initiation of ART

ALT=alanine aminotransferase; ART=antiretroviral therapy; AST=aspartate aminotransferase; CBC=complete blood cell; HIV=human immunodeficiency virus.

Adapted from Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children . ( 17 )

For children who are on stable ART, many clinicians consider 6-month intervals between monitoring laboratory tests.

In children receiving nevirapine, serum transaminase levels should be measured every 2 weeks for the first 4 weeks of therapy, then monthly for 3 months, and every 3 to 4 months thereafter.

Some clinicians do not recommend a CD4 cell count or percentage at this time, considering it too early to expect an immunologic response.

Initial evaluation of an HIV-infected infant or child should include the mother’s medical history, child’s medical history, family history, and social history. A comprehensive physical examination should be performed and documented, including a developmental evaluation. Assessment of HIV-infected adolescent patients, as for all adolescents, should include a sexual history, substance use history, and sexual maturity staging.

Initial laboratory testing in an HIV-infected patient should include CD4 percentage and absolute cell counts, plasma quantitative HIV RNA concentration (viral load), HIV genotype to assess for baseline drug resistance mutations, complete blood cell count with differential, serum chemical analyses with liver and renal function tests, a lipid profile, and urinalysis ( Table 5 ). For children younger than 5 years old, CD4 percentage is often used for monitoring immune status because the absolute CD4 cell count in this age group varies with age-related changes in absolute lymphocyte count. Screening for hepatitis B and C infection and tuberculosis is recommended for all HIV-infected patients. In addition, sexually active adolescents should be screened for Chlamydia infection, gonorrhea, syphilis, and human papillomavirus infections. In contrast to the guidelines for cervical cancer screening in healthy women, cervical Papanicolaou smears are indicated routinely in all sexually active, HIV-infected adolescent girls, with colposcopy recommended for evaluation of abnormal results. Similarly, most experts perform anal Papanicolaou smears in HIV-infected adolescent MSM and HIV-infected sexually active women; anoscopy is recommended for evaluation of abnormal results.

HIV infection is a multisystem disease; clinical manifestations range from asymptomatic to complications that affect virtually every organ system ( Table 1 ). The CDC classification system designates clinical stages based on the patient’s medical history and degree of immunosuppression based on CD4 cell count or percentage ( Table 6 and Table 7 ). This information permits an estimated risk of future morbidity and mortality and provides a rationale for instituting specific opportunistic infection (OI) prophylaxis and initiating or deferring ART.

CD4 T-Lymphocyte–Based Assessment of Degree of Immunosuppression in Human Immunodeficiency Virus Infection ( 39 )

Clinical Staging of HIV Infection ( 39 ) a

HIV=human immunodeficiency virus.

Until 2014, CD4-based immunosuppression (none, moderate, severe) was categorized separately from a clinical staging in children (<13 years old): N, no signs or symptoms; A, mild signs or symptoms; B, moderate signs or symptoms; C, severe, AIDS-defining illness.( 40 )

The goals of ART are to maximize the quality and longevity of life through complete suppression of viral replication (goal of nondetectable viral load), preservation or restoration of immunologic function (goal of normal CD4 cell count or percentage), and prevention of or improvement in clinical disease status (goal of asymptomatic state). Additional prevention goals for ART include prevention of MTCT in pregnant women and reduction in sexual transmission for HIV-infected youth who have uninfected sexual partners.

The decision to start ART requires balancing of health benefits of HIV treatment with the potential adverse effects of ART and patient readiness to take daily medications. On the basis of clinical trial evidence indicating that prompt ART initiation in HIV-infected infants markedly reduces risk of death and morbidity, ( 41 ) ART is routinely recommended for all infants (age <12 months). For both prevention of MTCT and maternal health reasons, ART is also routinely recommended for all pregnant women. ART has generally been recommended for children (beyond infancy), adolescents, and adults based on clinical stage of their HIV infection, level of CD4-defined immunodeficiency, and, to a lesser extent, plasma viral load ( Table 8 ). ( 17 )( 42 ) Current US guidelines have moved to recommend ART for all adolescents and adults based on several factors: currently available ARV regimens are simpler, safer, and highly potent; cohort studies suggest clinical benefits even at higher CD4 levels; and treating HIV-infected people markedly reduces HIV transmission to sexual partners. ( 43 ) In fact, some experts advocate for intensive testing accompanied by immediate ART for those who test positive (the test-and-treat approach) as a way to contain the spread of HIV in communities and populations. ( 44 ) Because preadolescent children are not at risk of sexual transmission and have not been found to benefit from ART at higher CD4 cell counts, current guidelines permit but do not strongly recommend ART for children who do not meet clinical and laboratory criteria.

Summary of Recommendations for Starting Antiretroviral Therapy ( 17 )( 38 )

HIV=human immunodeficiency virus; VL=viral load.

The most common ART regimens include 2 nucleoside (or nucleotide) reverse transcriptase inhibitors and one of the following: nonnucleoside reverse transcriptase inhibitor, protease inhibitor, or integrase inhibitor. The preferred and alternative initial ARV drug regimens vary by age, will be altered if baseline ARV drug resistance is detected, are updated frequently (see www.aidsinfo.gov ), and should generally be prescribed by or in collaboration with an HIV specialist, so they will not be detailed here.

ART is generally composed of at least 3 ARV drugs from at least 2 different ARV drug classes. For older children and adults starting ART for the first time, most ARV regimen options can be given once daily, often as a single pill that is a coformulation of 3 ARV drugs. For infants and younger children, there are fewer ARV options, the regimen is given as separate ARV drugs, administration is at least twice daily, and some of the liquid formulations (especially lopinavir-ritonavir) have poor palatability. For patients of all ages, ART efficacy depends on high levels of adherence to the regimen; as frequency of missed ARV doses increases, achieving ART goals becomes less likely and the emergence of drug resistance increases. For ARV drugs (such as efavirenz) in which a single point mutation in the viral genome results in complete drug resistance, resistance emerges quickly with poor adherence; for other drugs (such as most protease inhibitors) that require multiple viral mutations to make the virus resistant, resistance emerges only after longer periods of nonadherence.

Planning treatment collaboratively with the patient and family strengthens the therapeutic relationship and promotes successful adherence and HIV control. Enlisting adult support in the home is beneficial regardless of the patient’s age. Frequent clinical follow-up with viral load testing allows the clinician to identify problems early and help patients and families find successful solutions. Children starting a new ARV regimen should be evaluated in person or by telephone within 1 to 2 weeks of starting ART to screen for adverse effects and to assess adherence. Many clinicians will plan additional contacts (in person or by telephone) with children and caregivers to support adherence during the first few weeks of therapy. Some clinicians also recommend an HIV RNA measurement within the initial weeks of therapy for early assessment of response and adherence to therapy. Patients generally achieve a undetectable viral load within 6 months, although suppression of extremely high viral loads in some infants may take several weeks longer. Failure to achieve undetectable viral load in this time frame strongly suggests suboptimal adherence rather than viral resistance to the ARV regimen. Immediate and intensive adherence counseling and support are warranted because continued nonadherence can allow for development of drug resistance.

Once HIV infection is controlled on a stable regimen, most patients are seen every 3 to 4 months for routine monitoring of viral load, CD4 cell response, and clinical status, including evaluation for potential medication adverse effects or toxic effects ( Table 5 ). For patients having difficulty taking (eg, because of poor palatability) or tolerating (eg, because of adverse effects, such as nausea or diarrhea) one ARV drug in the regimen, substitution of one new ARV drug can be effective. Patients who experience treatment failure with drug resistance will usually be offered a new regimen (change at least 2 of the ARV drugs) based on the resistance patterns as well as robust adherence counseling and support.

Drug-drug interactions among different ARV drugs and between ARV and non-ARV drugs (including nonprescription and herbal medicines) are common, complicated, and potentially dangerous. Interactions can result in excessive toxic effects or loss of efficacy. As part of every clinical encounter, and especially when a new drug will be prescribed, the patient’s complete medication list should be reviewed and confirmed with the patient (and family); potential adverse drug interactions should be evaluated in collaboration with a pharmacist and/or through use of other available resources. ( 45 )( 46 )( 47 )

Effective ART markedly reduces the risk of OIs and improves the protective response elicited by many immunizations. However, regular assessment of need for OI prophylaxis and attention to recommended immunizations remain essential; guidelines for preventing and treating OIs, including immunization recommendations, are updated regularly ( http://aidsinfo.nih.gov/contentfiles/lvguidelines/oi_guidelines_pediatrics.pdf ).

As part of every HIV monitoring visit, patients should be evaluated for indications for OI prophylaxis based on their immunologic (CD4) status, illness history, and exposures. This is especially important for infants, all patients who have not yet started ART, and patients in whom ART fails to result in virologic suppression (most commonly due to nonadherence).

PCP is one of the most common and deadly OIs. Cotrimoxazole is recommended for all HIV-exposed infants until HIV infection is presumptively or definitively excluded, for all HIV-infected infants until age 12 months, and for HIV-infected children and adolescents older than 1 year with CD4 values in the severe immune suppression category. In addition, children who have had PCP prophylaxis should receive cotrimoxazole prophylaxis after PCP treatment, at least until they have sustained improvement of immunologic status on ART.

Mycobacterium avium complex causes disease in patients with even more advanced immunosuppression than the threshold at which PCP occurs. Primary prevention of M avium complex with azithromycin or clarithromycin is thus recommended at lower CD4 values (age ≥6 years with CD4 cell count <50/μL; ages 2 to <6 years with CD4 cell count <75/μL; ages 1 to <2 years with CD4 cell count <500/μL; ages <1 year old with CD4 cell count <750/μL).

As part of every HIV monitoring visit, patients should be evaluated for indicated vaccines. Although this recommendation seems common sense, studies have found that HIV-infected children are at increased risk of not receiving recommended vaccines. ( 48 )( 49 ) The recommended immunization schedule for HIV-infected children and youth is mostly the same as that for HIV-uninfected peers and is presented in Figure 1 and Figure 2 of the OI guidelines. ( 23 ) There are, however, several important exceptions ( Table 9 ).

Summary of How Immunization Recommendations for HIV-Infected Children Differ From Standard Immunization Schedule

ART=antiretroviral therapy; HBsAb=hepatitis B surface antibody; HBV=hepatitis B virus; Hib= Haemophilus influenzae type b; HIV=human immunodeficiency virus; MCV=meningococcal conjugate vaccine; MMR=measles-mumps-rubella; MMR-V=measles-mumps-rubella-varicella; PCV13=13-valent pneumococcal conjugate vaccine; PPSV23=23-valent pneumococcal polysaccharide vaccine.

Although ART markedly reduces the risk of infections due to pneumococcus and other encapsulated bacteria, these infections continue to occur at higher rates in HIV-infected children. As a result, in addition to receiving the standard series of pneumococcal conjugate vaccine in the first 2 years of life, HIV-infected children should also receive the 23-valent pneumococcal polysaccharide vaccine at age 2 years and then 3 to 5 years later. Furthermore, older children (ages 6-18 years) who never received the 13-valent pneumococcal conjugate vaccine should receive one dose. Finally, children who are not fully vaccinated against Haemophilus influenzae type b by age 5 years should receive a single dose of H influenzae type b conjugate vaccine.

HIV-infected children have been found to be less likely to respond to some vaccines. Thus, they should receive a 2-dose primary series of meningococcal conjugate vaccine instead of a single dose. They should also have anti–hepatitis B surface antibody measured 1 to 2 months after completing the HBV vaccine series to confirm a protective response.

Because of the potential for attenuated live vaccines to cause disease in immunocompromised hosts, use of live vaccines is either not recommended or limited to children without severe immune suppression. Limited data demonstrate that live-attenuated intranasal influenza vaccine is safe and immunogenic in HIV-infected children without severe immunosuppression, ( 50 ) but, until more data are available, injectable influenza vaccine rather than live-attenuated intranasal influenza vaccine is recommended for all HIV-infected children. Measles-mumps-rubella (MMR) and varicella vaccines are recommended for HIV-infected children who do not have evidence of severe immunosuppression. The MMR and varicella combination vaccine, however, should not be used because it contains a higher titer of varicella vaccine (than the monovalent varicella vaccine) and has not been studied in HIV-infected children.

Many people in the United States with perinatal HIV infection received their MMR (and most other) vaccines as infants and young children in an era before ART was available. Pre-ART responses to MMR are not as reliable or durable as responses in HIV-infected children receiving ART. On the basis of evidence that high proportions of US youth with perinatal HIV infection lack immunity to MMR and evidence that reimmunization is effective in those who were not immune when MMR vaccination preceded ART, it is recommended that individuals with perinatal HIV infection who were vaccinated before effective ART should receive 2 appropriately spaced doses of MMR vaccine doses once effective cART has been established, unless they have other acceptable current evidence of MMR immunity.

With effective cART, HIV-infected children experience much lower rates of serious illness, can participate in the same activities as their peers, and expect to live long and relatively healthy lives. Whether life expectancy with treated perinatal HIV infection will be the same as that for people without perinatal HIV infection is unknown because the oldest people with perinatal infection are just reaching their 30s.

The pattern of OIs and other illnesses that were typical of untreated HIV infection ( Table 1 ) is uncommon today, although these problems continue to occur in children with unrecognized HIV infection and in children (especially adolescents) who are not able to receive cART reliably. The spectrum of problems seen in children and youth receiving effective cART includes complications of chronic HIV infection itself and residual effects of problems that occurred before cART was initiated, adverse effects of ARV drugs, and comorbidities that are more common in US communities burdened by poverty, mental illness, and substance abuse where perinatal HIV infection is most likely to occur ( Table 10 ).

Complications and Problems in Perinatally Infected Children and Youth Receiving Effective cART

ARV=antiretroviral; cART=combination antiretroviral therapy; HIV=human immunodeficiency virus; NRTI=nucleoside reverse transcriptase inhibitor.

See Chapter 113, Siberry GK and Hazra R. Management of HIV Infection, in Principles and Practice of Pediatric Infectious Diseases , 4 th ed., Long SS, Pickering LK and Prober CG, eds. Elsevier Saunders, 2011, Philadelphia.( 51 )

Learning of a new diagnosis of HIV infection for oneself or one’s child is emotionally devastating for most people. While providing a listening ear and emotional support, clinicians also can offer hope and reassurance about the availability of effective treatment that can result in improved quality of life and survival for people living with HIV infection in the United States.

HIV infection remains a stigmatizing diagnosis. Ignorance, misinformation, and fear in families and communities cause people living with HIV infection to keep their status a secret. However, this practice has negative consequences, such as isolating the HIV-positive individual from social support and risking additional spread of HIV to sexual partners. Planned disclosure to family members and friends can increase practical and emotional support for the HIV-positive person. Sexual partners can make informed decisions about how to protect themselves from exposure to HIV.

In contrast to adolescents and adults, disclosure of HIV status to children should be undertaken over time, providing sequential pieces of practical health information that match the developmental capacity of the child. This process builds a strong foundation for children to participate meaningfully in their HIV care. Most perinatally infected children learn of their HIV diagnosis by name between ages 8 and 10 years.

Most people do not adhere to the treatment recommendations of their health care practitioners all of the time. Infants and young children depend on their adult caretakers for adherence. Developmentally normal behaviors and stages (eg, toddlers and adolescents) can make adherence to medications especially difficult.

Poor adherence leads to poor health outcomes in many diseases, such as asthma and diabetes. However, HIV treatment demands very high levels of adherence to drug regimens to avoid the development of viral resistance and the loss of future efficacy of anti-HIV drugs. The need for intensive education and support for children and adolescents living with HIV infection cannot be overstated.

Children and adolescents who have HIV infection can participate fully in the educational and extracurricular activities in school. There is no obligation to notify school personnel of a student’s HIV infection status. Any sport may be played if the student’s health status allows. For all athletes, regardless of HIV infection status, skin lesions should be covered properly, and athletic personnel should use standard precautions when handling blood or body fluids that have visible blood. Certain high-contact sports (such as wrestling and boxing) may create a situation that favors viral transmission (likely bleeding plus skin breaks). Some experts advise athletes who have a detectable viral load to avoid such high-contact sports.

Children born with HIV infection in the United States during the 1980s are now young adults. They continue to be the pioneers who challenge our assumptions and identify unmet needs for care and support services. There is a pressing need to develop and implement programs to transition youth successfully to adult HIV health care clinicians. ( 52 ) Practical concerns, such as transmitting a complete and coherent medical record, and psychological concerns, such as the loss of long-term supportive relationships, must be addressed.

NOTE: The content of this article is solely the responsibility of the author and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health (NIH). The author is a U.S. government employee who must comply with the NIH Public Access Policy, and the author or NIH will deposit, or have deposited, in the NIH PubMed Central archive, an electronic version of the final, peer-reviewed manuscript to be made publicly available no later than 12 months after the official date of publication.

English: http://www.healthychildren.org/English/health-issues/conditions/sexually-transmitted/Pages/Where-We-Stand-Preventing-Prenatal-Transmission-of-HIV-.aspx

Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/sexually-transmitted/paginas/where-we-stand-preventing-prenatal-transmission-of-hiv-.aspx

English: http://www.healthychildren.org/English/health-issues/conditions/sexually-transmitted/Pages/HIV-Human-Immunodeficiency-Virus.aspx

Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/sexually-transmitted/paginas/hiv-human-immunodeficiency-virus.aspx

antiretroviral therapy

antiretroviral

combination antiretroviral therapy

Centers for Disease Control and Prevention

enzyme-linked immunoassay

human immunodeficiency virus

Mycobacterium avium complex

measles-mumps-rubella

men who have sex with men

maternal-to-child transmission

opportunistic infection

Pneumocystis pneumonia

polymerase chain reaction

sexually transmitted infection

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Neonatal HIV

Introduction.

Over 95% of HIV-infected pediatric cases are a result of vertical transmission. The pathophysiology of the HIV disease state in the pediatric population is similar to adults. However, differences occur in the clinical presentation, mode of infection, and therapeutic options. The pediatric and neonatal populations have a weaker immune system than adults; therefore, if infected with HIV, they are at a greater risk of opportunistic infections. As such, the delay of treatment may result in a rapid progression of the disease.

One of the greatest advancements in medicine has been the prevention of mother-to-child transmission (MTCT) of HIV type 1 (HIV-1). The rate of transmission of HIV to neonates has been reduced to less than 1% with the implementation of appropriate strategies and careful planning. The increase in comprehensive serologic screening and the treatment of HIV-infected pregnant females has resulted in the reduction of vertical transmission. There are evidence-based prevention modalities that can be utilized at different stages of pregnancy and postpartum to improve outcomes. Antiretroviral therapies (ART) can be prescribed during gestation, antepartum during vaginal or elective cesarean delivery, postnatally to the neonate, or when breastfeeding. [1] [2]

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HIV is a ribonucleic acid (RNA) viral pathogen with 2 subtypes: HIV-1 and HIV-2. HIV-1 is the most common type worldwide and is more transmissible and progresses faster than HIV-2. Presumably, this Retroviridae family originated from wild chimpanzees in Central Africa. [3] The virus is transmitted across mucous membranes via penetrative unprotected sexual intercourse or intravenous drug use, blood transfusions in developing countries, vertical transmission, or through breastfeeding. [4] [5] The risk of transmission via lactation is about 12-14%, with the risk increasing in high viral load states. [6] [7] Overall, the probability of vertical transmission is about 25% without the utilization of appropriate ART therapy during pregnancy. Several risk factors that increase the chance of this transmission were observed in clinical trials. The risk factors include elevated maternal plasma viral RNA concentrations, maternal breast milk viral load, acute maternal seroconversion, advanced maternal disease, and decreased CD4+ T-cell count of the mother. [8] [9] [10] [11] [12]

Epidemiology

The burden of MTCT is a worldwide epidemic, with an estimated 160,000 infants infected annually with HIV as of 2018. The majority of mothers and neonates infected with HIV are located in sub-Saharan Africa. [13] Overall, the rate of perinatal transmission of HIV has decreased substantially over the past 20 years to less than 1% in the United States and Europe. [14] [15] In the United States, approximately more than 5,000 pregnant females are HIV positive. [16]  In the year 2013, nationwide in the United States, there were only 69 infants born with HIV infection, leading to an estimated incidence of 1.8 out of 100,000 live births for perinatally-acquired HIV infection. [14]  The Centers for Disease Control and Prevention (CDC) in the United States (US) has set goals to eliminate perinatal HIV spread, which has caused a significant decline in MTCT transmission. The goal is to reduce the incidence of perinatal HIV to less than 1 in 100,000 births. [14] During the peak of HIV transmission in 1991, the reported incidence of neonates born with HIV was 42.8 per 100,000 births, with a substantial decline to 1.3 per 100,000 live-born infants in 2015. [17] Due to racial disparities in healthcare, the incidence of perinatal HIV is 5 times greater in Black versus White infants. [18]

Pathophysiology

The main target for HIV entry into the cells is through infection of cells expressing the CD4 receptor and chemokine receptors CCR5 and CXCR4. [19] Additionally, the HIV virus infects dendritic cells, activated CD4 T-lymphocytes, monocytes, and macrophages. [20]  The result is increased host susceptibility to diseases due to decreased immune-protective functions. 

Infants with HIV-1 infections have higher viral loads and a faster progression to AIDS than adults with HIV. [21] [22] The most common mode of transmission in a neonate with HIV is mother-to-child transmission (MTCT). The virus may be transmitted during different stages of pregnancy and postpartum, with the perinatal period as the most common transmission time. [23]

In-utero Transmission

The mechanism of in-utero transmission is predicted to be by transcytosis across placental cells. The placenta may also host the virus to replicate before moving to the fetus. [24] The HIV-1 virus may also traverse the trophoblastic placental barrier via endocytosis, specifically crossing cytotrophoblasts or syncytiotrophoblasts within the uterine wall. HIV-1 may also spread to the fetus via villous capillaries. The risk of in-utero transmission increases with inflammation and infection of the placenta and amniotic membranes. [24] [25] [26] [27] [28]

Intrapartum Transmission

Intrapartum transmission is predicted to be the greatest risk of vertical infections. The risk increases with longer exposure to maternal cervicovaginal secretions and blood. Research also demonstrates that the chance of infection is greater with membrane rupture of more than 4 hours. [29] Moreover, data also demonstrates that neonates with low birth weights and those born prematurely have an increased rate of transmission due to their reduced immunologic defenses and weaker skin barrier. [30]

Postnatal MTCT 

Postnatal MTCT occurs during breastfeeding. The mechanism of transmission through breast milk is not fully understood. However, multiple large prospective cohort trials have demonstrated a greater risk of spread of the HIV virus with breast-feeding. In addition to breast milk, studies have also confirmed that HIV RNA can also be found in colostrum. [31] [32] Potential entry of the HIV virus from breast milk to the infant is through their intestines or tonsillar tissues. [33] [34] [35] [36]

Histopathology

Due to the nature of the disease state, early identification of HIV may be difficult due to subtle clinical symptoms. As such, the use of histopathology of tissue samples may help identify HIV in patients. The capsid size of the HIV-1 virus varies between 110 and 146 nm. [37] It can be visualized with structured illumination microscopy (SIM). It is almost impossible to visualize individual virions using confocal microscopy. Assessing the histopathology of the placenta may identify the presence of intrauterine HIV infection. Multiple studies have demonstrated that full-term placenta from HIV-1–positive females contained infection in syncytiotrophoblasts, cytotrophoblasts, and villous-endothelial cells. [38] In vitro, studies of trophoblast barriers have demonstrated that the direct interaction between the trophoblast barrier and HIV-1 infected cells resulted in viral transcytosis. [24]

History and Physical

Neonates may not display any symptoms for the initial few months of life, as such complicating the diagnosis of HIV. Studies have suggested that children may remain asymptomatic until 3-5 years of age. In untreated children, the most commonly exhibited manifestations of HIV infection include but are not limited to recurrent bacteremia, increased opportunistic infections, frequent diarrhea, cardiomyopathy, hepatitis, generalized lymphadenopathy, splenomegaly, hepatomegaly, oral candidiasis, cancers, and central nervous system manifestations, such as growth delay, delayed cognition, low IQ, and frequently global developmental delay.

The CDC strongly recommends testing all pregnant females for HIV as part of the standard prenatal care. This testing proves to have a better prognosis for the neonate. However, due to a lack of adequate healthcare access in certain geographical areas of the world, the unknown HIV status of pregnant females leads to inadequate treatment and poor outcomes for the neonate. [39] [40] Females who have an unknown HIV status should be offered a rapid diagnostic test at the time of delivery. A definitive HIV diagnosis can be made in infants by the age of 4 to 6 months using virologic testing.

Neonatal HIV diagnostics differs from that of adults and older children. It is not appropriate to test for HIV antibodies. The utilization of novel combination antigen/antibody immunoassays to confirm the diagnosis of HIV in neonates is not recommended as positive results confer passive transfer of maternal antibodies. Maternal HIV antibodies persist until 18 months. [5] [40] Using viral load assays or nucleic acid tests (NATS), which include qualitative RNA assays, quantitative HIV RNA assay, or DNA polymerase chain reaction (PCR) assays, is more appropriate to confirm the diagnosis of HIV in neonates. The only FDA-approved qualitative RNA test is the APTIMA HIV-1 RNA Qualitative Assay. [41] These assays are able to detect the virus in at least 30% to 50% of cases at birth and an almost 100% confirmation by the age of 4 to 6 months. HIV quantitative RNA assay has been found to be just as comparable to HIV DNA PCR, with 100% specificity at birth, 1 month, 3 months, and 6 months. [42] Two negative virologic tests completed at 1 month and before 6 months of age are required to definitely exclude the diagnosis of HIV. Additionally, the infant must have negative clinical evidence and other laboratory markers of HIV, including normal to high CD4 T-lymphocyte count. [5] [43]

Infants are categorized as high or low risk for HIV infection. Neonates born to mothers who received adequate prenatal care and were adherent to their ART, and who had undetectable viral loads are considered low risk. On the contrary, neonates are considered high risk if they were born to mothers who lacked prenatal care, had elevated HIV viral loads, and had a new diagnosis of HIV infection while pregnant. [5]

The table below indicates (X) the proposed recommended testing schedule for HIV perinatal exposure. [43] [40]

After a confirmed diagnosis of HIV, additional labs should be ordered, including CD4+ T-cell count, CD8+ T-cell count, plasma viral load of RNA, growth or development factors, and HIV-associated conditions, such as anemia, leukopenia, thrombocytopenia, hepatic transaminitis, etc. Before initiating ART, obtain genetic testing, a baseline CD4 count, plasma viral load, complete blood count (CBC), hepatic function, renal function, comprehensive metabolic panel, urinalysis, serum lipids, and blood glucose.

Treatment / Management

The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV strongly recommends the initiation of ART in all pediatrics with HIV. [44] There has been a significant 80% to 90% decrease in morbidity and mortality since the introduction of ART initiation in neonates. [45] [46]  As confirmed by the CHER trial and other studies, there is a decrease in viral reservoirs, opportunistic infections, and disease progression to AIDS with early initiation of effective and early ART. [47] [48] [49] [50] [51] [52] Infants with any level of risk of exposure to HIV should be started on the appropriate ART within 6 hours of birth. The goals of treatment for HIV-exposed neonates include a reduction in morbidity and mortality, suppression of viral replication, facilitation of HIV remission, viral control, prevention of disease progression, maintenance of immunologic function, reduction of opportunistic infections, and prevention of drug resistance. [53] [54]   (A1)

There aren’t many randomized control trials that compare different regimens in pediatrics and neonates, and the available literature is variable. Most of the data is extracted from non-randomized studies, pharmacokinetic trials, and phase 1 or 2 of drug trials. In general, the initiation of an antiretroviral regimen in pediatrics should include 2 nucleoside reverse transcriptase inhibitors (NRTIs) with an additional drug from another class, including an integrase strand transfer inhibitor (INSTI), a protease inhibitor (PI) with a booster, or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Before initiating a regimen, Factors to consider include the patient’s age, weight, family preference, drug resistance, genetic testing, mutation testing, and sexual maturity rating (SMR). In children with other confections, such as hepatitis B virus (HBV), the choice of agent should include coverage for HIV and the co-contagion. 

There are 3 studies that compared the addition of a PI-boosted versus NNRTI to the 2 NRTI backbones. In the P1060 trial, a total of 288 children from 6 African countries and India with ages from 2 to 36 months were enrolled in a randomized trial. The children received zidovudine (ZDV) plus lamivudine as the NRTI backbone and were randomized to either the PI with booster group (ritonavir booster [LPV/r]) or NNRTI group (nevirapine [NVP]). The data demonstrated that LPV/r is superior to NVP in NVP-naive children; however, there were limitations. [55]  Whereas the PROMOTE trial did not find any differences between the 2 groups. [56] Of note, LPV/r should be avoided in neonates before 42 weeks of age and those who are younger than 14 days. (A1)

Data for utilizing an INSTI-based regimen are extracted from safety trials and adult comparative trials. Four INSTIs are approved for the treatment of ART-naïve children with HIV, which include: bictegravir (BID), dolutegrevir (DTG), Elvitegravir/cobicistat (EVG/c), and raltegravir (RAL). [57] INSTI regimens are attractive due to their lack of drug interactions, low toxicity, and virologic efficacy. RAL is FDA-approved for neonates and infants weighing 2 kg or more. DTG is FDA-approved for children 30 kg or more, and BIC is approved for children weighing 25 kg or more. [58] [59]

Zidovudine (ZDV) plus lamivudine (3TC) or emtricitabine (FTC) are the preferred dual NRTI backbone in neonates and infants under 3 months. ZDV is FDA-approved for prophylaxis and for HIV treatment initiation in infants ≥ 4 weeks of age. [60] [61] [62] [63]  The preferred regimen for infants 3 months and older is abacavir (ABC) plus 3TC or FTC. [64] [65] [66] [67] Alternatively, ZDV plus ABC can be used in infants 3 months and older; however, European studies have demonstrated lower rates of viral suppression and increased toxicity with this combination. [65] [68]  In addition to the 2 NRTI backbones, the following combination regimens are preferred in each age group: (A1)

• NVP: Age under 14 days 
• RAL: Age under 14 days and a weight of 2 kg or more
• LPV/r or RAL (alternative: NVP): Age 14 days or older to 3 years 

Differential Diagnosis

There are other diseases that need exclusion when diagnosing HIV. These include malnutrition, lymphadenopathy, pediatric chronic anemia, malabsorption syndrome, constitutional growth delay, autoimmune and chronic benign neutropenia, and other immunodeficiencies. Furthermore, the clinician should also look for other congenital co-infections, including syphilis, TORCH infections (Toxoplasmosis, Rubella, Cytomegalovirus, herpes simplex virus), hepatitis B, hepatitis C, or tuberculosis infection.

Toxicity and Adverse Effect Management

Any ART is associated with a variety of side effects. Many ARTs result in increased levels of hepatic transaminases as a result of hepatitis. Baseline labs are recommended before initiation of any regimen.

• Zidovudine:  Can induce leukopenia, anemia, and macrocytosis
• Protease inhibitors: May lead to hyperglycemia
• Atazanavir: Can cause hyperbilirubinemia.

If untreated, HIV can increase the rate of morbidity and mortality. However, due to the advancement of ART, increased monitoring, and data from clinical trials, pediatric and adult patients have better prognoses and outcomes. The average survival rate is about 10 years of age, with approximately 15% of children having a rapid progression of the disease. The clinician should collaborate with the patient to optimize their nutrition, control viral replication, initiate aggressive treatment for opportunistic infections, and decrease social stressors. The risk of complications is greater with co-infections and hematological disturbances, such as anemia, thrombocytopenia, and neutropenia.

Complications

Complications of HIV infection in neonates and pediatric populations occur as a result of their immunocompromised status. They are at greater risk for opportunistic infections, candida esophagitis, Pneumocystis jirovecii pneumonia, and cancers. Furthermore, complications are more likely to occur with antiretroviral drug resistance. However, with careful monitoring and drug-resistance testing, the ability to select more optimized and effective regimens is possible.

Consultations

Consultation with a perinatologist and a pediatric infectious disease consultant is strongly encouraged to help provide a more comprehensive workup, diagnosis, and ongoing monitoring and management.

Deterrence and Patient Education

Before initiating or altering ART, the clinician should identify potential barriers and compliance issues. Developing novel drugs and enhanced formulations has led to better medication tolerability, less toxicity, and increased adherence.

HIV-positive mothers should be discouraged from breastfeeding neonates who do not have a confirmed HIV-positive status. If a female continues to breastfeed, the infant should be monitored and tested every 3 months throughout breastfeeding and postdiscontinuation of breastfeeding at the interval of 4 to 6 weeks, 3 months, and at 6 months. [69] [70] Mothers should also be warned about the risks of feeding premasticated food to the infant. [71] [72] [73]

Pearls and Other Issues

Key facts to keep in mind about neonatal HIV are as follows:

• When making a selection for appropriate ART to initiate in a pregnant female, it is important to consider tolerability, neonatal risk of exposure, pharmacokinetic differences, and overall risk-benefit of each regimen.
• The monitoring of infants with HIV is challenging as there is variability with viral loads and CD4 counts depending on the age.
• Studies have demonstrated that administering zidovudine (ZDV) monotherapy to both the mother and neonate reduces MTCT from 25% to 8%. The MTCT rate is reduced to less than 1% when combined with other ART. [7] ZDV exhibits its actions by metabolizing into its active form in the placenta, thus inhibiting the replication of HIV within the placental cells.
• Repeated negative HIV test results are needed postpartum due to the increased risk of transmission of HIV during labor and delivery. [5]

Enhancing Healthcare Team Outcomes

The treatment of perinatal HIV exposure involves a team approach involving an infectious disease specialist, perinatalist, pediatrician, neonatologist, obstetrician, HIV pharmacist, and nursing staff. Prompt and early communication between all team members assures comprehensive and optimized care for the neonate. Infectious disease specialists and neonatologists are usually involved in acute management during the neonatal period. Infectious disease specialists are responsible for monitoring disease progression and drug regimens.

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HIV in Neonates and Infants

Affiliations.

• 1 Division of Pediatric Infectious Diseases, Children's Healthcare of Atlanta, Emory University School of Medicine, 2015 Uppergate Drive, Suite 500, Atlanta, GA 30322, USA. Electronic address: [email protected].
• 2 Section of Infectious Diseases and International Health, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 03756, USA.
• PMID: 34030814
• DOI: 10.1016/j.clp.2021.03.004

Advances in perinatal HIV management have averted a significant number of infections in neonates and have made the possibility of elimination of mother-to-child transmission a reality; however, significant gaps in implementation of early testing programs as well as the expansion of therapeutic strategies to neonates are hindering prevention efforts and access to safer, more effective and easier to administer treatment. This article provides insights on the current state of perinatal HIV, recent advances, and future needs.

Keywords: HIV; Neonates; Prevention; Treatment.

Copyright © 2021 Elsevier Inc. All rights reserved.

Publication types

• HIV Infections* / drug therapy
• HIV Infections* / epidemiology
• Infant, Newborn
• Infectious Disease Transmission, Vertical / prevention & control
• Pregnancy Complications, Infectious* / drug therapy
• Pregnancy Complications, Infectious* / epidemiology

VINI VIJAYAN, MD, FOUZIA NAEEM, MD, AND ANGELA F. VEESENMEYER, MD, MPH

This is a corrected version of the article that appeared in print.

Am Fam Physician. 2021;104(1):58-62

Related Letter to the Editor: Additional Information on the Management of Infants Born to Mothers With HIV Infection

Patient information: See related handout on preventing HIV infection in babies , written by the authors of this article.

Author disclosure: No relevant financial affiliations.

In the United States, approximately 5,000 women living with HIV infection give birth each year. HIV can be transmitted from a mother to her child at any time during pregnancy, labor and delivery, and breastfeeding. Because of effective preventive measures, the transmission rate from pregnant women to their children has declined significantly. Strategies to prevent mother-to-child transmission include maternal and infant antiretroviral therapy and formula-feeding instead of breastfeeding. All infants born to mothers with HIV infection should receive antiretroviral postexposure prophylaxis as soon as possible, ideally within six hours after delivery. The type of prophylaxis depends on whether the mother has achieved virologic suppression, defined by an HIV RNA load of less than 50 copies per mL, and if the infant is at high risk of vertical transmission of HIV. Risk factors for vertical transmission include maternal seroconversion during pregnancy or breastfeeding, high maternal plasma viral RNA load during pregnancy, and advanced maternal HIV disease.

In the United States, approximately 5,000 women living with HIV infection give birth each year. 1 Since the initial Pediatric AIDS Clinical Trials Group Protocol 076 (PACTG 076) study was published in 1994, advances in the management of HIV infection have led to a dramatic decline in the incidence of perinatally infected infants. 2 , 3 The annual rate of perinatal HIV transmission has decreased by more than 95% in the United States since the early 1990s. 2 , 3 In 2017, only 73 infants were born with HIV infection in the United States. Five states (Florida, Texas, Georgia, Louisiana, and Maryland) accounted for 38% of infants born with HIV infection in the United States in 2016. 4 – 6

Antenatal testing and treatment of pregnant women have reduced vertical transmission rates; however, opportunities remain to further decrease vertical transmission, and inadequate antenatal testing for HIV persists. 7 , 8 The Centers for Disease Control and Prevention wants to eliminate perinatal HIV transmission in the United States, with a goal of reducing perinatal transmission to an incidence of less than one infection per 100,000 live births and a rate of less than 1% among HIV-exposed infants. 8 – 10

Perinatal Transmission

Perinatal transmission of HIV can occur in pregnancy, labor and delivery, and breastfeeding, with the greatest risk during labor and delivery. 11 Strategies to prevent mother-to-child transmission include giving antiretroviral therapy (ART) to mothers with HIV infection and their infants, scheduling cesarean deliveries for women with an HIV RNA load greater than 1,000 copies per mL or an unknown viral load at the time of delivery, and providing formula instead of breast milk to infants of mothers living with HIV. [ corrected ] Infants at highest risk of vertical transmission include those whose mothers have a viral load greater than 1,000 copies per mL within the four weeks before expected delivery, who received no ART or less than four weeks of ART by the time of delivery, who have advanced maternal HIV disease, or who acquired HIV infection during pregnancy or breastfeeding. 11 – 13

Current Guidelines for Perinatal HIV Management

All pregnant women should be screened for HIV when establishing prenatal care and with each pregnancy. 12 Those found to be HIV-positive should start ART. 12 Repeat testing in the third trimester is recommended for women who are at increased risk of acquiring HIV infection (i.e., women who inject drugs, exchange sex for money or drugs, have sex partners with HIV infection, or have a sexually transmitted infection during pregnancy). Any woman who presents in labor without a documented HIV-negative test result should have expedited HIV testing. 14 A positive test result should prompt intrapartum intravenous zidovudine (ZDV; Retrovir) for the mother and an antiretroviral regimen for the infant after delivery. 14

A scheduled cesarean delivery at 38 weeks' gestation is recommended for pregnant patients with an HIV RNA load greater than 1,000 copies per mL or an unknown viral load at the time of delivery to minimize perinatal transmission of the virus. 13 , 14 In the PACTG 076 study, antepartum ZDV, intrapartum ZDV, and six weeks of ZDV prophylaxis for the infant decreased perinatal transmission by 66%. 3 Based on this study, continuous intravenous ZDV during labor was recommended for all pregnant women with HIV infection. However, a more recent study found that intrapartum ZDV did not affect the risk of perinatal HIV transmission among women with an HIV RNA viral load of less than 400 copies per mL at the time of delivery. 15 Current recommendations state that intravenous ZDV should be administered only to women with an HIV RNA viral load greater than 1,000 copies per mL on polymerase chain reaction testing or if the viral load is unknown at the time of delivery. 12 , 14 , 16

Management of the Infant After Delivery

All infants born to mothers with HIV infection should receive antiretroviral postexposure prophylaxis as soon as possible, ideally within six hours of delivery. The choice of prophylaxis depends on whether the mother has achieved virologic suppression and if the infant has risk factors known to increase perinatal transmission of the virus 11 – 13 ( Table 1 17 ) . Previous guidelines recommended a six-week course of ZDV for all newborns exposed to maternal HIV infection. 18 Newer evidence supports only four weeks of ZDV prophylaxis in infants if the mother has virologic suppression during pregnancy and near delivery and no concerns related to antiretroviral adherence. 19 , 20

For infants at high risk of perinatal acquisition of HIV infection, presumptive therapy for six weeks with a combination of three drugs (ZDV, lamivudine [Epivir], raltegravir [Isentress]) is recommended instead of ZDV monotherapy. 12 This three-drug regimen serves as prophylaxis and is also the preliminary treatment for an infant with documented HIV infection. 18 , 21 – 23

The use of antiretroviral drugs other than this regimen is not recommended in premature newborns (younger than 37 weeks' gestation) because of a lack of dosing and safety data.

Recommended HIV regimens for infant prophylaxis are shown in Table 1 . 17 Infants with documented HIV infection should be started immediately on therapy in collaboration with a pediatric infectious diseases specialist.

Assessing HIV Infection Status in Exposed Infants

Infants born to mothers with HIV infection should have serial testing with an HIV nucleic acid test (NAT). Test selection depends on the age of the infant and the availability of the test. Virologic tests that detect HIV DNA or HIV RNA by polymerase chain reaction are used for diagnosis in infants. HIV antibody testing or combined HIV antigen or antibody assays should not be used in infants with perinatal or postnatal HIV exposure. These tests cannot distinguish between active infection and passive transfer of maternal HIV antibodies. 18 , 24 Blood samples from the umbilical cord should not be used for diagnostic evaluation because of potential contamination with maternal blood.

The timing of testing depends on whether the infant is considered low or high risk. 17 Any positive HIV test results in an infant should be confirmed with a repeat NAT, and a pediatric infectious diseases specialist should be contacted. 18 , 24

The presumptive exclusion of HIV infection in nonbreastfed infants is based on two negative NATs (one test at four days of age and one test at four weeks of age), or one negative NAT at eight weeks of age, or one negative HIV antibody test at six months of age. The definitive exclusion of HIV infection in nonbreastfed infants is based on two or more negative NATs (one test at four weeks of age and one test at four months of age) or two negative antibody tests from separate specimens obtained at six months of age. Some experts perform antibody testing at 12 to 18 months to document clearance of maternal antibodies and to confirm the child's HIV seronegative status. 18 , 24

Prophylaxis with trimethoprim/sulfamethoxazole should begin at four to six weeks of age if HIV infection cannot be presumptively excluded because of the risk of Pneumocystis jiroveci pneumonia in HIV-infected infants. Prophylaxis should be continued until HIV infection has been definitively or presumptively excluded. If HIV infection has been presumptively excluded, prophylaxis does not need to be initiated. 18 , 24

Care of the HIV-Exposed Infant After Delivery

The newborn infant should be bathed and cleansed of maternal secretions at the time of birth. Antiretroviral prophylaxis should be initiated within six to 12 hours of delivery. A baseline complete blood count and differential should be obtained. The mother's prenatal care and exposure to infections such as syphilis, hepatitis B, hepatitis C, tuberculosis, and herpes simplex should be assessed and managed. Other infections to consider include Zika virus, toxoplasmosis, and cytomegalovirus. The mother should not be discharged from the hospital without antiretroviral medications for the baby. 12 The infant should have an appointment with a family physician or pediatrician at two weeks of age to discuss medication adherence, possible adverse effects, and HIV diagnostic testing. If the infant's HIV test result is positive, the physician should contact a pediatric infectious diseases specialist for further management. Infants should be monitored closely for adverse effects resulting from ART, and hemoglobin and neutrophil counts should be measured four weeks after initiating ART.

Clinicians providing care to infants exposed to HIV infection should closely monitor them for growth and development and signs of acute HIV infection such as fever, rash, pneumonia, or opportunistic infections. All routinely recommended vaccines should be administered to infants exposed to HIV infection. The physician should counsel the family about methods to prevent postnatal HIV exposure. Women with HIV infection should not breastfeed their infants or donate to milk banks. Parents should also be educated about formula feeding, and infants should not receive solid foods before four to six months of age. 24 Because of the potential for transmission of HIV through premastication of food, the Centers for Disease Control and Prevention recommends that physicians ask caregivers about the practice of premastication and counsel them not to premasticate food for their infants. 18 , 24 , 25 For additional recommendations, see the American Academy of Pediatrics guideline on management of the infant exposed to HIV. 26

This article updates a previous article on this topic by Krist and Crawford-Faucher . 27

Data Sources: A PubMed search was completed in Clinical Queries using the key words perinatal HIV exposure, maternal to child transmission of HIV, and perinatal HIV prevention. The search included practice guidelines, meta-analyses, randomized controlled trials, and clinical trials. A PubMed search was also completed using the key words author name and publication year for relevant trials noted in guidelines. Also searched were Essential Evidence Plus, the Centers for Disease Control and Prevention, and the U.S. Department of Health and Human Services. Search dates: January 15, 2020; August 1, 2020; and December 18, 2020.

Centers for Disease Control and Prevention (CDC).. Achievements in public health. Reduction in perinatal transmission of HIV infection—United States, 1985–2005. MMWR Morb Mortal Wkly Rep. 2006;55(21):592-597.

Taylor AW, Nesheim SR, Zhang X, et al. Estimated perinatal HIV infection among infants born in the United States, 2002–2013. JAMA Pediatr. 2017;171(5):435-442.

Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331(18):1173-1180.

Centers for Disease Control and Prevention. Monitoring selected national HIV prevention and care objectives by using HIV surveillance data—United States and 6 dependent areas, 2017. HIV Surveillance Supplemental Report 2019. 2019;24(3). Accessed January 15, 2020. https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-supplemental-report-vol-24-3.pdf

• Centers for Disease Control and Prevention.. Racial/ethnic disparities among children with diagnoses of perinatal HIV infection - 34 states, 2004–2007 [published correction appears in MMWR Morb Mortal Wkly Rep . 2010;59(5):136]. MMWR Morb Mortal Wkly Rep. 2010;59(4):97-101.

Nesheim SR, FitzHarris LF, Mahle Gray K, et al. Epidemiology of perinatal HIV transmission in the United States in the era of its elimination. Pediatr Infect Dis J. 2019;38(6):611-616.

Collins L, Meade J, Secord E. Barriers to prevention of and treatment for perinatal HIV in the United States. Arch Paediatr Dev Pathol. 2017;1(2):1007.

Andrews MM, Storm DS, Burr CK, et al. Perinatal HIV service coordination: closing gaps in the HIV care continuum for pregnant women and eliminating perinatal HIV transmission in the United States. Public Health Rep. 2018;133(5):532-542.

Nesheim S, Taylor A, Lampe MA, et al. A framework for elimination of perinatal transmission of HIV in the United States. Pediatrics. 2012;130(4):738-744.

Gnanashanmugam D, Rakhmanina N, Crawford KW, et al. Eliminating perinatal HIV in the United States: mission possible?. AIDS. 2019;33(3):377-385.

Centers for Disease Control and Prevention. HIV transmission. October 28, 2020. Accessed December 18, 2020. https://www.cdc.gov/hiv/basics/transmission.html

Members of the Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission. Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States. Updated April 14, 2020. Accessed August 1, 2020. https://clinicalinfo.hiv.gov/en/guidelines/perinatal/antiretroviral-management-newborns-perinatal-hiv-exposure-or-hiv-infection

• European Mode of Delivery Collaboration. Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomised clinical trial [published correction appears in Lancet . 1999;353(9165): 1714]. Lancet. 1999;353(9158):1035-1039.

Scott RK, Crochet S, Huang CC. Universal rapid human immunodeficiency virus screening at delivery: a cost-effectiveness analysis. Infect Dis Obstet Gynecol. 2018:6024698.

Briand N, Warszawski J, Mandelbrot L, et al. Is intrapartum intravenous zidovudine for prevention of mother-to-child HIV-1 transmission still useful in the combination antiretroviral therapy era?. Clin Infect Dis. 2013;57(6):903-914.

Andiman W, Bryson Y, de Martino M, et al.; International Perinatal HIV Group. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1-a meta-analysis of 15 prospective cohort studies. N Engl J Med. 1999;340(13):977-987.

Members of the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Updated April 14, 2020. Accessed August 11, 2020. https://clinicalinfo.hiv.gov/en/guidelines/pediatric-arv/antiretroviral-management-newborns-perinatal-hiv-exposure-or-hiv-infection

Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1996;335(22):1621-1629.

Neubert J, Pfeffer M, Borkhardt A, et al. Risk adapted transmission prophylaxis to prevent vertical HIV-1 transmission: effectiveness and safety of an abbreviated regimen of postnatal oral zidovudine. BMC Pregnancy Childbirth. 2013;13:22.

Nguyen TTT, Kobbe R, Schulze-Sturm U, et al. Reducing hematologic toxicity with short course postexposure prophylaxis with zidovudine for HIV-1 exposed infants with low transmission risk. Pediatr Infect Dis J. 2019;38(7):727-730.

Lommerse J, Clarke D, Kerbusch T, et al. Maternal-neonatal raltegravir population pharmacokinetics modeling: implications for initial neonatal dosing. CPT Pharmacometrics Syst Pharmacol. 2019;8(9):643-653.

Anugulruengkitt S, Suntarattiwong P, Ounchanum P, et al.; CIPHER_AEPEP study team. Safety of 6-week neonatal triple-combination antiretroviral postexposure prophylaxis in high-risk HIV-exposed infants. Pediatr Infect Dis J. 2019;38(10):1045-1050.

Fowler MG, Qin M, Fiscus SA, et al.; IMPAACT 1077BF/ 1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737.

Kimberlin DW, Brady MT, Jackson MA, et al., eds. HIV infection. In: Red Book: 2018 Report of the Committee on Infectious Diseases . 31st ed. American Academy of Pediatrics; 2018:459–476.

Gaur AH, Dominguez KL, Kalish ML, et al. Practice of feeding premasticated food to infants: a potential risk factor for HIV transmission. Pediatrics. 2009;124(2):658-666.

Chadwick EG, Ezeanolue EE Committee on Pediatric AIDS. Evaluation and management of the infant exposed to HIV in the United States. Pediatrics. 2020;146(5):e2020029058.

Krist AH, Crawford-Faucher A. Management of newborns exposed to maternal HIV infection. Am Fam Physician . 2002;65(10):2049–2057. Accessed November 23, 2020. https://www.aafp.org/afp/2002/0515/p2049.html

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INTRODUCTION

The case definition and classification of pediatric HIV infection, clinical manifestations of some of the AIDS-defining conditions ( table 1 ), and outcomes of HIV infection in children are reviewed here. The epidemiology of pediatric HIV, prophylactic treatment of infants born to mothers with HIV, diagnostic testing for HIV in young children, approach to febrile HIV-infected infants and children, and issues related to HIV infection in adolescents are discussed separately:

● (See "Epidemiology of pediatric HIV infection" .)

● (See "Intrapartum and postpartum management of pregnant women with HIV and infant prophylaxis in resource-rich settings", section on 'Infant prophylaxis' .)

● (See "Diagnostic testing for HIV infection in infants and children younger than 18 months" .)

• Open access
• Published: 03 November 2021

The effects of exposure to HIV in neonates at a referral hospital in South Africa

• Helena Mellqvist 1 , 2 ,
• Robin T. Saggers 3 , 4 ,
• Anders Elfvin 2 , 5 ,
• Elisabet Hentz 2 , 5 &
• Daynia E. Ballot 3  

BMC Pediatrics volume  21 , Article number:  485 ( 2021 ) Cite this article

1435 Accesses

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Fewer infants are infected with HIV through mother-to-child transmission, making HIV-exposed but uninfected (HEU) infants a growing population. HIV-exposure seems to affect immunology, early growth and development, and is associated with higher morbidity and mortality rates. Currently, there is a lack of information regarding the clinical effects of HIV-exposure during the neonatal period.

To identify a possible difference in mortality and common neonatal morbidities in HEU neonates compared to HIV-unexposed neonates.

This was a retrospective, descriptive study of all neonates admitted to the neonatal unit at Charlotte Maxeke Johannesburg Academic Hospital between 1 January 2017 and 31 December 2018. HEU neonates were compared to HIV-unexposed neonates.

There were 3236 neonates included, where 855 neonates were HEU. The HEU neonates had significantly lower birth weight and gestational age. The HEU neonates had higher rates of neonatal sepsis (19.8% vs 14.2%, OR 1.49, p  <  0.001), specifically for late onset sepsis, and required more respiratory support. NCPAP and invasive ventilation was more common in the HEU group (36.3% vs 31.3% required NCPAP, p  = 0.008, and 20.1% vs 15,0% required invasive ventilation, p  <  0.001). Chronic lung disease was more common among HIV-exposed neonates (12.2% vs 8.7%, OR 1.46, p  = 0.003). The difference in mortality rates between the study groups was not significant (10.8% of HEU neonates and 13.3% of HIV-unexposed).

Conclusions

HEU neonates had higher rates of neonatal sepsis, particularly late-onset sepsis, required more respiratory support and had higher rates of chronic lung disease. Mortality of HEU neonates was not different HIV-unexposed neonates.

Peer Review reports

Human Immunodeficiency Virus (HIV) is one of the world’s biggest health threats. In 2018, the Republic of South Africa had the third highest prevalence of HIV in the world, with 20.4% of adults infected according to the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimations, which equals 7.5 million people. [ 1 ] In addition, 260,000 children between the ages of 0–14 years of age were infected. One of the biggest tragedies of the epidemic, is the transmission of the virus from mother to child, which can occur in utero, intrapartum or postnatally (predominantly through breastfeeding). [ 2 , 3 ] HIV-infection during infancy has a high risk of mortality, with a net survival of 52% at 1 year if infected perinatally and 78% at 1 year post infection if infected through breastfeeding. [ 4 ]

In an effort to stop the HIV/AIDS-epidemic, South Africa has implemented the largest treatment programme in the world, with nearly 4.8 million people on treatment. Treatment for prevention of mother-to-child transmission (PMTCT) was given to 87% of HIV-positive, pregnant women in South Africa during 2018. [ 1 ] The nation has adapted the Option B+ by World Health Organisation, which is that all pregnant and breastfeeding women should receive lifelong anti-retroviral therapy (ART), regardless of CD4 count or clinical stage. [ 5 ] The therapy provided is a fixed-dose combination (FDC) of Tenofovir, Lamivudine or Emtricitabine and Efavirenz. This FDC-therapy should be initiated at the first antenatal care visit, or at least 12 weeks prior to labour. If the mother is consistently on ART, her HIV-exposed infant will receive HIV-prophylaxis of Nevirapine immediately after birth. The infant will be tested for HIV using polymerase chain reaction (PCR) at birth as well as at 10 weeks of age and 6 weeks after cessation of breastfeeding, as early infant diagnosis and treatment has shown to reduce mortality and prevent disease progression [ 6 , 7 ]. An uninfected infant is given HIV-prophylaxis with Nevirapine daily until at least 6 weeks of age. The mother will then continue with lifelong anti-retroviral therapy. [ 8 ] Annually, approximately 53,000 HIV-infections in infants are averted due to PMTCT in South Africa. Still, 4.89% of children with HIV-positive mothers born during 2018 in South Africa, were infected with the virus. [ 1 ] The averted infections result in a growing population of HIV-exposed uninfected (HEU) infants.

Several studies have been conducted to specify the health effects of HIV-exposure during early life, with many showing heterogenous results. [ 9 ] Some studies have shown increased mortality in HEU children compared to unexposed children [ 10 , 11 , 12 ], while others have shown no difference in mortality rates [ 13 , 14 ]. Another example of this heterogenicity is seen when observing neonatal sepsis, where one large meta-analysis showed that HEU neonates were more than twice as likely to have neonatal Group B Streptococcus (GBS) disease compared to HIV-unexposed neonates. Specifically, no significant difference was found in the rate of early-onset disease but HEU’s were 4.43 times more likely to have late-onset neonatal GBS disease (95% CI: 1.81–10.85; p  = 0.001). [ 15 ] At the same time, a South African study from 2012 showed HEU neonates to have a lower risk of early-onset sepsis and a similar rate of late-onset sepsis compared to HIV-unexposed neonates. [ 16 ]

Other research has shown more definitive results. In the HEU population, infectious diseases, such as tuberculosis, pneumonia and lower respiratory tract infection are more frequent and occasionally also more severe; for example, HEU infants with pneumonia have higher rates of treatment failure and in-hospital mortality. [ 17 , 18 , 19 , 20 ] The disease-causing pathogens amongst HEU children with pneumonia has also been shown to be unusually diverse, with infections caused by Pseudomonas aeruginosa, Escherichia coli, Pneumocystis jirovecii and Aspergillus spp. [ 21 ]

There are several possible reasons for increased mortality and morbidity in HIV exposed infants: differences in environmental factors, including socioeconomic factors, co-infections and ART-exposure, lower birth weight and gestational age and altered immune factors. [ 3 ] HIV-exposure is associated with low birth weight (defined as birth weight < 2500 g) and prematurity (defined as gestational age < 37 weeks), and higher proportions of infants are small for gestational age (defined as birth weight for gestational age below the tenth percentile of a standard population). [ 22 , 23 ] The exposure to a chronic immune activation that HIV causes in the mother has also been shown to affect the infant’s immunology, with lower absolute levels of CD4+ T cells and naive CD8+ T cells, but increased levels of immature double-negative (CD4–CD8–) T cells, which may indicate disturbed thymic function. [ 24 ] In addition, HEU infant have lower levels of maternal transferred antibodies at birth. [ 25 ]

Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) has developed the Project to Improve Neonatal Care (PRINCE), an on-going clinical audit in order to provide real-time data to identify areas for improvement. The prevalence of HIV amongst antenatal women in the city of Johannesburg in 2015 was 29.6%, in relation to the national point estimate of HIV-prevalence among antenatal women of 30.8%. [ 26 ] With the growing population of HEU neonates, more studies are needed investigating this group of patients in order to improve their care.

The aim of the study was to identify a possible difference in the mortality and the characteristics of the hospital stay in HIV-exposed uninfected neonates compared to HIV-unexposed neonates.

Study design

This was a secondary analysis of an existing database of neonates admitted to the neonatal unit at CMJAH between 1 January 2017 and 31 December 2018. The inclusion criterion was known maternal HIV-status. Neonates with a birth weight below 500 g were considered non-viable and excluded. Neonates with positive or intermediate birth HIV-PCR were excluded, as well as neonates on whom no HIV-PCR was conducted.

Definitions

Maternal and neonatal information was collected. Clinical outcome included duration of hospital stay and outcome (death or survival to discharge.) Place of birth was either ‘inborn’ if born at the study hospital or ‘outborn’. Resuscitation in delivery room was defined as the use of face mask ventilation. Diseases were defined according to the Vermont-Oxford Network (VON) definitions. [ 27 ] Grades 2 and 3 necrotizing enterocolitis (NEC), diagnosed both clinically and radiologically according to the modified Bell’s staging criteria, were included in the NEC variable. Retinopathy of prematurity included grades 3 and 4, whereas intraventricular haemorrhage included grade 3 and 4. Chronic lung disease was defined as requiring oxygen on day 28 of life. Sepsis was classified as culture proven only, with onset within 72 h of birth being classified as early-onset and after 72 h as late-onset sepsis.

The neonatal records at CMJAH are stored on the REDCap (Research Electronic Data Capture) database, hosted by University of Witwatersrand. [ 28 ] REDCap is a secure web-based programme that aids data capture for the purposes of clinical audit and quality improvement. Every week clinical staff collected data from records of patients discharged from the unit. This information was verified and entered onto the REDCap database. Maternal and infant characteristics, as well as information regarding clinical outcome and hospital stay was retrieved from the database.

Statistical analysis

Data was analysed using IBM SPSS (Version 26). We described normally distributed continuous variables using mean and standard deviation and categorical variables using frequency and percentages. Skewed data was described using median and interquartile range. We divided the study sample into HIV-exposed uninfected and HIV-unexposed groups. Continuous variables were compared using unpaired t-test or Mann-Whitney U test as appropriate, while categorical variables were compared using the Chi-square test. A 2-sided p -value < 0.05 was considered significant.

Ethical considerations

All methods were carried out in accordance with relevant guidelines and regulations. Since this was a retrospective review of an existing database, informed consent was waived, and ethics approval obtained from the Human Research Ethics Committee (HREC) of the University of the Witwatersrand (clearance certificate number M190873).

A total of 3370 neonates were admitted to the neonatal unit between 1 January 2017 and 31 December 2018. The inclusion process is described in Fig.  1 . Of 3350 neonates with known maternal HIV-status, 962 neonates were born to mothers with HIV and consequently were HIV-exposed (28.7%). Of the HIV-exposed neonates, 879/895 (98.2%) received HIV-prophylaxis and 873 (90.7%) had successful HIV-PCR done at birth. Eighteen of these neonates tested HIV-positive, which resulted in a transmission rate of 2.1% of the tested neonates. Therefore, 855 neonates can be considered as HIV-exposed but uninfected (HEU) at birth and were included in the analysis. The control group consisted of 2381 HIV-unexposed neonates.

Flowchart of the study population of HIV-exposed and HIV-unexposed neonates

The maternal characteristics of the study population are described in Table  1 . In summary, the HIV-positive mothers had on average higher age and more pregnancies, but fewer parities (all significant differences with p -values < 0.001). The attendance at antenatal care was lower in the HIV-positive group. Other infectious diseases such as tuberculosis and syphilis were more common amongst HIV-positive mothers. The majority of HIV positive mothers (98.5% 801/815) were on ART.

The majority of the neonates in both groups were delivered at the study hospital, but more HEU neonates were outborn (203/847, 24.0% compared to 435/2358, 18.4%; p  <  0.001). HEU neonates also had higher occurrence of vaginal delivery than HIV-unexposed (395/817, 48.3% vs 947/2313, 40.9%; p  <  0.001). Caesarean section occurred in a total of 1788 cases, with 1459 (82.2%) being emergency surgeries. There was no significant association with HIV-exposure and emergency or elective caesarean section. The characteristics of the included neonates are described in Table  2 . The HEU neonates had significantly lower birth weight and gestational age.

A total of 408 deaths occurred during the study period: 92/855 (10.8%) were HEU compared to 13.3% (316/2381) of the HIV-unexposed neonates. The difference in mortality between the study groups was not significant ( p  = 0.058). The median age on outcome (discharge or death) was 6 days in the HIV-unexposed group and 8 days in the HEU group ( p  = 0.005). The median length of stay at the neonatal unit was 6 days in the HIV-unexposed group and seven in the HEU group ( p  = 0.015). When defined as early neonatal mortality (death within the first 7 days of life) to take days at risk into consideration, the difference in mortality was still not significant.

The difference in respiratory support and diagnoses are shown in Fig.  2 . Initial resuscitation in the delivery room and oxygen after initial resuscitation was required equally in both groups, but HIV-exposed neonates had higher frequency of respiratory support requirements after initial resuscitation. NCPAP was required by 36.3% of HEU, compared to 31.3% of HIV-unexposed ( p  = 0.008). Invasive ventilation was also required more by HEU ( p  < 0.001), yet with no significant difference in the duration of respiratory support between the study groups.

Use of respiratory support and respiratory morbidities between HIV-exposed uninfected and HIV-unexposed neonates. * significant differences with 2-sided p -values below α = 0,05. HEU = HIV-exposed uninfected; NCPAP = nasal continuous positive airway pressure

Chronic lung disease was more common amongst HEU neonates ( p  = 0.003) with an OR of 1.46 (95% CI 1.13–1.88). Twenty-eight neonates had pneumothorax (nine HEU and 19 HIV-unexposed), with no significant difference in frequency between the study groups.

A total of 506 neonates had neonatal sepsis during the time-period studied. Thirty-eight of these neonates had both early- and late-onset sepsis. The distribution between the HIV-exposure groups is shown in Table  3 . Any neonatal sepsis (early and/or late) was associated with HIV-exposure. LOS was significantly more common amongst HEU (16.5% compared to 12.1%), but EOS did not have a significant association with HIV-exposure on its own.

Other neonatal diseases such as necrotising enterocolitis, retinopathy of prematurity, intraventricular haemorrhage and patent ductus arteriosus were not significantly different between the two groups. Clinical features at birth such as hypothermia and low 5-min Apgar score was also not significantly different between the two groups.

This study found an association between HIV exposure and higher rates of neonatal sepsis, specifically LOS, and the requirement of more respiratory support. The characteristics of the included neonates and mothers in this study are potentially not representable for all babies born at the study site, as the study population only included neonates admitted to the neonatal unit. Realistically, the mean birth weight and gestational age in the study group are lower in the study population than in the general population of neonates born at the study site, including full-term, healthy neonates. HIV-infected children have more hospital admissions, making it possible for the HIV-exposure rate to be falsely high. [ 11 ] This argument is also strengthened by a study from the paediatric intensive care unit at CMJAH from 2013 to 2014 which showed a HIV-exposure rate of 34.1%, potentially caused by more severe illnesses amongst HIV-exposed children. [ 29 ] Nationally in 2017, 28.7% of women receiving antenatal care were HIV-positive, but in another urban hospital in Johannesburg the rate was lower at 23.2%. [ 30 , 31 ]

A study conducted at the neonatal unit at CMJAH between 2015 and 2017 (overlapping the study period of this report, and therefore including some of the same population) showed comparable HIV-exposure rate of 28.6%, infection rate of 2.52% and a birth HIV-PCR rate of 88.1%. [ 32 ] Notable is a trend towards lower infection rate and higher rates of PCR done at birth in this study, but since the years are not separated in either of the studies a statistical comparison cannot be made fully. The 90.7% birth HIV-PCR rate found in this study shows great potential for improvement as ideally it should be 100%. Neonates with indeterminate or invalid PCR result contribute to lowering this rate. With the current laboratory testing system, there is a lag of approximately three days between taking a PCR test and obtaining the result. As point-of-care testing becomes more widely accessible, birth HIV-PCR results may become more readily available.

The findings of this study also strengthen previous reports on HIV-exposure’s association with birth at lower gestational age and lower birth weight. The reason as to why this difference exists is not yet established. Many have discussed that the main factor is unhealthier mothers, not only from the chronic disease but also since HIV-infected women in South Africa often have lower socioeconomic status. In a large meta-analysis, HIV-exposed neonates were more likely to have low birth weight in developing countries compared with women in developed countries showing maternal health to be a strong contributing factor. [ 22 ] Keeping this in mind, this association with low birth weight was demonstrated in developed countries, although not as strongly linked, making the association not fully explained.

The mortality rates in this study were not significantly different between the study groups, despite the differences in characteristics and illness. The increased requirement of respiratory support was also found in the study from 2013 to 2014; HIV exposure may be associated with more severe illness. [ 29 ] Another possible reason is more prematurity amongst HIV-exposed neonates. Interestingly, neonatal sepsis and specifically LOS was found to be significantly more common amongst HEU neonates, which previously had shown heterogenous associations. Other neonatal morbidities were not found to be significant.

Possible confounders in this study are maternal factors other than HIV-infection, such as comorbidities like maternal tuberculosis and/or syphilis and higher maternal age. Additionally, HIV-positive women were found to have more pregnancies and lower number of parities. A possible reason for this is due to more miscarriages, as other studies have shown, but that information was not collected in this study. [ 33 ] This finding could be a possible new field of research.

A question remaining is the causative relationship, as HIV-exposure is not only exposure to the virus and chronic maternal immune activation – it is also exposure to ART-drugs, vertical transmission of other pathogens and poorer maternal health. Other studies have shown that these environmental factors cannot explain the association fully, since HIV-exposure seems to affect neonatal immunology. [ 24 , 25 ] Further studies establishing the causes are needed in order to identify preventable reasons and to bridge the health gap between HIV-exposed and unexposed neonates.

Methodological considerations

As this is a retrospective study, there are some methodological aspects to consider. The analysis was limited by unavailable information, where maternal disease status, CD4 count, duration of ART, and high or low risk of HIV-transmission was unknown. The study also did not take multiple births into account. The benefit of the chosen method is that a large study population was available for analysis.

The aim of the study was to compare the rates of mortality and morbidity between HEU and HU neonates, only associations are described rather than causative relationships. Since the study was based on an admitted population, there are limitations as to the applicability of the results. These results are not applicable to all neonates but may be applicable to other admitted populations in similar settings.

Just less than a third (28,7%) of neonates admitted during the study period were HIV-exposed uninfected. This study suggests that HIV-exposure amongst neonates is associated with birth at a lower gestational age and lower birth weight. HIV-exposure was also associated with increased rates of neonatal sepsis, respiratory support, and chronic lung disease. The clinical consequences that should follow affects the care of both mothers and neonate. HIV-infected women might benefit from more nutritional education and support during pregnancy in antenatal care facilities, to help close the gap in birth weight and gestational age. Health care providers caring for HIV-exposed neonates should be mindful of the increased risk in neonatal sepsis and respiratory disease, in order to identify and if possible, treat these severe illnesses at an early stage.

Availability of data and materials

The data that support the findings of this study are available on request from the corresponding author [RTS]. The data are not publicly available due to them containing information that could compromise research participant privacy.

Abbreviations

Acquired Immunodeficiency Syndrome

Antiretroviral therapy

Confidence interval

Charlotte Maxeke Johannesburg Academic Hospital

Early-onset sepsis

Fixed dose combination

Group B Streptococcus

• HIV-exposed uninfected

Human Immunodeficiency Virus

Interquartile range

Late-onset sepsis

Necrotizing enterocolitis

Nasal continuous positive airway pressure

Polymerase chain reaction

Prevention of mother to child transmission

Research Electronic Data Capture

Standard deviation

Vermont Oxford Network

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Acknowledgements

Thank you to Rose Bandini (Project to Improve Neonatal Care, CMJAH) who was a great source of knowledge and support.

This study was financially supported by Stena A Ohlssons Stiftelse för Forskning and Landenska Donationsfonden with their scholarships awarded to HM. Further, this work was supported by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (ALFGBG- 117661).

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Helena Mellqvist

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Helena Mellqvist, Anders Elfvin & Elisabet Hentz

School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Robin T. Saggers & Daynia E. Ballot

Department of Paediatrics and Child Health, Charlotte Maxeke Johannesburg Academic Hospital, Jubilee Road, Parktown, Johannesburg, South Africa

Robin T. Saggers

Region Västra Götaland, Department of Pediatrics, The Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden

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HM conceptualized the study, performed data collection, analyzed and interpreted the results, drafted the initial manuscript, and revised the manuscript. RTS, AE, EH and DEB supervised the study, reviewed and revised the manuscript. All authors read and approved the final manuscript.

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All methods were carried out in accordance with relevant guidelines and regulations. Since this was a retrospective review of an existing database, informed consent was waived by the Institutional Review Board. The study was approved by the Human Research Ethics Committee (HREC) of the University of the Witwatersrand (clearance certificate number M190873).

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The research for this study was done in partial fulfillment of HM’s undergraduate degree at the University of Gothenburg, Gothenburg, Sweden. This was performed during a research elective to the University of the Witwatersrand, Johannesburg, South Africa.

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Mellqvist, H., Saggers, R.T., Elfvin, A. et al. The effects of exposure to HIV in neonates at a referral hospital in South Africa. BMC Pediatr 21 , 485 (2021). https://doi.org/10.1186/s12887-021-02969-6

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HIV and Pregnancy: A Retrospective Descriptive Cross-sectional Study of Prevalence, Maternal, Obstetrical, and Neonatal Outcome at a Tertiary Care Hospital in Oman

Nada ali salim al hasani.

1 Obstetric and Gynecology Residency Training Program, Oman Medical Speciality Board, Muscat, Oman

Tamima Al Dughaishi

2 Fetomaternal Medicine, Department of Obstetrics and Gynecology, Sultan Qaboos University Hospital, Muscat, Oman

Abdullah A. Balkhair

3 Infectious Diseases Unit, Sultan Qaboos University Hospital, Muscat, Oman

We sought to investigate the prevalence of HIV in pregnant women and the maternal, obstetrical, and neonatal outcomes over 13 years (2005–2017) at Sultan Qaboos University Hospital, a tertiary hospital in Muscat, Oman.

Our study design was a retrospective descriptive cross-sectional study of HIV-positive women in the department of obstetrics and gynecology. We had an unlimited sample size due to the rarity of the disease. We aimed to include all pregnant Omani women who tested positive for HIV in their antenatal screening from 1 January 2005 to 31 December 2017. The patient records were reviewed using the hospital information system service.

There were a total of 13 688 women with 104 281 pregnancies over the study period. The prevalence of Omani pregnant women with HIV was 0.1% (1:1000) with 0.03% of seropositive pregnancies (3:10 000). Of these seropositive pregnancies, 78.6% were known HIV carriers, while 21.4% were newly diagnosed cases. The live birth rate was 90.3%, with 9.7% resulting in miscarriage. All the miscarriages were to known HIV-positive mothers who were managed in accordance with international guidelines. Of the live births, 10.7% were unknown HIV-positive mothers with a mean gestational age of 39.67 weeks and a mean birth weight of 3.2 kg. The rate of mother-to-child transmission (MTCT) of HIV in this group was 33.3%. In contrast, 89.3% of the live births to known HIV-positive mothers delivered neonates with a mean gestational age of 37.4 weeks and a mean birth weight of 2.6 kg with 0.0% MTCT. Modes of delivery, antepartum, intrapartum and postpartum complications as well as long-term neonatal outcomes were analyzed according to the status of the mother at first presentation.

Conclusions

Strategies have been placed by programs in Oman to focus on the wellbeing of pregnant women and the protection of newborns against HIV infection. Strict implementations on preventing MTCT allowed preventing HIV in children possible. Antiretroviral therapy significantly reduces vertical transmission of HIV, in addition to abstinence of breastfeeding. More importantly, all HIV-positive pregnant women should follow the prevention of MTCT programs set out by the Ministry of Health.

Introduction

HIV infection remains a major global public health issue. Humans acquire it via the exchange of bodily fluids, mainly through unprotected intercourse, and women pass it on via mother-to-child transmission (MTCT) during pregnancy, childbirth, and breastfeeding. Other known means of transmission include the use of infected syringes by drug abusers and blood transfusions. 1

According to a report issued by the World Health Organization (WHO) in 2019, approximately 38 million people were living with HIV globally. 2 In 2016, the American Foundation for Aids Research census showed that 51% of all adults living with HIV were women, and it is believed to be the leading cause of death for women in the reproductive age group worldwide. 3 , 4

In the absence of any intervention, MTCT ranges from 15%–45%. 4 With advancements in healthcare, improved access to and availability of antiretroviral therapy (ART), there has been a 50% reduction in new HIV cases. Preventative strategies have reduced MTCT to < 5%. 4

In Oman, the first notified case of AIDS was in 1984. 5 Up to 2019, the total number of cases of HIV/AIDS registered with the Ministry of Health (MOH) was 3232. Of those, 884 (27.4%) were female, the majority of which were of childbearing age; 63.1% were between the ages of 25–49 years, and 17.6% aged 15–24 years. 5 There has been an exponential increase in the number of documented HIV cases in recent years, and this has been attributed to the decrease in stigmatization, applying protocols of detection such as antenatal screening (ANS) of pregnant women and their contacts as well as the availability of treatment in health institutions. 5 The most common mode of transmission to children is MTCT from HIV-infected woman.

Oman established the Maternal and Child Health Program in 1987, intending to identify and care for all pregnant women and their offspring. In 2009, HIV testing was made mandatory for all women attending antenatal clinics for early detection, support, management, and prevention of transmission. In a study conducted by the MOH between 2009 and 2014, the testing coverage for HIV in pregnant women was 98% with a prevalence of 0.02% and an annual rate of HIV in the newborn due to MTCT of 0.01% or 10 per 100 000 live births. 6

In Sultan Qaboos University Hospital (SQUH), a study looked into HIV-1 and 2 among pregnant women over 10 years between January 1995 and December 2005 and found a prevalence of 0.13%. 7 The study did not look into the outcomes of the patient or their offspring, and it did not give information on whether or not patients were on ART or their antenatal management.

Worldwide, studies have been done to look into the effects on pregnancy and outcomes. For example, a retrospective study published in 2015, looked into the maternal and perinatal outcomes of HIV-infected women in a tertiary care hospital in Nigeria. They concluded that HIV-positive status increased adverse birth outcomes of pregnancy such as anemia, puerperal sepsis, low birth weight, preterm births, and higher cesarean section rate amongst women who tested positive for HIV. It also showed that ART appeared to reduce the risk of preterm births in HIV-positive cohorts. 8

On the contrary, a prospective observational study published in 2015 looked into antiretroviral therapy in relation to birth outcomes in Dar es Salaam, Tanzania. They not only compared the outcome of ART versus non-exposure to ART during pregnancy, but also the outcomes related to the ART therapy used (e.g., zidovudine monotherapy vs. highly active antiretroviral therapy (HAART)) and found that there was an increased risk of adverse birth outcomes associated with the use of HAART. 9

We sought to investigate the prevalence of HIV in pregnant Omani women, and identify the maternal, obstetrical, and neonatal outcomes over 13 years (2005–2017) at SQUH, a tertiary hospital in Muscat, Oman.

This was a retrospective, descriptive, cross-sectional study of HIV-positive pregnant women that were managed and delivered in the department of obstetrics and gynecology (OBGYN) at SQUH. We set an unlimited sample size during the study period (1 January 2005 to 31 December 2017) due to the relatively low prevalence of the disease. We included all pregnant Omani women who tested positive for HIV-1 or 2 on ANS during this period. We excluded all non-Omani’s to get a true prevalence of HIV in the Omani population.

After obtaining ethical approval from the hospital’s ethics committee, we collected data from the hospital information system.

Our data collection sheet included a variety of variables, including initial demographics, past medical, surgical, and obstetrical history, and allergies. Each woman who tested positive was then divided by the number of pregnancies, and each pregnancy was considered a separate case.

Each case was then looked into further: whether or not HIV status was known during the pregnancy; the gestation at first presentation whether it was a single or multifetal pregnancy; the viral load and CD4 count per trimester; the use of ART; and the gestational age at which they have started treatment, compliance to medication, the outcome of pregnancy, mode of delivery, confounding obstetrical complications, antepartum complications, acquired antepartum opportunistic infections, intrapartum complications, whether or not they received intrapartum ART prophylaxis, and postpartum complications. We also looked at whether or not these patients were advised for or against breastfeeding.

Data collected regarding fetal outcomes included gestational age at delivery, birth weight, sex, Apgar scores, and whether or not they required neonatal intensive care unit (NICU) admission. Additionally, neonatal prophylactic ART, postnatal HIV status on testing, emergency visits, and outpatient department visits were explored.

Data were then transferred to EpiData. The information was analyzed using SPSS Statistics (IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp.) to calculate measures of central tendency and dispersion.

A total of 104 281 ANS (number of pregnancies) were done over the study period. Excluding repeated pregnancies, this number dropped to 13 688, corresponding to the number of patients, to achieve prevalence.

Twenty-nine Omani pregnant women tested positive for HIV on ANS. Fourteen (48.3%) had proven positive for HIV after further testing with polymerase chain reaction. Therefore, the true prevalence of Omani pregnant women in SQUH who tested positive for HIV was 0.1% or 1:1000 women. There were 31 pregnancies amongst these 14 women, and therefore the prevalence of seropositive pregnancies was 0.03% (3:10 000 pregnancies). The remainder 15 women (51.7%) were false positives to HIV on initial screening.

Eleven (78.6%) out of the 14 patients were known HIV carriers and three (21.4%) of the 14 women were newly diagnosed cases at the time of first presentation (not known before having HIV), as shown in Figure 1 .

Demonstrates the total number of true HIV-positive women during the study period and further divides them into known and unknown cases.

Of the 31 pregnancies, there were three (9.7%) miscarriages and 28 (90.3%) live births. All of the miscarriages were known to have HIV, with singleton pregnancies, and presented in their first trimester. All (100%) were on ART from the first trimester and miscarried during the first trimester. One of three was medically managed with misoprostol, one was surgically managed with suction evacuation, and no data was available for the third miscarriage. The viral load was < 1000 copies/mL and in fact undetectable (< 50 copies/mL) and the CD4 count was > 500 cells/mm 3 in two-thirds of cases. No data was available for the third miscarriage.

Of the 28 live births, three (10.7%) had unknown HIV status as they presented in the third trimester during active labor. Routine ANS identified them as seropositive. All were singleton pregnancies and did not receive antenatal ART due to their unknown status. One in three (33.3%) had a normal vaginal delivery, while the remaining two (66.7%) resulted in emergency cesarean section (one with suspected chorioamnionitis and the other in breech position). There were no known antepartum complications, confounding factors, or known acquired infections. One of the three had intrapartum fever (suspected chorioamnionitis). None of the patients received intrapartum ART prophylaxis due to their unknown status, while 66.7% suffered from puerperal fever (one who delivered by emergency cesarean section for suspected chorioamnionitis, while the other normal vaginal delivery suffered from breast engorgement).

The mean gestational age at delivery was 39.6±0.5 weeks gestation (range = 39–40 weeks) with a mean birth weight of 3.2±0.35 kg (min 2.9 kg, max 3.6 kg). All three were advised to breastfeed as per routine, and all were advised to discontinue breastfeeding and offered cabergoline after ANS revealed positive status for HIV. One patient refused to stop breastfeeding.

All three neonates were born females with Apgar scores of 9 and 10 at one and five minutes, respectively, and none required admission to the NICU post-delivery. Two out of three babies (66.7%) received postnatal ART, with one (33.3%) testing positive for HIV. None had visits to the emergency room, and only 33.3% had an outpatient department visit to follow-up on HIV status (one did not attend their appointment, whereas the other was lost to follow-up).

The viral load of the mother with a seropositive infant after birth was 4644 copies/mL with a CD4 count of 395 cells/mm 3 . The viral load of the other mother who had a spontaneous vaginal birth was 22 333 copies/mL with a CD4 count of 401 cells/mm 3 . The third unknown HIV patient (who delivered by emergency cesarean for breech labor) had no documented viral load/CD4 count post-delivery.

Of the 25 known HIV-positive pregnancies, 16.0% presented in the first trimester, 68.0% in the second trimester, and 16.0% in the third trimester. All known cases were followed up with the infectious disease team. All were on ART during pregnancy. Eighty percent were on ART before pregnancy, 4.0% were started in the first trimester, and 16.0% started in the second trimester. With regards to compliance to medication, 87.0% were compliant with their medication.

Table 1 illustrates the percentage of patients according to viral load and CD4 count per trimester.

*A viral load of < 1000 is considered suppressed.

** A CD4 count < 500 is considered immunocompromised.

Of the 25 pregnancies, 96.0% were singleton with one set of twins (4.0%). With regards to the mode of delivery, 45.8% had spontaneous vaginal delivery, 8.3% were induced (one for postdate and the other for unprovoked deceleration), 20.8% had elective cesarean section (for previous cesarean section, fetus with intrauterine growth restriction (IUGR), and diaphragmatic hernia), and 25.0% had emergency cesarean sections (one for previous two cesarean sections in labor-twin pregnancy at 33 weeks gestation, was booked for elective cesarean but attended with preterm labor, one was breech in labor (also booked for elective cesarean section), two with premature rupture of membrane and prolonged latent phase, and one with preterm labor with uncontrolled retroviral disease).

The vast majority (72.0%) had no obstetrical cofounding factors, 8.0% had diabetes mellitus, 4.0% with gestational diabetes, 4.0% with obstetric cholestasis, and 12.0% had other factors such as iron deficiency anemia, chronic idiopathic thrombocytopenic purpura, and fundal fibroid uterus.

With regards to antepartum complications, 40.0% had no antepartum complications, 20.0% had vaginal infections (e.g., candidiasis), and 40.0% had other complications which included; 40.0% IUGR/small for gestational age (SGA), of which 25.0% had associated diaphragmatic hernia, 10.0% with carpal tunnel syndrome, 10.0% admitted for glycemic control associated with hypokalemia, 10.0% with fetal pelvi-ureteric junction dilatation, 20.0% with threatened preterm labor of which 50.0% were associated with thrombocytopenia and pyelonephritis.

Regarding acquired opportunistic infections ( Pneumocystis jirovecii pneumonia, Mycobacterium avium complex), 4.0% suffered from pneumonia, but this was deemed community acquired. The majority (75.0%) did not suffer from intrapartum complications, 4.2% suffered from intrapartum pyrexia (patient with pyelonephritis), and 20.8% from others such as meconium-stained liquor (83.3%) and preterm premature rupture of the membrane (PPROM) at 37 weeks gestation (16.7%).

All patients received intrapartum ART prophylaxis. Two-thirds (66.7%) had no postpartum complications, while 4.2% had postpartum hemorrhage, 4.2% had puerperal fever, 8.3% had anemia, and 16.7% had other complications such as first degree perineal tear (25.0%), second degree perineal tear (25.0%), urinary tract infection post cesarean section (25.0%), and 25.0% with pulmonary edema and hypertension (suspected congestive cardiac failure).

Only 92.0% were advised to refrain from breastfeeding, with an alarming 8.0% advised to breastfeed, which was documented in the patient’s notes. Nonetheless, they were subsequently asked to refrain from breastfeeding once HIV status was alerted.

The mean gestational age at delivery was 37.4±1.9 weeks (range = 33–40 weeks gestation), 36.0% of which were preterm deliveries (< 37 completed weeks of gestation).

There was a total of 26 neonates (one set of twins), two of which were delivered elsewhere, so the following results are of the remaining 24 neonates.

The mean birth weight was 2.6±0.5 kg (range = 1.5–3.8 kg). Half of the neonates were male and half female. All had an Apgar score ≥ 6 at one minute and ≥ 8 at five minutes.

All neonates received postnatal ART prophylaxis and tested negative for HIV post-delivery. One-third of the neonates (33.3%) required NICU admissions, and four neonates (18.2%) attended the emergency room. The majority (81.8%) attended outpatient department follow-up further repeat testing of HIV status.

The prevalence of HIV in pregnant women during the study period was comparable to the preceding 10 year study at SQUH from 1995 to 2005 (prevalence of 0.1% and 0.13%, respectively). This value was 10-times higher than the national prevalence of HIV in pregnant women conducted by the Oman MOH (0.02%) during the screening period between 2009–2014, but still in keeping with the national prevalence of the general population of < 1.0%. 10

Surprisingly, there was a high false-positive rate on initial testing (51.7%), which was identified after 2011. After further investigations, it was noted that there was an upgrade to fourth generation enzyme-linked immunosorbent assay by the hospital laboratory, which deemed it more sensitive but not more specific to HIV than previous tests.

These false-positive results were included in our initial assessment of prevalence, as we aimed to identify those who had a positive result in the ANS, but were excluded in our analysis, as they would subsequently obscure the true results and analysis of MTCT.

The prevalence of miscarriages amongst the total number of HIV positive pregnancies was 9.7%, which reflects the general background miscarriage rate of 10%–20% 11 and is unlikely to be related to HIV as these patients were appropriately managed before and during their antenatal period, and compliant to medications which was reflected on their suppressed viral loads at the time of miscarriage.

When looking at the unknown HIV-positive women who did not receive any prenatal care at SQUH, all delivered to term with appropriate birth weights for gestational age and Apgar scores. The indications for cesarean sections were warranted for obstetrical and fetal causes. It comes as no surprise that the neonate born with HIV was from the patient who had an emergency cesarean section for suspected chorioamnionitis. Despite receiving postnatal ART, the patient refused to refrain from breastfeeding and refused cabergoline use, which further added to the MTCT. Nevertheless, with no intervention, the MTCT was 33.3%, which reflects the background transfer of HIV by MTCT in the absence of intervention. 4

Only one-third of these infants born to HIV-positive patients were followed up in the SQUH outpatient department. Ideally, all infants born to seropositive women are routinely followed up to 18 months regardless of their status. The infant that was followed up was the one who tested positive initially and was further referred to a pediatric tertiary center for communicable diseases. The poor follow-up for the other two infants was a result of missed appointments by parents who left against medical advice post-delivery, and one loss to follow-up who was detected again at two years of age by the family screening program.

Regarding the known HIV-positive women, 84.6% were seen in the outpatient department by the end of the second trimester. This is seen as ideal as a referral from the infectious disease department to OBGYN aims for the patient to be referred once pregnancy is identified and to be seen once viability is confirmed for management of pregnancy and labor and breastfeeding advice. With regards to the remainder 15.4% seen in the third trimester, one missed her second trimester appointment and attended in active labor, two had no follow-up and attended during their third trimester in active labor, and one received a late appointment at 34 weeks.

The compliance rate to ART in this cohort was 87.0%. The reasons noted for non-compliance to medications were change in medications, side effects such as diarrhea and vomiting, dizziness, abdominal pain, and low socioeconomic class.

When looking at the viral load in each trimester, 92% were suppressed to undetectable levels by the third trimester. 12

With regards to the mode of delivery, the vast majority had vaginal births. Cesarean sections were related to obstetrical and fetal factors rather than HIV per se. The exception was for the emergency cesarean section done for a patient with uncontrollable retroviral disease. This patient was non-compliant with her medications due to personal reasons and vomiting. She had a viral load of 63 681 copies/mL and a CD4 count of 123 cells/mm 3 in the third trimester. As a strategy to prevent MTCT, cesarean section was done to minimize the risk of transfer.

Similarly, most patients had no confounding factors, whereas 12.0% exhibited anemia of pregnancy, which, as mentioned previously, may have an increased risk of development due to HIV status. This was demonstrated in the study done in a tertiary hospital in Nigeria published in 2015 where a significant percentage (8.1%) of seropositive pregnant women had anemia compared to the control group (3.1%). 8 However, it is not unusual to have anemia in pregnancy. According to the WHO criteria, 52% of pregnant women from undeveloped or developing countries are anemic compared with 20% from industrialized nations. This is mainly attributed to high fetal demands for iron and render iron deficiency, the most common cause of anemia in pregnancy, with other causes contributing less frequently. 13

Similarly, a common antepartum complication of pregnancy, experienced by a fifth of the patients, are vaginal infections, particularly candidiasis. It is recognized that approximately 20% of asymptomatic women have vaginal colonization with candida, and there is a 30%–40% increased rate of colonization in pregnancy and uncontrolled diabetes. In addition to immunosuppression and antimicrobial therapy, these factors attribute to symptomatic candidiasis. 14 Therefore, we cannot conclude that HIV status alone is the direct cause of vaginal infections in the 20.0% of pregnant women in our study. The same is true for the SGA/IUGR fetuses where congenital infections such as Toxoplasma gondii , rubella, cytomegalovirus, herpes simplex virus, varicella-zoster virus, Treponema , and HIV only contribute to 5%–10% of fetal growth restriction, whereas maternal diseases such as anemia of pregnancy and malnutrition and uteroplacental dysfunction in which pre-eclampsia and abruption come under have a wider role. 15

Fortunately, there were no documented opportunistic infections in the seropositive pregnant women, which reflect the good compliance to medication, with suppressed viral loads and immunocompetence.

When looking at the intrapartum complications, only 4.2% suffered from intrapartum pyrexia - the source of infection identified from the data as pyelonephritis. One-fifth with meconium-stained liquor and 16.7% with PPROM. Again, multiple factors could lead to this, the normal process of labor and stresses of labor being some.

SQUH has shown excellent management of these seropositive women during active labor, where all received intrapartum ART prophylaxis and postnatal ART prophylaxis. It was unfortunate that 8.0% of the patients were advised as routine to breastfeed. Still, if we look at the Swiss cheese model of accident causation, they were eventually picked up in time to advise to stop, and this would be considered a near miss, as none of the neonates were affected by HIV.

The postpartum complications that occurred are no different from the general population. One thing to note is postpartum hemorrhage. SQUH practices delayed cord clamping during active management of the third stage of labor. Concerns regarding this could be raised given the belief that delay in the separation of the placenta may increase the exposure of the fetus to maternal blood. The WHO recommendation for prevention and treatment of postpartum hemorrhage has stated that the proven benefits of a 1–3 minute delay in clamping the cord outweigh the theoretical, and unproven harms, and late cord clamping is recommended even among women living with HIV or women with unknown HIV status as long as there is no acute feto-maternal compromise. 16

With regard to preterm delivery, 36.0% were delivered at < 37 weeks gestation. This included the twin pregnancy presenting at 33 weeks with labor pains, an emergency cesarean was done for her given her obstetrical history of three previous cesareans. This, in turn, skewed the mean gestational age at delivery and mean birth weight in view of preterm and twins (1.5 kg and 1.7 kg, respectively). Likewise, two other 33 weeks gestation fetuses resulted in emergency cesarean section; one for breech in labor (birth weight 2.1 kg) and the other for preterm labor with uncontrolled retroviral disease mentioned previously (birth weight 2.0 kg). Therefore, when looking at the mean gestational age, as well as birth weight, we are more inclined to attribute it to obstetrical factors rather than HIV, with the exception of the last patient. To justify this, although preterm births are higher in HIV positive cohort as shown in the Nigerian study compared to the control group, ART reduced the risk of preterm birth in the HIV positive cohort, 8 which our patients were all taking.

The NICU admissions were for small gestational age neonates, prematurity, presumed sepsis, respiratory distress, and congenital diaphragmatic hernia (CDH) with multiple birth defects. The emergency attendance was due to suspected sepsis (norovirus at five weeks age, and another with CDH/multiple congenital disabilities), one at eight months with viral upper respiratory tract infection, and one with community-acquired pneumonia.

With regard to outpatient department follow for HIV status monitoring, the following infants had regular follow-up for pelviureteric junction dilatation and hydronephrosis; persistent metabolic acidaemia to a mother with systemic lupus erythematosus/Sjögren syndrome; megameatus for circumcision at nine months; stridor with no cardiac cause; left congenital diaphragmatic hernia with pulmonary hyperplasia, multiple jejunal perforation, cholestasis, delayed milestones, and dysmorphism.

Looking at birth defects, we cannot conclude HIV as direct cause per se in this study. However, the fetus with multiple congenital anomalies — born with left CDH, pulmonary hyperplasia, multiple jejunal perforation, cholestasis, delayed milestones, and subtle dysmorphism — was born to a mother who was on Trizivir (a combination of abacavir, lamivudine, and zidovudine) before pregnancy. Looking at the Food and Drug Administration label; data available from the Antiretroviral Pregnancy Registry show no difference in the overall risk of birth defects for Abacavir, Lamivudine, or Zidovudine compared with the background rate of 2.7%. 17 Therefore, these birth defects are unlikely related to the medication administered.

Strategies have been placed by programs in Oman to focus on pregnant women’s wellbeing and the protection of newborns against HIV infection. By strict implementations on preventing MTCT, preventing HIV in children has become possible. ART significantly reduces vertical transmission of HIV, in addition to abstinence of breastfeeding. An established interaction between researchers, clinicians, healthcare workers, and pharmacists has provided better care for mothers and their children. More importantly, all HIV-positive pregnant women should follow the prevention of MTCT programs set out by the MOH, and their male partners should be involved in antenatal care.

This study focused on pregnant women presenting at a single center which is a tertiary care facility, rather than a multi-center trial. The disease under investigation is of low prevalence nationally, and therefore, analysis of results was limited to the low number of cases obtained. Not all deliveries were conducted in the center, and there was a high level of loss to follow-up due to individual and structural factors.

The authors declared no conflicts of interest. No funding was received for this study.

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• Published: 09 April 2024

Late presentations and missed opportunities among newly diagnosed HIV patients presenting to a specialty clinic in Lebanon

• Maya Mahmoud 1 ,
• Tala Ballouz 2 ,
• Chloe Lahoud 3 ,
• Jana Adnan 3 ,
• Paola Abi Habib 3 ,
• Reem Saab 3 ,
• Haya Farhat 3   na1 ,
• Mohammad El Hussein 3   na1 &
• Nesrine Rizk 4  

Scientific Reports volume  14 , Article number:  8296 ( 2024 ) Cite this article

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Late presentation to medical care of individuals infected with the human immunodeficiency virus (HIV) is linked to poor outcomes and increased morbidity and mortality. Missed opportunities for a prompt diagnosis are frequently reported among late presenters. We aimed to estimate the proportion of late presenters and missed opportunities in diagnosis among newly diagnosed HIV-positive subjects presenting to a specialty clinic in Lebanon. This is a retrospective chart review of all newly diagnosed adult HIV-positive subjects presenting to clinic from 2012 to 2022. Demographic, laboratory, and clinical data were collected at initial HIV diagnosis or presentation to medical care. We defined late presentation as having a CD4 count < 350 or AIDS-defining event regardless of CD4 count. Advanced disease is defined as having a CD4 count below 200 cells/μL or the presence of an AIDS-defining illness, regardless of the CD4 count. A missed opportunity was defined as the presence of an indicator condition (IC) that suggests infection with HIV/AIDS during 3 years preceding the actual HIV diagnosis and not followed by a recommendation for HIV testing. The proportions for demographic, epidemiological, and clinical characteristics are calculated by excluding cases with missing information from the denominator. Our cohort included 150 subjects (92.7% males; 63.6% men who have sex with men (MSM); 33.3% heterosexuals; median age 30.5 years at diagnosis). 77 (51.3%) were late presenters and 53 (35.3% of all subjects, 68.8% of late presenters) had advanced HIV on presentation. Up to 76.5% of late presenters had a presentation with an HIV-related condition at a healthcare provider without getting HIV test within the previous 3 years. The most frequent ICs were weight loss, generalized lymphadenopathy, constitutional symptoms, and chronic idiopathic diarrhea. Overall mortality rate was 4% (6/150 individuals). All-cause mortality among those who presented with AIDS was 15.4% (6/39 subjects). In our setting, late presentations and missed opportunities for HIV diagnosis are common. In the Middle East, AIDS mortality remains high with a large gap in HIV testing. To effectively influence policies, comprehensive analyses should focus on estimating the preventable health and financial burdens of late HIV presentations. Another concern pertains to healthcare providers’ attitudes and competencies.

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Introduction

Antiretroviral therapy (ART) remains one of the most important medical advancements in the twentieth century. There is ample evidence that effective ART improves cellular immunity and subsequently reduces AIDS-related morbidity and mortality. However, achieving the full benefits of ART is dependent on early HIV detection and initiation of treatment 1 . Late diagnosis of HIV has been associated with poorer health outcomes 2 , increased healthcare costs, and risk of onward transmission 3 , 4 , 5 , 6 , 7 . Yet, even in countries with adequate HIV testing recommendations and healthcare resources, late presenters (defined as those with a CD4 count less than 350 cells/mm 3 or the presence of an AIDS-related illness at presentation) still constitute at least half of people living with HIV (PLWH) 8 , 9 , 10 , 11 and continue to be a hurdle to HIV eradication efforts globally 12 .

Several sociodemographic, psychosocial, and structural risk factors—at the patient, provider, and policy level—have been identified to be associated with late presentation. Fear of HIV-related stigma and discrimination, poor social support, and low risk perception are among some of the common patient-related factors preventing people from seeking timely testing. Providers have described insufficient time and resources, the laborious process of counseling and consent, as well as low provider-perceived risk of transmission as barriers to offering an HIV test 13 , 14 . Studies of missed opportunities for earlier diagnoses have shown that individuals with late presentations had often presented to healthcare settings several times, sometimes with indicator conditions (ICs) before an HIV test was eventually made 15 . Meanwhile, the presence of punitive laws and policies, such as the criminalization of sex work and same-sex sexual acts, in some countries deter individuals from seeking HIV testing 16 .

While several studies have been conducted worldwide to investigate late presentations and missed opportunities, only a few have been conducted in the Middle East and North Africa (MENA) region 15 , 17 , 18 , 19 . Although the region has seen significant improvements in HIV services, early HIV diagnosis remains a challenge 7 . Recent numbers from the region show that only 67% of PLWH are aware of their status, and a considerable proportion of individuals newly diagnosed with HIV present with an advanced stage 20 . In Lebanon, the first HIV case was reported in 1984 21 , which has evolved to reach approximately 3000 cases in 2021 22 . The prevalence rate of HIV in Lebanon is less than 0.1%, with indications of a concentrated epidemic among marginalized populations, especially MSM. The prevalence of missed diagnoses and late presentations in Lebanon is unknown.

In this study, we aimed to (1) assess the epidemiologic characteristics of subjects presenting to an HIV clinic in an academic medical center in Lebanon, (2) examine the rate and risk factors of late presentations, and (3) quantify missed opportunities among late presenters.

Materials and methods

Our study is a retrospective chart review of all newly diagnosed, treatment-naïve HIV-positive individuals, aged more than 18 years old, who presented to the American University of Beirut Medical Center (AUBMC) between January 1, 2012 and December 31, 2022. The AUBMC is an academic medical center in Lebanon with over 365 beds and a large outpatient department. The HIV-centered services started in 1984 and includes outpatient and inpatient services. The study was approved by the ethics committee, the Institutional Review Board (IRB) of the American University of Beirut Medical Center (AUBMC). The requirement for informed consent was waived by the Institutional Review Board at AUBMC due to the retrospective nature of the study. All research activities and methods were performed in accordance with the guidelines stated in the declaration of Helsinki and Belmont Report for research involving human subjects.

The subjects’ medical records were reviewed to collect demographic and clinical data including age at diagnosis, gender, nationality, sexual orientation, HIV transmission route, CD4 cell count, AIDS-defining conditions, and clinical indicator diseases at the time of diagnosis of HIV infection. MSM were defined as male participants reporting a homosexual or bisexual HIV-transmission mode and/or a sexual preference at the time of visit.

Outcome definitions

The primary outcome of interest was the proportion of individuals with a late presentation, defined as presenting for care with a CD4 cell count below 350 cells/μL at HIV diagnosis, or presenting with an AIDS-defining event regardless of the CD4 cell count 23 . Secondary outcomes included (1) factors associated with late presentation, (2) the proportion of individuals presenting with advanced HIV disease (AHD), defined as a CD4 count below 200 cells/μL or the presence of an AIDS-defining illness regardless of CD4 count 24 , and (3) missed opportunities for diagnoses, defined as failure to diagnose HIV in the presence of an IC that should have triggered testing for HIV as per guidelines 25 . Indicator conditions (IC) are classified as “AIDS defining illnesses” events and “other events” that are known to be associated with advanced HIV but not categorized as AIDS-defining 26 . Any IC that was present in the 3 years preceding HIV diagnosis, and not followed by a recommendation for HIV testing was considered a missed opportunity for earlier HIV diagnosis. ICs documented within 1 month of HIV diagnosis were considered related to the newly diagnosed disease and therefore not considered as a missed opportunity.

Statistical methods

We used descriptive statistics to analyze participant characteristics and outcomes of interest. Continuous variables are reported as median with interquartile range (IQR); categorical or ordinal variables as frequencies (N) and percentages (%). We explored the associations of several predictor variables with the outcome of late presentation using univariate and multivariable logistic regression model. Model selection was based on findings from other studies and age at diagnosis, gender, mode of transmission, and nationality were included. The calculated proportions for demographic, epidemiological, and clinical characteristics are derived after excluding cases with missing information from the denominator. We reported odds ratio (OR) with 95% confidence intervals (CI). All analyses were conducted in R (version 4.1, May 2021).

Participant characteristics at diagnosis

A total of 150 individuals newly diagnosed with HIV presented to our clinic between 2012 and 2022. The median age was 30.5 years (IQR 26–42 years), and the majority identified as men (N = 139, 92.7%) and Lebanese (N = 119, 79.3%) (Table 1 ). Most of the non-Lebanese individuals were Arab nationals (primarily originating from Iraq, Syria and Saudi Arabia) presenting to Lebanon for medical care. Overall, 82 (63.6%) individuals acquired HIV through MSM contact and 43 (33.3%) through heterosexual contact. Only 3.1% (N = 4) of patients reported IV drug use as the mode of HIV transmission.

Twenty-four (16%) of our newly diagnosed patients were aged more than 50 years old. Among them, 23 were males, and 1 was female. Within this sub-group, the median age at diagnosis was 58 years old. The median CD4 count was 197 cells/mm 3 , compared to 353 in our patients aged less than 50 years, with 13 (54.2%) patients presenting with a CD4 count less than 200. Fifteen were heterosexuals, and nine were men who have sex with men (Supplementary Table 1 ).

Late presentation

Overall, 77 individuals (51.3%) were late presenters and had a CD4 cell count of < 350 cells/mm 3 at the time of HIV diagnosis. Among those, 43 (55.8%) had a CD4 cell count of < 200 cells/mm 3 and 39 (50.6%) presented with AIDS-related conditions. A total of six individuals out of 150 died (15.4% of those presenting with an AIDS defining illness, 4.0% of all participants). The median CD4 cell count at HIV diagnosis was 506.5 (436.2–638.8) and 191.0 (67.0–258.0) cells/mm3 in non-late presenters and late presenters, respectively.

Late presentation was significantly associated with older age (OR 1.05, 95% CI 1.02–1.09, p = 0.003). Although an association with MSM transmission was observed, it did not reach statistical significance (OR 2.47, 95% CI 0.98–6.66, p = 0.062) (Supplementary Table 2 ).

Missed opportunities for earlier HIV testing

To identify indicator conditions, we reviewed medical records before the presentation and HIV diagnosis. Comprehensive data on indicator conditions were present in 51 of 77 charts of late presenters (66.2%). In total, there were 68 ICs among 39 participants (76.5%) in the preceding 3 years prior to HIV testing. Of the 39 participants with a missed opportunity for HIV diagnosis, 27 (69.2%) subjects had one or more AIDS-defining conditions and 9 (23.1%) subjects had ICs consistent with AIDS defining conditions. The most frequent ICs were unexplained weight loss (18/68, 26.5%), unexplained lymphadenopathy (9/68, 13.2%) unexplained fatigue and malaise (7/68, 10.3%), unexplained chronic diarrhea (6/68, 8.8%) and unexplained fever with no apparent etiology (6/68, 8.8%). Seven AIDS-defining ICs were identified. Those included recurrent pneumonia in five cases, four of which were confirmed to be pneumocystis jirovecii pneumonia (PCP) (Table 2 ).

Late presenters with advanced HIV

Among the 77 late presenters, 53 (68.8% of late presenters and 35.3% of all newly diagnosed) presented with an advanced HIV stage. Of these 53 participants, 39 (73.6%) had at least one AIDS defining illness at the time of diagnosis (44 conditions in total). The most frequent presentations were HIV wasting (16/44, 36.4%), PCP (9/44, 20.5%), candida esophagitis (4/44, 9.1%), cerebral toxoplasmosis (3/44, 6.8%), mycobacterium tuberculosis infection (2/44, 4.5%), Kaposi sarcoma (2/44, 4.5%), and Burkitt lymphoma (2/44, 4.5%) (Table 3 ).

Key findings

To the best of our knowledge, this is one of few studies in the MENA region assessing late presentations of HIV and missed opportunities for earlier diagnosis 17 , 18 , 19 , 27 , 28 . We found that more than half of the newly diagnosed subjects in our cohort (51.3%) were late presenters and 35.3% had advanced HIV disease on presentation. Mortality from HIV-related death was around 5% among our cohort while mortality from HIV in the world is approximately 2% 29 . Mortality among those presenting with AIDS in our cohort was approximately 16%. Almost three in four of late presenters had attended a medical facility for an IC in the 3 years preceding diagnosis; of these, almost one in four presented with an AIDS defining conditions without getting tested for HIV.

Evidence in context

As of December 2022, Lebanon had an estimated 2600 PLWH, with an incidence rate below 0.03% 30 . It is important to note that reported numbers likely underestimate the true count of PLWH in Lebanon, primarily due to reliance on passive reporting. Our findings correspond with those presented in the national report. In fact, the 2018 UNAIDS report revealed that 26% of individuals newly diagnosed with HIV in Lebanon presented at an advanced stage, characterized by an initial CD4 count below 200 cells/mm 3 31 . Few studies have described late presentations in the MENA region 32 , 33 . Our results are in line with data from Turkey and Iran. Studies conducted in Turkey found that 50–69% of the PLWH presented late to medical care, and 25–40% of subjects had advanced HIV at the time of diagnosis 26 , 34 , 35 , 36 , 37 . Similarly, a large retrospective cohort study conducted in Iran revealed a prevalence of late diagnosis in around 58.2% of subjects 17 . Surveillance studies from Yemen and Saudi Arabia showed higher prevalence of late HIV. The cohort study from Yemen showed that 83% of PLWH presented with a CD4 less than 350 and 52% with CD4 count less than 200 18 . The study from Saudi Arabia included 977 subjects and revealed that 20% of HIV positive subjects had a CD4 < 350 at diagnosis, and 50% presented with AIDS at diagnosis 19 . Late diagnosis indicates a gap in HIV testing 38 , 39 , which is a notable observation from the countries of the MENA region. In fact, according to the UNAIDS, by the end of 2018, more than half of PLWH in the MENA region were not aware of their seropositivity status 40 .

In our study, subjects who presented late were older and were men who had sex with men. Interestingly, women only represented 7.3% of our population (11 out of 150), indicating potential additional social obstacles that women encounter when seeking HIV care. This aligns with national data from Lebanon, indicating that the country faces a concentrated HIV epidemic among MSM, comprising 12% of cases 41 . While our study did not specifically address barriers to testing, the increased prevalence of late presenters among individuals aged more than 50 years and MSM in our cohort may be attributed to persistent barriers to adequate HIV testing 39 . This phenomenon could be linked to lower testing rates in these demographics, potentially influenced by social, cultural and legal barriers such as criminalization of homosexuality, stigma preventing adequate sexual education, lack of access to HIV testing and poor comprehensive sexual and reproductive health provision 42 . Around six out of ten people with HIV are from marginalized groups, including MSM, transgender individuals, IV drug users, sex workers, and their clients 43 . However, it is precisely these marginalized communities who encounter significant challenges in accessing HIV prevention, testing, treatment, and care services due to stigma and discrimination. We performed subgroup analyses for the subgroups late presenters with and without advanced disease (presented in Supplemental Table 3 ). As expected, the only difference was the CD4 count, 281 and 89 cells/mml for the without and with advanced disease, respectively.

PLWH in Lebanon continue to face social stigmatization and discrimination impacting different aspects of their lives. Particularly, the MSM population experiences homophobia and legal consequences, given that the Lebanese penal code prohibits sexual relations deemed "contradicting the laws of nature", punishable by up to a year in prison. Nevertheless, Lebanon is relatively more accepting of sexual rights compared to other countries in the MENA region, making it a favorable location for getting tested and treated for HIV 44 . HIV testing is available at medical laboratories, hospitals, or free of charge at Voluntary Counseling and Testing (VCT) centers in Lebanon. These centers are spread throughout the country, ensuring accessibility for the entire population, including refugees. Lebanon follows a comprehensive "treatment for all" strategy in addressing HIV/AIDS 45 . The Ministry of Public Health (MOPH) provides free treatment to over 60% of individuals aware of their HIV status including Syrian and Palestinian refugees.

There is a paucity of published data on missed opportunities in the MENA region. Similar to our findings, a study from Morocco reported that 69% of their 650-subject cohort had missed opportunities for HIV testing 15 . In contrast, studies from countries outside the MENA region such as Italy, Sweden, Germany and UK showed that 21–27% of newly diagnosed HIV subjects who sought medical care for ICs were not offered HIV testing 46 , 47 , 48 , 49 , 50 . The missed opportunity proportion is higher in our cohort. Limited awareness or knowledge among healthcare workers, along with negative perceptions and stigma associated with HIV within this group, may account for missed opportunities. Risk factors for HIV infection might not be adequately addressed by the treating physician. Firstly, subjects may not have disclosed their sexual activity, sexual orientation, and gender identity because of fear of discrimination and stigma. Secondly, healthcare workers with negative perceptions towards specific populations—sex workers, IV drug users, LGBTQ + community- and lack of adequate training regarding sexual health matters often fail to properly address the behaviors and sexual orientations of their subjects 51 .

Missed opportunities can lead to late detection and diagnosis of HIV with consequent associated complications including higher morbidity and mortality, altered response to antiretroviral therapy (ART) , increased cost of medical care, and HIV transmission within the community 46 , 52 , 53 . More efforts are needed to provide HIV-specific training and to eliminate stigma and discrimination related to HIV among healthcare providers.

Limitations

Our study has several limitations that may have influenced our findings. Firstly, being a single-center study could restrict the generalizability of our results to the broader Lebanese population or other populations. The retrospective nature of our study also posed limitations on data collection, particularly regarding socioeconomic aspects such as housing situation, poverty, and risky sexual practices, which could have offered additional insights into factors associated with late presentation and missed opportunities.

Moreover, there is a potential underestimation of the proportion of missed opportunities in our population. Our results rely on data collected from medical records, and other opportunities may have been present but not documented. Conversely, we cannot guarantee that verbal recommendations for HIV testing by healthcare providers were documented or, if refused by the subject, leading to a possible overestimation of missed opportunities.

The collected data also lacked crucial clinical details on management and follow-up. Notably, some subjects were discharged to home with hospice care, despite their initial diagnosis being conducted at our center. The initiation of Antiretroviral Therapy (ART) presents an intriguing aspect; however, our data collection did not encompass this specific information for all subjects. Similarly, details regarding the time to death and potential Immune Reconstitution Inflammatory Syndrome (IRIS) were not included in our data collection.

Unforeseen circumstances significantly impacted our study, especially after 2019, affecting clinic follow-up, detailed history, and thorough evaluation and diagnostic investigation. Lebanon faced political turmoil and economic failure starting in 2019, resulting in disruptions to clinical operations and ongoing follow-up. The subsequent COVID-19 pandemic further compounded the situation by imposing additional movement restrictions through lockdowns, leading to several subjects either being lost to follow-up or conducting virtual visits.

In our cohort, and likely in the MENA region, late presentation with HIV and missed opportunities for HIV diagnosis are common, even in instances where HIV testing is clearly indicated. To effectively influence policies, it is imperative to expand research efforts and conduct comprehensive analyses to quantify the proportion of late presenters and missed opportunities in the region, and to explore the factors contributing to these findings. Future studies should prioritize the estimation of the preventable financial burden associated with late HIV presentation resulting from diminished productivity and increased healthcare expenditure. Another concern pertaining to healthcare providers’ attitudes and competencies should trigger a serious reform in the healthcare provider curricula regarding sexual health and reproductive health issues.

Data availability

De-identified participant data that underlie the results reported in this article can be shared upon reasonable requests to the corresponding author. Data requestors will need to sign a data access agreement form.

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These authors contributed equally: Haya Farhat and Mohammad El Hussein.

Authors and Affiliations

Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon

Maya Mahmoud

Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich (UZH), Zurich, Switzerland

Tala Ballouz

Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon

Chloe Lahoud, Jana Adnan, Paola Abi Habib, Reem Saab, Haya Farhat & Mohammad El Hussein

Division of Infectious Diseases, Department of Internal Medicine, American University of Beirut Medical Center, Riad El Solh, Beirut, 1107 2020, Lebanon

Nesrine Rizk

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M.M: data collection, data interpretation, manuscript writing, manuscript review and editing. T.B: manuscript writing and conceptualization, data analysis and interpretation. C.L: data collection, manuscript review and editing. J.A: data collection, manuscript review and editing. P.A.H: data collection, manuscript review and editing. R.S: data collection, manuscript review and editing. H.F: data collection, manuscript review and editing. M.E.H: data collection. N.R: manuscript writing, manuscript review and editing, and conceptualization.

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Correspondence to Nesrine Rizk .

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Mahmoud, M., Ballouz, T., Lahoud, C. et al. Late presentations and missed opportunities among newly diagnosed HIV patients presenting to a specialty clinic in Lebanon. Sci Rep 14 , 8296 (2024). https://doi.org/10.1038/s41598-024-55277-1

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Face presentation at term: incidence, risk factors and influence on maternal and neonatal outcomes

• Maternal-Fetal Medicine
• Published: 09 April 2024

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• Yongqing Zhang 1   na1 ,
• Tiantian Fu 1   na1 ,
• Luping Chen 1 ,
• Yinluan Ouyang 1 ,
• Xiujun Han 1 &
• Danqing Chen   ORCID: orcid.org/0000-0002-0201-7215 1  

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The incidence, diagnosis, management and outcome of face presentation at term were analysed.

A retrospective, gestational age-matched case–control study including 27 singletons with face presentation at term was conducted between April 2006 and February 2021. For each case, four women who had the same gestational age and delivered in the same month with vertex position and singletons were selected as the controls (control group, n = 108). Conditional logistic regression was used to assess the risk factors of face presentation. The maternal and neonatal outcomes of the face presentation group were followed up.

The incidence of face presentation at term was 0.14‰. After conditional logistic regression, the two factors associated with face presentation were high parity (adjusted odds ratio [aOR] 2.76, 95% CI 1.19–6.39)] and amniotic fluid index > 18 cm (aOR 2.60, 95% CI 1.08–6.27). Among the 27 cases, the diagnosis was made before the onset of labor, during the latent phase of labor, during the active phase of labor, and during the cesarean section in 3.7% (1/27), 40.7% (11/27), 11.1% (3/27) and 44.4% (12/27) of cases, respectively. In one case of cervical dilation with a diameter of 5 cm, we innovatively used a vaginal speculum for rapid diagnosis of face presentation. The rate of cesarean section and postpartum haemorrhage ≥ 500 ml in the face presentation group was higher than that of the control group (88.9% vs. 13.9%, P  < 0.001, and 14.8% vs. 2.8%, P  = 0.024), but the Apgar scores were similar in both sets of newborns. Among the 27 cases of face presentation, there were three cases of adverse maternal and neonatal outcomes, including one case of neonatal right brachial plexus injury and two cases of severe laceration of the lower segment of the uterus with postpartum haemorrhage ≥ 1000 ml.

Conclusions

Face presentation was rare. Early diagnosis is difficult, and thus easily neglected. High parity and amniotic fluid index > 18 cm are risk factors for face presentation. An early diagnosis and proper management of face presentation could lead to good maternal and neonatal outcomes.

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Acknowledgements

The authors wish to acknowledge Menglin Zhou, Zhengyun Chen and Guohui Yan for their valuable assistance for the manuscript.

No specific funding was obtained for this study.

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Yongqing Zhang and Tiantian Fu have contributed equally to this work.

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Department of Obstetrics, School of Medicine, Women’s Hospital, Zhejiang University, 1st Xueshi Road, Hangzhou, 310006, Zhejiang, People’s Republic of China

Yongqing Zhang, Tiantian Fu, Luping Chen, Yinluan Ouyang, Xiujun Han & Danqing Chen

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YZ: conceptualization, methodology, writing—original draft. TF: conceptualization, formal analysis, writing—original draft. LC: data collection, follow-up. YO: investigation, resources. XH: investigation, formal analysis, supervision. DC: conceptualization, writing—review and editing, supervision. All authors read and approved the final manuscript.

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Correspondence to Xiujun Han or Danqing Chen .

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Our study was planned in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Local Ethics Committee of the Women’s hospital, school of medicine, Zhejiang university ( Ethical No. IRB-20210211-R ).

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As this was a retrospective study, written informed consents were not obtained, but all patients’ records/information were anonymized before analysis. The images used in this paper (Figs. 1 , 2 , 3 ) were given informed consent by the pregnant woman.

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Zhang, Y., Fu, T., Chen, L. et al. Face presentation at term: incidence, risk factors and influence on maternal and neonatal outcomes. Arch Gynecol Obstet (2024). https://doi.org/10.1007/s00404-024-07406-4

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Received : 09 July 2023

Accepted : 28 January 2024

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DOI : https://doi.org/10.1007/s00404-024-07406-4

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