case study of newborn with jaundice

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Case progression, lessons for the clinician, case 1: severe jaundice in a 2-day-old term neonate.

AUTHOR DISCLOSURE

Drs Lyle and Turcu have 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. Dr Turcu's current affiliation is Department of Pediatrics, Division of Newborn Medicine, Tufts Medical Center, Boston, MA.

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Allison Lyle , Rodica Turcu; Case 1: Severe Jaundice in a 2-day-old Term Neonate. Neoreviews August 2019; 20 (8): e464–e467. https://doi.org/10.1542/neo.20-8-e464

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A 2-day-old, 2.68-kg term male neonate is brought to the emergency department with lethargy, poor feeding, and significant generalized jaundice. He was born via spontaneous vaginal delivery at home to a gravida 4, para 3 Amish woman under the supervision of a midwife, at an estimated gestational age of 39 weeks after an uncomplicated pregnancy with scant prenatal care. Jaundice was noticed 7 hours after birth. The neonate has only breastfed 5 to 6 times since birth, and passed a normal-colored stool at home. Prenatal laboratory findings are unavailable because of limited prenatal care. The mother’s blood type is AB, Rh negative. The mother’s obstetric history includes a previous miscarriage (4 years earlier), a previous stillbirth at 30 weeks’ gestation (3 years earlier), and a term pregnancy (2 years earlier). She had received Rh o (D) immune globulin 3 weeks after the miscarriage, 2 weeks after the stillbirth delivery, and 2 weeks after the most recent pregnancy. The mother, father, and 2-year-old brother are reportedly healthy.

Review of systems at admission is significant for decreased activity, poor feeding, and generalized, intense yellow discoloration of the skin. The infant has no fever, vomiting, diarrhea, constipation, bloody stools, seizures, or hypertonia. Physical examination reveals a weak cry, lethargy, scleral icterus, soft liver edge 3 cm below the right costal margin, and significant generalized jaundice of the entire body. No dysmorphic features are appreciated.

Initial evaluation revealed a total serum bilirubin (TB) of 49.4 mg/dL (845 μmol/L), conjugated bilirubin of 42 mg/dL (718 μmol/L), unconjugated bilirubin of 10.7 mg/dL (183 μmol/L), reticulocyte count greater than 23, and hemoglobin of 12.6 g/dL (126 g/L). Urinalysis demonstrated dark brown urine. Serum aspartate aminotransferase (AST) was elevated at 239 U/L (4 μkat/L), serum alanine aminotransferase (ALT) was elevated at 55 U/L (0.9 μkat/L), serum alkaline phosphatase was 186 U/L (3.1 μkat/L), and partial thromboplastin time was elevated at 30.7 seconds. Urine culture revealed Escherichia coli at 10,000 to 100,000 colony-forming units. Peripheral smear demonstrated mild anemia with marked reticulocytosis and numerous immature erythroids. The neonate’s blood type was B, Rh positive. Direct Coombs test result was 4+, indicating antibody-mediated hemolysis in the newborn. A jaundice chip, which targets 5 genes ( ABCB11, ABCB4, ATP8B1, JAG1 , and TJP2 ), was drawn (the negative result was not received until later, ruling out Alagille syndrome and progressive familial intrahepatic cholestasis as possible causes). Endocrinopathies (hypothyroidism and hypopituitarism) were excluded (normal thyroid-stimulating hormone and free thyroxine). Newborn screening results were normal. Abdominal ultrasonography showed a normal-appearing liver and gallbladder, no biliary ductal dilation, and patent vessels.

The 2004 American Academy of Pediatrics guidelines for treatment of hyperbilirubinemia state that, “In unusual situations in which the direct bilirubin level is 50% or more of the TB, there are no good data to provide guidance for therapy.”( 1 ) Treatment included intensive phototherapy, intravenous fluids, double volume exchange transfusion, intravenous immunoglobulin, ampicillin, cefotaxime, acyclovir, and phenobarbital (for activation of the promotor sequence of hepatic UGT1A1). The Fig demonstrates the decline of bilirubin after each of these interventions. Enteral feeds were initiated after 2 days of hospitalization, which the infant tolerated well.

Bilirubin levels over time.

At discharge on hospital day 7, laboratory findings were as follows: TB 9.3 mg/dL (159 μmol/L), conjugated bilirubin 4.5 mg/dL (77 μmol/L), unconjugated bilirubin 2.5 mg/dL (42.8 μmol/L), AST 81 U/L (1.3 μkat/L), ALT 36 U/L (0.6 μkat/L), and alkaline phosphatase 82 U/L (1.4 μkat/L). Hepatobiliary iminodiacetic acid scan was offered, but the parents declined because of the normal hepatic ultrasound scan with decreasing bilirubin levels. They also declined brain magnetic resonance imaging because the neurologic findings at discharge were reassuring.

The infant was evaluated in the developmental pediatrics clinic at 2 months, 19 days of age. Growth was appropriate: weight 5.88 kg (36th percentile), length 59.7cm (35th percentile), and head circumference 38.5cm (9th percentile). Jaundice had resolved. TB concentration was 0.8 mg/dL (13.7 μmol/L) and direct bilirubin 0.0 mg/dL (0.0 μmol/L). He appeared developmentally appropriate with normal findings on neurologic examination. He continues to be followed closely.

Jaundice in the first few days after birth is a common neonatal problem, occurring in approximately two-thirds of newborns. ( 2 ) Most cases are represented by unconjugated hyperbilirubinemia, which is usually treated with phototherapy. Conjugated hyperbilirubinemia is much less common in the neonatal period, and is indicative of cholestasis. Neonatal jaundice caused by unconjugated versus conjugated hyperbilirubinemia cannot be differentiated with physical examination alone. Direct bilirubin concentration greater than 1.0 mg/dL (17.1 μmol/L) with TB less than 5 mg/dL (85.5 μmol/L), or a direct bilirubin greater than 20% of the TB (if TB >5 mg/dL) is diagnostic of conjugated hyperbilirubinemia. Conjugated hyperbilirubinemia and cholestasis can have infectious, metabolic, or obstructive causes, and is the most common marker of cholestasis. ( 3 )( 4 )( 5 )( 6 )( 7 ) Common causes of obstructive cholestasis include biliary atresia, choledochal cysts, bile duct paucity, neonatal sclerosing cholangitis, inspissated bile syndrome, gallstones/biliary sludge, cystic fibrosis, and Caroli disease. ( 2 )( 7 )( 8 )

The current patient was born full term, had inadequate prenatal care, and demonstrated significant generalized jaundice within the first 7 hours after birth. He presented with hemolytic anemia (likely because of Rh incompatibility) and conjugated hyperbilirubinemia (which was unusual given that Rh incompatibility usually results in unconjugated hyperbilirubinemia). The most common causes of cholestasis had been excluded: Alagille syndrome and progressive familial intrahepatic cholestasis (negative jaundice chip), hypothyroidism and hypopituitarism (normal thyroid-stimulating hormone and free thyroxine), congenital heart disease (normal chest radiograph and a patent foramen ovale on echocardiography). Urinary tract infection with E coli could have been a contributory factor, but it is an unlikely main cause. In cases of suspected cholestasis, ultrasonography is the initial imaging modality of choice. ( 9 ) After all test results returned, the exclusion diagnosis in this case remained Rh incompatibility with severe chronic hemolysis, complicated by inspissated bile syndrome.

Inspissated bile syndrome is a rare clinical entity, with an incidence of 1 in 175,000 live births as reported in England. ( 9 )( 10 ) The medical literature reveals a paucity of neonatal inspissated bile syndrome cases; the few cases reported are in the setting of cystic fibrosis or metabolic disorders, ( 6 )( 11 ) ABO incompatibility after transfusion, ( 12 ) or drug-induced. ( 13 ) In these cases, the infant was older at the time of presentation, and TB and conjugated bilirubin levels were well below the values recorded for our patient.

Two-thirds of newborns will experience jaundice within the first few days after birth.

Conjugated hyperbilirubinemia is less common than unconjugated hyperbilirubinemia and is indicative of cholestasis caused by infection, metabolism defects, or obstruction.

Common causes of obstructive cholestasis include biliary atresia, choledochal cysts, bile duct paucity, neonatal sclerosing cholangitis, inspissated bile syndrome, gallstones/biliary sludge, cystic fibrosis, and Caroli disease.

Evaluation for neonatal cholestasis includes blood, urine, and cerebrospinal fluid cultures, urinalysis, cerebrospinal fluid studies, complete blood cell count with differential, comprehensive metabolic panel, prothrombin time/international normalized ratio, and partial thromboplastin time. Newborn screening results should be reviewed for possible metabolic causes. Abdominal ultrasonography should be performed to assess for biliary atresia. A jaundice chip is useful if Alagille syndrome or progressive familial intrahepatic cholestasis is suspected.

Note: This case is based on a presentation by Drs Lyle and Turcu at the Joint Plenary Poster Session of the Southern Regional Meeting of American Federation for Medical Research, New Orleans, LA, on February 22, 2018 (Poster No. 303).

Know the factors, including red cell life span, enzyme defects, and red cell structural abnormalities, associated with an increase in bilirubin production.

Know the factors associated with a decrease in neonatal serum bilirubin excretion, including those that affect the enterohepatic circulation of bilirubin.

Know bilirubin physiology, including pathways of synthesis, transport, and metabolism, in the fetus and neonate.

NOTE The editors and staff of NeoReviews find themselves in the fortunate position of having too many submissions for the Index of Suspicion in the Nursery column. Our available publication slots for the column are filled, and because we do not think it is fair to delay publication unduly, we have decided not to accept new cases for the present. We will make an announcement in NeoReviews when we resume accepting new cases. We apologize for having to take this step, but we wish to be fair to all authors and to publish only timely medical information. We are grateful for your interest in the journal.

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Neonatal Jaundice

Case Presentation

Martin and Kim were both twenty-five when they had Michael, their first child. Kim remained very healthy during her pregnancy and went into labor at 9:00 a.m., just 3 days after her due date. Delivery went quite smoothly, and that evening, mother and child rested comfortably. Two days later, Kim and Michael were released from the hospital. That evening at feeding time, Kim noticed that the whites of Michael's eyes seemed just slightly yellow, a condition that worsened noticeably by the next morning. Kim called the pediatrician and made an appointment for that morning.

Upon examining Michael, the pediatrician informed Martin and Kim that the infant had neonatal jaundice, a condition quite common in newborns and one that need not cause them too much concern. The physician explained that neonatal jaundice was the result of the normal destruction of old or worn fetal red blood cells and the inability of the newborn's liver to effectively process bilirubin, a chemical produced when red blood cells are destroyed. The physician told the parents he would like to see Michael every other day in order to monitor blood bilirubin concentration until the bilirubin concentration dropped into the normal range. He recommended that Kim feed Michael frequently and instructed them to place Michael in sunlight whenever possible.

Case Background

Neonatal jaundice in a disorder that affects nearly 50% of all newborns to at least a small degree. The yellow coloration of the skin and sclera of the eyes is due to the accumulation of bilirubin in adipose tissue and its adherence to collagen fibers. In neonatal jaundice, the excess bilirubin is not due to an abnormal level of red blood cell destruction. It is due to the inability of the young liver cells to conjugate bilirubin, or make it soluble in bile, so that it can be excreted and removed from the body by the digestive tract. This inability is corrected, usually within one week, as the liver cells synthesize the conjugation enzymes. If uncorrected, sufficiently high bilirubin concentrations can cause brain damage. Frequent feedings of a newborn with jaundice increase gastrointestinal tract motility and decrease the likelihood of reabsorbing significant amounts of bilirubin in the small intestine. Radiation from sunlight alters the chemical form of bilirubin, making is easier for the liver to excrete.

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A guide to neonatal jaundice

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• Peer review
• Ben Green , foundation year one doctor 1 ,
• Lydia Burland , foundation year two doctor 2 ,
• Chris Smith , consultant paediatrician 1
• 1 Leeds General Infirmary, Leeds Teaching Hospitals Trust, Leeds LS1 3EX, UK
• 2 Dewsbury and District Hospital, Dewsbury, West Yorkshire WF13 4HS, UK

What should the junior doctor know?

Neonatal jaundice or hyperbilirubinaemia, is one of the most commonly observed conditions in the newborn infant. It specifically refers to the distinct yellow discolouration of sclera and skin, resulting from the accumulation of bilirubin. Although neonatal jaundice can be the result of serious underlying pathology, it is more typically a normal transitional phenomenon that resolves spontaneously. Around 60% of infants born at term will develop this condition. The risk is inversely proportional to gestational age, with those born before 37 weeks having an 80% risk during the first week of life. 1 Treatment might be indicated if the concentration of bilirubin is initially high, if it continues to rise, or if specific pathology is identified; the aim being to prevent complications of hyperbilirubinaemia such as kernicterus, which left untreated can lead to lifelong neurological disability or even death.

Neonatal jaundice is commonly seen in paediatrics, and all doctors working in this specialty should have an up to date working knowledge of this topic. While the junior doctor would not be expected to instigate management, having an awareness of the common causes, as well as knowing how to identify those at risk and those requiring further intervention, is of vital importance.

What are the causes of neonatal jaundice?

Neonatal jaundice can be broadly categorised into physiological and pathological jaundice. Physiological jaundice is by far the most common cause and is easily recognisable, typically appearing two to three days after birth in an otherwise well infant and normally resolving by 2 weeks of age. Physiological jaundice results through two distinct mechanisms—either through relative polycythaemia causing a rapid breakdown of fetal erythrocytes after birth and exposure to normal environmental oxygen concentrations, or through the reduced ability of the neonatal liver to excrete raised concentrations of bilirubin. 2

Pathological causes fall into three distinct groups: those resulting in early jaundice, prolonged jaundice, and conjugated jaundice (fig 1). ⇓ Some causes, however, can fall into more than one category—notably infection, which is an important cause of jaundice and must not be missed. Signs of infection can often be non-specific in neonates; features such as lethargy, poor feeding, and hypothermia or pyrexia, however, can point to an underlying infection and should be further investigated. It is additionally important to understand basic terminology regarding bilirubin and how it is measured clinically. Box 1 provides basic definitions.

Box 1: Definitions of types of bilirubin

Unconjugated: The unconjugated (indirect) bilirubin refers to insoluble bilirubin that is free in the plasma. It is classified as indirect as the concentration can be calculated only by subtracting direct from total bilirubin

Conjugated: The conjugated (direct) bilirubin refers to soluble bilirubin that is bound to glucuronic acid. This is excreted in the urine and undergoes enterohepatic circulation

Total: Total bilirubin measures total bilirubin concentration—that is, conjugated and unconjugated fractions

Split: Split bilirubin refers to the individual concentration of conjugated and unconjugated bilirubin

Fig 1 Causes of early, prolonged, and conjugated neonatal jaundice 1 3 4

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Early jaundice begins within the first 24 hours of life and should prompt investigation as the cause is always pathological. The most common causes include haematoma or bruising associated with delivery and congenital or postnatal infection. Less common causes include red cell haemolysis, which is most commonly caused by glucose 6 phosphate dehydrogenase (G6PD) deficiency; this can cause a particularly aggressive form of jaundice and is common in those of African, Eastern Mediterranean, or South East Asian descent. More rarely haemolysis is caused by ABO and rhesus incompatibility, as well as inborn errors of bilirubin metabolism. 4 “Breast feeding jaundice” can also cause an early jaundice within the first few days of life because of inadequate production or intake of breast milk; this is distinct from “breast milk jaundice.” When a diagnosis is being considered, it is important to take into account relevant risk factors, including a detailed history of pregnancy: factors including maternal blood group, maternal infections, and factors related to delivery such as prolonged rupture of membranes (PROM) are all important and can help determine a cause—for instance, PROM increases the chances of early jaundice being linked to infection.

Prolonged jaundice is defined as that lasting more than 14 days in the term infant or more than 21 days in a preterm infant, defined as less than 37 weeks’ gestational age. 1 Again full investigation is warranted, although the most common cause is breast milk jaundice. While the exact mechanism of breast milk jaundice is yet to be elucidated, it is largely benign and self limiting, usually occurring four to seven days after birth and resolving completely by week 12. 5 It is important to realise that breast milk jaundice is a diagnosis of exclusion, and that while it is beneficial to offer parents reassurance, the diagnosis does not exclude the need for further treatment if bilirubin concentrations are above the threshold for treatment. Other notable causes of prolonged jaundice include infection, thyroid disorders, metabolic disorders, and hepatobiliary disease.

Conjugated jaundice is most commonly caused by parenteral nutrition but can otherwise be caused by liver disease secondary to conditions such as infection and hepatitis and surgical causes such as biliary/duodenal atresia involving the ampulla of Vater and choledochal cysts. 6 An important clinical pattern involves conjugated hyperbilirubinaemia in conjunction with pale stools and dark urine—that is, an obstructive presentation that can indicate either biliary or duodenal atresia. Obstructive jaundice is another commonly tested clinical pattern that is important to recognise, not least because surgical correction is time critical.

How can I identify those who are at risk?

Identification of infants at risk can help to enable early diagnosis and timely intervention. As such, doctors should have a sound awareness of known risk factors, which will help to facilitate the recognition of those neonates requiring additional care. Several factors are recognised to increase the risk of neonatal jaundice, including race, with an increased risk in those of American Indian, South East Asian, and Indian descent; conversely, there is a decreased risk in black infants. Other risk factors include the use of vacuum devices during delivery as this increases the risk of haematoma or extensive bruising after birth. 7

Certain additional risk factors are associated with severe jaundice and therefore more commonly require intervention. Factors including exclusive breast feeding, previous jaundice in a sibling requiring phototherapy, gestational age under 38 weeks, and visible jaundice occurring within the first 24 hours of birth can all contribute to a state of severe hyperbilirubinaemia. 1 While many of these factors can be clinically apparent, this does not exclude the need for a thorough history to establish subjective risk factors.

How should I investigate a neonate with jaundice?

Early recognition has been shown to improve outcomes. While identification of an infant with jaundice might seem simple, variation in skin tone and other factors can, in some cases, make identification difficult. Figure 2 summarises several recommendations, as suggested by the National Institute for Health and Care Excellence (NICE) ⇓ .

Fig 2 Identification and investigation of neonatal jaundice. Timings refer to the onset of jaundice. Light grey boxes indicate actions, while darker grey boxes indicate investigations. HCP=healthcare professional; SBR=split bilirubin; FBC=full blood count; LFTs=liver function tests; DCT=direct Coomb’s test; TORCH=toxoplasmosis, others (including but not limited to syphilis), rubella, cytomegalovirus, herpes simplex 1

Investigation of infants presenting with jaundice depends on their age at presentation, whether the infant is clinically well, and the length of time for which jaundice has been present. The most useful initial investigation consists of measurement of total and split bilirubin concentrations, and this should ideally be requested in all infants who merit clinical concern. Although local guidance varies, figure 2 ⇑ summarises the important investigations depending on age at presentation: investigations vary slightly according to whether jaundice presents within 24 hours, after 24 hours, or after two weeks. It should be noted that testing of the maternal blood type can also be helpful in identifying a cause—such as ABO or rhesus incompatibility. All of the above mentioned investigations could be realistically requested by an astute house officer.

In patients with conjugated jaundice or signs of cholestatic disease, imaging studies such as ultrasongraphy is typically preferred to rule out surgical causes. Further investigations such as HIDA (hepatobiliary iminodiacetic acid) scanning is reserved for particularly complex cases. Surgical management ultimately depends on the underlying cause.

How do I manage a neonate with jaundice?

The management of neonatal jaundice is highly specialised and therefore the role of the junior doctor is somewhat limited; an awareness of available treatments, however, means that junior doctors are competent to explain procedures to parents/relatives (box 2). Treatment generally aims to resolve the underlying cause in addition to correcting hyperbilirubinaemia. This is achieved by two main methods: phototherapy and exchange transfusion. The indications for treatment depend on the serum bilirubin concentration as well as the age of the infant (fig 3 ⇓ ); it is important to note that treatment boundaries vary significantly depending on exact gestation. 8

Box 2: Talking to the parents: clarifying the role of the junior doctor

A commonly overlooked part of effective management is ensuring that the parents are fully informed. As a junior doctor, it is possible that you will be asked to talk to concerned parents of a neonate with jaundice. While this article obviously can’t cover every eventuality, we have tried to establish some key points on which to base a consultation.

Introduce yourself and check the identity of the parents/relatives

Explain in basic terms why the baby is jaundiced—that is, early break down of red blood cells and immaturity of liver enzymes

Explain what is being done and whether or not the baby requires treatment

Elicit and respond to parental ideas, concerns, and expectations

Offer reassurance whenever appropriate to do so

Most importantly, don’t be afraid to admit when you don’t know something, if this is the case

Fig 3 Treatment protocol for neonatal jaundice. As serum bilirubin concentration increases, the likelihood of phototherapy and exchange transfusion being required also increases. This is also partly dependent on the age of the infant, with younger infants being more likely to require intervention for any given concentration

The goal of phototherapy is to reduce the concentration of circulating unconjugated bilirubin by using visible light in the blue spectrum. The absorbed light energy causes a change in the structure of the bilirubin molecules, resulting in a more hydrophilic lower molecular weight product that can be excreted in bile and urine without the need for conjugation. 9

For most infants with a bilirubin concentration on or above the threshold for phototherapy treatment, single phototherapy treatment is appropriate. If the infant is preterm, the bilirubin concentrations are rising rapidly, or the concentration is close to the threshold for exchange transfusion fibreoptic phototherapy or multiple light therapy might be more appropriate. 1 During phototherapy parents should be encouraged to interact with the infant, with short breaks for feeds and changing if single light therapy is in use; multiple light therapy, however, should not be interrupted.

For a small group of infants who present with severe hyperbilirubinaemia, for whom multiple light phototherapy is not successful or who show signs of acute bilirubin encephalopathy, urgent exchange transfusion is necessary. Features of acute bilirubin encephalopathy can include lethargy, irritability, abnormal posture, apnoea, and convulsions. Exchange transfusion aims to modify the blood’s composition by removing small volumes of blood containing excess bilirubin and replacing it with prewarmed blood or plasma, thereby maintaining overall volume. Typical exchange transfusion causes a reduction of about 50% in serum bilirubin concentration, but the result can be transient and therefore close monitoring is essential after transfusion.

While it is important to correct hyperbilirubinaemia, the underlying cause must also be dealt with. Physiological and breast milk jaundice can require phototherapy, though they are self limiting and don’t normally require further management. Pathological causes are treated in the same manner but might additionally require further specific interventions. Surgical management is indicated only in conditions that cause bile outflow obstruction, such as biliary and duodenal atresia.

What is the prognosis for neonates with jaundice?

With modern diagnostic techniques and the widespread availability of treatment, the prognosis after neonatal jaundice is generally excellent. To minimise the risk of complications, infants should be regularly monitored. This can be easily achieved through the use of transcutaneous bilirubin meters in babies over 35 weeks, though a simple venous or capillary blood sample might be required if concentrations are high. Serum bilirubin concentrations should be rechecked four to six hours after initiation of phototherapy, and after six to 12 hours if the concentrations have begun to fall. Multiple light therapy should be considered if the concentrations are static or are continuing to rise. Once concentrations have fallen to >50 µmol/L below the treatment threshold, phototherapy can be stopped, with repeat concentrations being measured 12-18 hours later to check for rebound hyperbilirubinaemia. 1

The main complication arising from hyperbilirubinaemia is kernicterus, which can result from unrecognised or untreated hyperbilirubinaemia. This is a syndrome of acute neurological dysfunction resulting from deposition of bilirubin in the brain, and, although extremely rare, 10 long term sequelae can include permanent brain damage and cerebral palsy. Kernicterus tends to occur in three distinct phases, and it is therefore vital that junior doctors recognise the signs and symptoms present during the first stage, when treatment is still likely to be effective. Typical features including hypotonia progressing to opisthotonos (a state of spastic hyperextension), high pitched cry, apathy, and poor feeding should raise concern regarding the possibility of kernicterus. 11 Infants at particularly high risk include those with blood disorders such as ABO and/or rhesus incompatibility; such infants should be closely monitored for complications. 12 Although the features described are relatively non-specific, it is recommended that you consult a senior colleague immediately if you identify these changes, either in an infant with jaundice or an infant who is known to be at high risk.

Originally published as: Student BMJ 2014;22:g2836

Competing interests: None declared.

Provenance and peer review: Not commissioned; externally peer reviewed.

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• http://orcid.org/0000-0002-2072-8491 Gracinda Nogueira Oliveira 1 ,
• Isabel Dinis 2 ,
• Maria José Noruegas 3 ,
• Alice Mirante 2
• 1 Department of Paediatrics , Hospital Pediátrico de Coimbra , Coimbra , Portugal
• 2 Department of Paediatric Endocrinology, Diabetes and Growth , Hospital Pediátrico de Coimbra , Coimbra , Portugal
• 3 Department of Radiology , Hospital Pediátrico de Coimbra , Coimbra , Portugal
• Correspondence to Dr Gracinda Nogueira Oliveira, gracenoliveira{at}gmail.com

https://doi.org/10.1136/bcr-2017-223306

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A 22-year-old gravida 2, para 1 (G2P1) woman with immunoglobulin anti-D prophylaxis, insulin-treated gestational diabetes and first-trimester cytomegalovirus (CMV) infection vaginally delivered a 39-week boy weighing 3720 g (90th centile) and with Apgar scores of 8 and 10 at 1 and 5 min. Prenatal ultrasonographic assessment throughout gestation was normal. Nursery stay was uneventful. He was discharged on day 2, with a normal examination, except for the appearance of jaundice, with a transcutaneous bilirubin of 248 µmol/L (cut-off 250 µmol/L), not meeting the criteria for phototherapy. A follow-up clinic on day 4, arranged for bilirubin measurement and CMV testing, surprisingly revealed poor general appearance, lethargy, very icteric skin and a minor weight loss (9% of birth weight). Both liver and splenic edges were palpable. Vital signs were normal. Blood routine showed haemoglobin of 19 g/dL, haematocrit of 58%, white blood cells 11.6x10 9 /L and platelet count 128x10 9 /L. Biochemistry revealed total serum bilirubin of 694 µmol/L (cut-off 350 µmol/L), indirect bilirubin of 681 µmol/L, and a normal glucose, urea, creatinine and coagulation study. He was admitted for intensive phototherapy, and his total serum bilirubin level decreased to 289 µmol/L in 9 hours, but rebound hyperbilirubinaemia followed whenever attempts to discontinue were made. He remained icteric, hypotonic, required enteral tube feeding and had a persistent hyponatraemia treated with oral sodium chloride. On day 9 cranial ultrasound (US) was normal, but abdominal US uncovered enlarged adrenal glands, with a hypoechoic heterogeneous mass, measuring 32×21×17 mm on the right and 33×23×17 mm on the left, suggesting a bilateral adrenal haemorrhage (AH). CMV viruria came negative, and subsequent studies showed increased thyroid-stimulating hormone (TSH) and normal free thyroxine 4 levels, leading to the initiation of levothyroxine treatment on day 14. Transfer to a tertiary paediatric hospital was arranged on day 28. Abdominal Doppler US on day 30 confirmed the bilateral AH ( figure 1A ). The complete hormone evaluation showed raised adrenocorticotropic hormone (ACTH), prolactin, aldosterone and renin, and low cortisol level, which, together with an elevated TSH, disclosed hypothyroidism secondary to adrenal insufficiency (AI). Under hydrocortisone treatment, started on day 39, hypotonia resolved and feeding improved with an adequate weight gain. Neurological and metabolic evaluations were normal. Thyroid parameters normalised at 3 months and levothyroxine was suspended. At 6 months fludrocortisone was added to control the inappropriately activated renin-angiotensin-aldosterone system. Two-month and 6-month follow-up US revealed an ongoing and significant regression of both adrenal masses in size and echogenicity ( figure 1B , C ). Presently, at 22 months, he remains asymptomatic but continues on corticosteroid replacement therapy for hormonal control. The most recent US, at 12 months, showed an even smaller bilateral haemorrhage with a maximum diameter of 6 mm.

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(A) One-month ultrasound (US): hypoechoic and heterogeneous ovoid mass with no blood flow at colour Doppler and surrounding calcification compatible with haemorrhage. (B) Two-month US shows at least a 50% bilateral decrease in the cystic mass area and echogenicity. (C) Six-month US shows further bilateral decrease in size and echogenicity. L, left adrenal gland; R, right adrenal gland.

Both serum cortisol and ACTH should be measured in newborns with AH to exclude primary AI. 2 Hyponatraemia in our patient was most likely the result of hypervolaemia due to an increased antidiuretic hormone (ADH) secretion elicited by cortisol deficiency. AI in a newborn with bilateral AH requires supplementation with both glucocorticoids and mineralocorticoids. 2 A close follow-up using serial US is required, and AH usually resolves between 3 weeks and 6 months. 2 , 3 However, a longer period of time is possible in accordance with our case.

Learning points

Bilateral adrenal haemorrhage (AH) is a rare neonatal event that should be recognised in the presence of persistent unexplained jaundice and predisposing factors.

Abdominal Doppler ultrasound is the examination of choice in neonates with suspected AH, allowing organ injury assessment and exclusion of other abnormalities at diagnosis and a non-invasive monitoring at follow-up.

AH is usually self-limiting, but rare bilateral cases may cause adrenal insufficiency and require corticosteroid therapy.

• Oztürkmen-Akay H ,
• Devecioğlu C , et al
• Qureshi UA ,
• Rasool A , et al
• Karagüzel G ,
• Aslan Y , et al

Contributors GNO conceptualised the case report, did a literature review, integrated the data and wrote the manuscript. ID and MJN contributed to the conception, drafting and critical revision of the article. AM closely supervised the management of the patient and the writing of the case report.

Competing interests None declared.

Patient consent Parental/guardian consent obtained.

Provenance and peer review Not commissioned; externally peer reviewed.

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Maternal and neonatal factors associated with neonatal jaundice in Jordan: a case-control study

Khitam Ibrahem Shlash Mohammad

Jordan University of Science & Technology, Jordan

View articles · Email Khitam Ibrahem Shlash

Maram Al–Shdefat

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Suhaila Halasa

The University of Jordan, Jordan

Rachel Joseph

School of Nursing, Liberty University, USA

Mohammad Alafi

Medical student, Faculty of Medicine, Jordan University of Science and Technology, Jordan

Mohammed ALBashtawy

Community Health Nursing Department, Princess Salma Faculty of Nursing, Al Al-Bayt University, Jordan

Abdullah Alkhawaldeh

Asem Abdalrahim

Associate professor, Community Health Nursing Department, Princess Salma Faculty of Nursing, Al Al-Bayt University, Jordan

Malakeh Malak

Associate professor, Community Health Nursing Department, Faculty of Nursing, Al Zaetonah University, Jordan

Debra Creedy

Professor of Perinatal Mental Health, Maternal, Newborn and Families Research Collaborative, Menzies Institute of Health Queensland, Griffith University, Australia

Jenny Gamble

Professor and Head of Midwifery, Newborn and Families Research Collaborative, Menzies Institute of Health Queensland, Griffith University, Australia

Background/Aims

Neonatal jaundice is a common cause of hospitalisation. This study aimed to identify maternal and neonatal factors associated with neonatal jaundice among hospitalised neonates in north Jordan.

This was a case control study involving 312 mothers and their neonates (106 cases, 206 controls), recruited from two governmental hospitals in north Jordan. A structured interview was used to collect data. Neonatal medical records were accessed for clinical data.

Maternal factors associated with higher risk of jaundice included having higher education, being employed and having had a caesarean section. Neonatal factors associated with higher risk of jaundice included being preterm, receiving <5 feeds per day and having ABO incompatibility.

Conclusions

Using evidence-based guidelines for the assessment and management of risk factors helps to reduce the prevalence of jaundice requiring hospitalisation among neonates. Raising mothers' awareness of neonatal jaundice through interventions and education sessions during antenatal care, in particular for high-risk mothers, is also likely to help reduce its prevalence.

Neonatal jaundice is a common cause of hospitalisation for both full-term and preterm neonates ( Mojtahedil et al, 2018 ). Almost all newborns have a total serum bilirubin level of >1mg/dL, the upper limit of normal for adults ( Aynalem et al, 2020 ). High levels (≥5mg/dL) manifest clinically as jaundice and, a consequence of increased breakdown of red blood cells and/or decreased hepatic excretion of bilirubin, producing a yellow-orange discoloration of the skin and sclera ( Brits et al, 2018 ; Olatubi et al, 2019 ). Neonatal jaundice commonly occurs in the first week after birth, although it is not harmful, is self-limiting and usually improves without treatment ( Awang et al, 2020 ; Ricci et al, 2021 ).

Factors associated with the development of neonatal jaundice include prematurity, ABO incompatibility, Rh incompatibility, glucose-6-phosphate dehydrogenase (G6PD), sepsis, breast problems (eg sore or cracked nipples or breast engorgement, associated with inadequate intake of breast milk), breastfeeding patterns, prolonged labor, having siblings who had neonatal jaundice, high birth weight, primiparity, male gender, mode of birth and maternal diabetes mellitus ( Olatubi et al, 2019 ; Seyedi et al, 2019 ; Abbas et al, 2020 ; Aynalem et al, 2020 ; Boskabadi et al, 2020 ; West and Josiah, 2020 ; Bogale et al, 2021 ; Karasneh et al, 2021 ; Wongnate, 2021 ). Acute bilirubin encephalopathy (kernicterus) is a major complications of hyperbilirubinemia, which can cause a spectrum of neurologic problems ( Aynalem et al, 2020 ). Surviving neonates may have long-term neurodevelopmental deficits, such as cerebral palsy, sensorineural hearing loss, intellectual difficulties and gross developmental delays ( Aynalem et al, 2020 ).

The prevalence of neonatal jaundice in high-income countries is low, affecting approximately 4.4 per 10 000 live births in America and 3.2 in Europe ( Slusher et al, 2017 ). In low- and middle-income countries, the prevalence is significantly higher; at 31.6% in Ethiopia ( Bogale et al, 2021 ), 35.9% in Nigeria ( Olatubi et al, 2019 ), 44.4% in Rwanda ( Murekatete et al, 2020 ), 55.2% in South Africa ( Brits et al, 2018 ) and 63% in South Asian countries, such as Malaysia ( Awang et al, 2020 ).

Little is known about the prevalence of neonatal jaundice in the Arab world. To the best of the authors' knowledge, only four published studies have been conducted on the prevalence of neonatal jaundice in the Middle Eastern region. These studies indicated higher prevalence rates than in high-income countries. The prevalence of neonatal jaundice in Iraq was 13.5%, with ABO incompatibility and Rh incompatibility identified as major risk factors (Sadeq et al, 2015). Another study from Iraq reported a 17.3% prevalence, and found that male neonates were at increased risk of developing neonatal jaundice than females ( Abbas et al, 2020 ). In Egypt the prevalence of neonatal jaundice was 45.6%, with ABO incompatibility, Rh incompatibility and G6PD found to be the leading causes of hyperbilirubinemia ( Abd Elmoktader et al, 2019 ). A case-control study in Gaza highlighted breastfeeding as a risk factor for the development of neonatal jaundice in comparison to bottlefeeding, but this may be because 74.7% of the case group were breastfeeding ( Abu Mostafa et al, 2017 ). Despite these findings, there is a lack of research on the association between maternal/neonatal factors and neonatal jaundice.

In Jordan, there has been no specific investigation of the prevalence and factors associated with the development of neonatal jaundice. There is also an absence of national guidelines for the evaluation and management of jaundice. Khasawneh et al (2013 ; 2020 ) determined that Jordanian doctors did not adhere to the American Academy of Pediatrics Guidelines (2004) when managing neonatal jaundice. More recently, an investigation of the clinical profile of neonatal admissions found that 10.7% were related to hyperbilirubinemia ( Khasawneh et al, 2020 ).

This study is intended to provide a baseline for determining the prevalence and correlated factors of neonatal jaundice, which can help healthcare providers develop appropriate management strategies. Therefore, the study aimed to investigate the prevalence of neonatal jaundice in Jordan, and the maternal and neonatal factors associated with its development.

A hospital-based unmatched case-control study design was used. A case-control design has many benefits, including that less time is required to conduct the study than is needed for a cohort study; this is because the condition has already occurred, which allows researchers to consider multiple risk factors simultaneously, and is useful in a preliminary study to establish an association.

For the purposes of this study, a case was defined as any neonate (term or preterm) admitted to the neonatal intensive care unit of one of the two selected hospitals and diagnosed as having jaundice by a pediatrician/physician, with a total serum bilirubin ≥5mg/dl as shown by laboratory test. A control was defined as any neonate (term or preterm) admitted to a neonatal intensive care unit with total serum bilirubin <5mg/dl and with no sign and symptoms of jaundice or liver disease. The two hospitals were purposively selected for the study, as they included neonatal intensive care units.

Based on a literature review, it was assumed that 33% of admissions to the neonatal intensive care units would have primary jaundice and there was a finite population size of 1000, according to the admission rates at the selected hospitals from 2020. The sample size was calculated using an online calculator ( Calculator.net, 2024 ) with a confidence level of 95% and a margin of error of 5%, yielding a sample size of 254 neonates. To account for non-response and incomplete records, the sample size was adjusted to approximately 300, to be split between 100 neonates admitted with jaundice as the primary cause (cases) and 200 neonates admitted for causes other than jaundice (controls).

As identifying matched control groups is time-consuming ( Shukla and Agarwal, 2016 ), convenience sampling was used. Consenting mothers who were Jordanian and could speak and read Arabic were included in the study. Neonates whose mothers did not consent or were diagnosed with liver problems were excluded from the study. Neonates with no laboratory proof of their total serum bilirubin level were also excluded.

Recruitment

Recruitment was conducted in the neonatal intensive care units of two government hospitals in the north of Jordan: the Princess Badeah Teaching Hospital and the Al-Mafraq Obstetrics and Gynecology Hospital. Confirmed cases of jaundice and control cases admitted between January and July 2021 were identified. Mothers were approached by a member of the team about the study when they came to visit their baby in the neonatal intensive care unit. Of the 810 mothers contacted, 362 met the inclusion criteria and were included in the study. A total of 50 mothers were excluded for missing data in medical records (n=13), withdrawal (n=22), and no response (n=15). The final sample of 312 consisted of 106 neonates who had developed jaundice (and their mothers, referred to as cases) and 206 neonates who had not developed jaundice (and their mothers, referred to as controls) giving a sample of 312 neonates (including both term and preterm neonates) and their mothers.

Data collection

Data were collected by reviewing the medical records of both neonates and their mothers. Identified mothers were interviewed using a structured questionnaire to validate the data from the medical records and collect any data not available in the record. The questionnaire was developed by the researchers based on the literature topic ( Mullany et al, 2010 ; Onyearugha et al, 2011 ; Israel-Aina and Omoigberale, 2012 ; Bhutani et al, 2013 ). The first section of the questionnaire gathered sought maternal sociodemographic characteristics. The second section collected neonatal data. The third and final section collected etiological factors.

The lead researcher met with the directors of participating hospitals and the chairperson of the neonatal intensive care unit to explain the purpose of the study and data collection. Participant mothers were interviewed by phone at a convenient time of their choice. All women were interviewed in their native language (Arabic) by research assistants who were trained in conducting interviews.

Data analysis

Data were analysed using the Statistical Package of Social Science (version 25). Frequencies means and standard deviations were calculated for demographic variables. Pearson's chi-square test was performed to determine associations between risk factors and neonatal jaundice. Multiple logistic regression analysis was performed to determine the odds ratios of risk factors that were significantly associated with neonatal jaundice. Multiple logistic regression analysis was performed to identify predictors of neonatal jaundice and establish the existence of specific differences among selected risk factors (independent factors). An alpha level of 0.05 was used for all statistical tests.

Ethical considerations

Ethical approval was obtained from the Institutional Review Board of Jordan University of Science and Technology (approval number: #724-2020) and from the Ministry of Health in Jordan. Mothers of eligible neonates who consented to participate were notified of confidentiality and their right to refuse participation, withdraw from the study at any time without explanation, not answer any questions and ask questions or clarifications at any time. Oral and written informed consent was obtained from the mothers. All communication was in Arabic.

Maternal demographic characteristics are shown in Table 1 . The largest proportion of participant mothers (38.5%) were 25–35 years old. Around one-third (35.9%) had completed high school, while 8.7% were illiterate. More than half were employed (54.5%). The largest proportion of mothers were in blood group A (28.8%), just over half (51.9%) had a vaginal birth and less than half (43.3%) had never had a baby who was jaundiced.

The demographic characteristics of the neonates are shown in Table 2 . More than half (57.4%) were preterm and the largest proportion (45.8%) had a birth weight of 2.5–4kg. Approximately half (53.8%) were female. One-third of neonates (30.8%) were in blood group B, more than half of the neonates (53.5%) were breastfeeding and nearly two-thirds (62.2%) were suckling properly. Mothers reported that 105 neonates (33.7%) had <5 feeds per day. A small proportion of neonates had possible ABO blood incompatibility (10.6%), Rhesus incompatibility (6.7%) or G6PD (4.8%).

Prevalence of neonatal jaundice

Of the 810 admissions to the neonatal intensive care unit during the data collection period (6 months), 170 (20.9%) were for jaundice. The time of onset varied, with 72.6% developing jaundice 24 hours after birth, and neonates had a mean total serum bilirubin of 18.06mg/dl (±3.81mg/dl). Less than a third (27.4%) developed jaundice within 24 hours of birth, with a mean total serum bilirubin of 14.44mg/dl (±4.00mg/dl). Almost half (49.1%) had severe jaundice, with a mean total serum bilirubin of 18.8mg/dl (±2.0mg/dl). Table 3 summarises the prevalence of different types and severity of jaundice among the cases.

Factors associated with neonatal jaundice

Pearson's chi-square test showed significant associations between total serum bilirubin and five maternal variables: age (P=0.03), education (P=0.001), occupation (P=0.002), mode of birth (P=0.001) and history of a baby with jaundice (P=0.009) ( Table 4 ). There were also significant associations with six neonatal variables: gestational age (P=0.001), birth weight(P=0.001), sex (P=0.004), blood group (P=0.028), number of daily feeds (P=0.002) and potential ABO incompatibility (P=0.002) ( Table 5 ).

Maternal and neonatal factors associated with total serum bilirubin were entered into multiple logistic regression ( Table 6 ). Of the maternal factors, only education, occupation and mode of birth were significantly associated with jaundice. Lower education (P=0.001), being employed (P=0.001) and having a caesarean section (P=0.003) increased the odds of developing jaundice. Among the neonatal factors, gestational age, number of feeds per day and ABO incompatibility were significantly related to jaundice. Preterm neonates (P=0.02), those who had fewer feeds per day (P<0.001) and those who were ABO incompatible (P=0.01) were more likely to develop jaundice.

This mismatched case-control study to examine factors associated with neonatal jaundice is the first targeted study of neonatal jaundice in Jordan, to the authors' knowledge. The prevalence of neonatal jaundice was 20.9%, which is consistent with rates reported in China (20.3%) and Uganda (22.7%) (Awang et al, 2019; Nyangabyaki-Twesigye et al, 2020 ). The prevalence was lower than some other low- and middle-income countries, such as Africa, Nepal, India, South Asia and Egypt, where the prevalence of neonatal jaundice is repotedly between 31% and 67% ( Brits et al, 2018 ; Abd Elmoktader et al, 2019 ; Awang et al, 2019; Olatubi et al, 2019 ; Oppong et al, 2019 ; Bogale et al, 2021 ). Lower rates have been reported in Iraq (13.5%) ( Sadeq et al, 2019 ), Ethiopia (13.3%) ( Haile, 2020 ), Indonesia (4.1%) ( Yahya et al, 2017 ) and Turkey (3.6%) (Bozkurt et al, 2019). These differences may be the result of variations in study design, setting, time and method of data collection. However, they may also be the result of differences in socio-cultural and economic conditions, level of obstetrics care, and gestational age ( Tender, 2018 ).

Several demographic and birth-related variables were associated with the development of neonatal jaundice. Neonates of educated mothers were at higher risk of developing jaundice than babies of less educated mothers. This is consistent with previous studies, which have reported that neonates of educated mothers are at increased risk of jaundice ( Aiswarya and Sajeeth, 2016 ). Women with higher education are more likely to be employed, which was also significantly linked with increased risk of jaundice in both the present study and in the wider literature ( Aiswarya and Sajeeth, 2016 ; Adoba et al, 2018 ; Tender, 2018 ).

Higher education and employment can impact infant feeding, and number of feeds was significantly associated with neonatal jaundice both in the present study and in the literature ( Adoba et al, 2018 ; Alkhaldi et al, 2023 ). These women may prefer an infant feeding method and schedule that will not restrict their daily activities ( Alkhaldi et al, 2023 ). This may be linked to a preference for formula feeding, although feeding method was not significantly associated with jaundice. However, breastfeeding promotion programmes and initiatives that educate women on the role of breastfeeding may be beneficial.

Mode of birth was linked with the development of neonatal jaundice, with caesarean section increasing the risk of jaundice. This is similar to studies in Malaysia and South Africa, where babies born via a caesarean section were at increased risk of jaundice than those born via vaginal birth ( Budi Wijaya, 2017 ; Awang et al, 2019; Murekatete et al, 2020 ). This may be related to the anesthesia used during caesarean section (isoflurane and bupivacaine), which could increase bilirubin levels in neonates ( Budi Wijaya, 2017 ). In addition, mothers who gave birth via caesarean section are more likely to experience breastfeeding problems ( Li et al, 2021 ), which, as explained above, can be linked with higher risk of jaundice.

In the present study, prematurity was significantly associated with the development of neonatal jaundice. A preterm neonate (born before 37 weeks' gestation) may not be capable of eliminating bilirubin as rapidly as full-term babies, who have a more mature liver ( Jena and Dash, 2018 ). This is consistent with most previous studies, which emphasised the risks associated with prematurity ( Devi and Vijaykumar, 2017 ; Oppong et al, 2019 ; Boskabadi et al, 2020 ; Murekatete et al, 2020 ; West and Josiah, 2020 ; Acharya and Paneru, 2021 ; Wongnate, 2021 ). Although one study from Ghana reported that prematurity was not a significant factor in the development of neonatal jaundice, only a small proportion of their sample were preterm babies ( Tender, 2018 ).

While it is known that ABO incompatibility can result in neonatal jaundice ( Abd Elmoktader et al, 2019 ; Lake et al, 2019 ; Sadeq et al, 2019 ; Boskabadi et al, 2020 ; Murekatete et al, 2020 ; West and Josiah, 2020 ; Bogale et al, 2021 ; Faustina et al, 2021 ; Wongnate, 2021 ), the findings from this study demonstrated that neonates with ABO blood incompatibility were over three times as likely to develop neonatal jaundice. ABO incompatibility leads to hemolysis disorder (destruction of red blood cells), increasing the level of bilirubin in the blood ( Ricci et al, 2021 ).

Fewer daily feeds increased the odds of developing jaundice. This is may be because a reduction in the volume and frequency of feeding can hinder defecation and the removal of bilirubin through the bowels ( Neal-Kluever et al, 2018 ). Similarly, frequent feeding prevents dehydration and facilitates frequent urination ( Neal-Kluever et al, 2018 ). Several other studies have also reported that decreased frequency of feeding and feeding problems increase the risk for neonatal jaundice ( Hassan and Zakerihamidi, 2017 ; Seyedi et al, 2019 ; Haile, 2020 ).

Limitations

This study had several limitations, including using a mismatched case-control design and selection bias, which limited the researchers' ability to identify the temporal relationship between various risk factors and neonatal jaundice. In addition, this study was conducted in one region, and more studies are needed in different settings to confirm the findings.

Implications for practice

To improve neonatal survival and reduce severe morbidities, early identification of risk factors for jaundice is vital, so that appropriate interventions can be implemented. It is essential to integrate accurate assessment as part of routine care for mother and neonate, in order to decrease the prevalence of this disorder, which is considered a neglected element of clinical practice in Jordan ( Al-Lawama et al, 2018 ). Healthcare providers need education and training on the prevalence, risk factors and negative effects of jaundice for mothers, infants and families as a whole.

Raising awareness among mothers by conducting antenatal education is recommended, particularly for high-risk mothers. In Jordan, there is no national practice guideline for the assessment and management of neonatal jaundice. Decision-makers should work to establish a national guideline to screen high-risk neonates for jaundice and follow up with them during the postnatal period. Using evidence-based guidelines for the assessment and management of risk factors of jaundice helps to reduce the prevalence of jaundice among neonates ( Al-Lawama et al, 2018 ). Addressing neonatal jaundice is also likely to reduce length of stay in intensive care, additionally reducing financial strains on the family and healthcare institutions.

The present study showed significant associations between a mother's education and occupation, mode of childbirth, prematurity, ABO incompatibility, reduced feeding, and the development of jaundice among neonates in northern Jordan. Identifying these factors will allow neonatal nurses to educate parents in an effort to prevent jaundice. Further research on management of jaundice and development of national guidelines may also allow healthcare providers address the issue. Preventing prematurity and low birth weight in babies also will be beneficial.

• Neonatal jaundice is a common cause of neonatal morbidity.
• Identifying at-risk factors will allow prevention and lessen length of hospital stay for the neonates.
• It is essential to integrate accurate assessment as a part of routine care provided to the mother and her neonate to decrease the prevalence of this disorder.
• Using evidence-based guidelines for the assessment and management of risk factors of jaundice helps in reducing the prevalence of jaundice among neonates.

CASE STUDY INVESTIGATION | The Effect of Neonatal Jaundice on Infants’ Auditory Mechanism in Nigeria

Audiology today.

• Hearing Loss
• Audiologists
• New Professionals

By Irene Okeke

This article is a part of the July/August 2017, Volume 29, Number 4, Audiology Today issue .

Jaundice is a common condition that requires medical attention in newborns worldwide. The yellow coloration of the skin and sclera in newborns with jaundice is the result of accumulation of unconjugated bilirubin. In many infants, unconjugated hyperbilirubinemia reflects a normal transitional phenomenon. In some cases, however, serum bilirubin levels may rise excessively, which can be cause for concern because unconjugated bilirubin is neurotoxic and can cause death in newborns, and lifelong neurologic sequelae in infants who survive—including hearing loss (Christensen and Yaish, 2015).

This issue of CSI examined the prevalence of neonatal jaundice in Nigeria, where it is a major cause of hearing loss for a long period of time. Audiological data collected from the International Hearing Center (the Center) over a period of 15 years shows that 265 patients with different degree of hearing loss were affected by neonatal jaundice

Biochemically, hyperbilirubinamia is the major cause of neonatal jaundice, but it could be mitigated by the use of some drugs (phenobarbitols, dexamethasone, and clofibrates) that causes the production of uridine diphospate glucoronyl transferase (UDPGT), an enzyme that helps to convert the bilirubin to water soluble bilirubin (conjugated bilirubin). This is because if unconjugated bilirubin is not converted, it could pass through the brain barrier membrane and cause neurotoxicity which results in auditory nerve damage thereby giving rise to hearing loss. Instead of these drugs, patients are normally given antibiotics that have little or no action on the enzyme UDPGT conversion of unconjugated bilirubin to conjugated water soluble bilirubin.

Introduction

Jaundice in infants is caused by the accumulation of unconjugated bilirubin. This normally reflects as the yellow coloration of the skin and sclera in newborns. Unconjugated bilirubin is neurotoxic and can lead to death in newborns or lifelong neurologic sequelae. Neonatal physiologic jaundice results from simultaneous occurrence of the following two phenomena:

Bilirubin production is elevated because of increased breakdown of fetal erythrocytes. This is the result of the shortened lifespan of fetal erythrocytes and the higher erythrocyte mass in neonates.

Hepatic excretory capacity is low both because of low concentrations of the binding protein ligandin in the hepatocytes and because of low activity of glucuronyl transferase, the enzyme responsible for binding bilirubin to glucuronic acid, thus making bilirubin water soluble (conjugation).

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• Open access
• Published: 24 March 2022

Maternal disease factors associated with neonatal jaundice: a case–control study

• Youngjae Yu 1 , 2   na1 ,
• Jinwha Choi 3   na1 ,
• Myeong Hoon Lee 1 , 2 ,
• KangHyun Kim 1 , 2 ,
• Hyun Mee Ryu 4 &
• Hyun Wook Han 1 , 2  

BMC Pregnancy and Childbirth volume  22 , Article number:  247 ( 2022 ) Cite this article

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Metrics details

Neonatal jaundice is common, and despite the considerable medical costs associated with it, there are still few studies on the maternal factors associated with it. Identification of maternal factors associated with neonatal jaundice is very important in terms of prevention, screening and management of neonatal jaundice. The current study aimed to identify maternal disease factors associated with neonatal jaundice.

We compared the maternal disease diagnostic codes during pregnancy (study A) and 1 year before conception (study B) in mothers whose insurance claims data included newborns treated for neonatal jaundice before birth registration via the National Health Insurance Service–National Sample Cohort (control group). To decrease the effect of confounding variables, the neonatal jaundice and control groups were matched at a ratio of 1:10 via propensity score matching using covariates including age and income.

The matched samples for studies A and B included 4,026 and 3,278 (jaundice group: 366 and 298) delivery cases, respectively. In both studies, the jaundice group had a higher proportion of patients who underwent cesarean section than the control group. In study A, other diseases of the digestive system had the highest odds ratio (OR) (K92; adjusted OR: 14.12, 95% confidence interval [CI]: 2.70–82.26). Meanwhile, gastritis and duodenitis had the lowest OR (K29; adjusted OR: 0.39, 95% CI: 0.22–0.69). In study B, salpingitis and oophoritis had the highest OR (N70; adjusted OR: 3.33, 95% CI: 1.59–6.94). Heartburn had the lowest OR (R12; adjusted OR: 0.29, 95% CI:0.12–0.71).

Conclusions

This study identified maternal disease factors correlated with neonatal jaundice during pregnancy and 1 year before conception. Maternal risk factors for neonatal jaundice included syphilis and leiomyoma during pregnancy, and salpingo-oophoritis before pregnancy. The protective factors included infection, inflammatory diseases, and dyspepsia.

Peer Review reports

Backgrounds

Neonatal jaundice is a common disease [ 1 ]. In Korea, it is the most common cause of admission among newborns [ 2 ], and medical expenses correlated with jaundice exceeded $10 million in 2012 [ 3 ]. Moreover, it still poses global burden particularly in low- and middle-income countries where the immediate assessment of serum bilirubin concentration is challenging and treatment is often delayed [ 4 , 5 ]. Moreover, recent studies have reported that neonatal jaundice may be a risk factor for pediatric diseases such as asthma [ 6 , 7 ], autism spectrum disorders [ 8 , 9 ], attention deficit hyperactivity disorder (ADHD) [ 10 ], and epilepsy [ 11 ]. Therefore, identifying maternal risk factors for neonatal jaundice is important in providing cost-effective healthcare expenditure and predicting jaundice-associated diseases.

However, recent studies have not assessed these factors and only a few predisposing factors, including maternal age, race, primiparity, teenage pregnancy, diabetes mellitus, Rh incompatibility, ABO incompatibility, oxytocin use during labor, and breastfeeding, were identified [ 4 , 12 ]. These factors were demographic or pregnancy-related, and there has been no study to identify risk factors for neonatal jaundice related to the mother's own disease.

Many studies so far were cross-sectional studies [ 13 , 14 ], and nation-wide study focused on neonatal jaundice requiring the treatment in clinical situation has not been done well. In Korea, all citizens are covered by the National Health Insurance [ 15 ], and a database for claims data has been established [ 16 ]. Moreover, the antenatal care (ANC) coverage of married women approaches about 100%, and the average number of antenatal care visits is over 13 times [ 17 ]. Based on the high ANC coverage and the longitudinal data on individuals, the study on the gestation or antenatal period can be conducted appropriately. Hence, the current study aimed to analyze the maternal disease risk factors for neonatal jaundice during pregnancy and 1 year before conception using data from the National Health Insurance claims database.

Data source and variables

The National Health Insurance Service–National Sample Cohort (NHIS-NSC) established by the National Health Insurance Service in South Korea was used [ 16 ]. This database (DB) is a representative sample that randomly selected 1 million people, accounting for about 2.2% of the Korean population in 2002. Moreover, it contains sample data obtained from 2002 to 2013 [ 18 ]. In this study, the qualification DB and treatment DB of the NHIS-NSC were used. Five variables of the qualification DB (patient ID, sex, year, age, and income rank), five variables of statement data (patient ID, claim number, visit date, principal diagnosis, and additional diagnosis), and three variables of type of disease data (claim number, visit date, and diagnosis) in the treatment DB were utilized. Age is divided into 19 groups from 0 to 85 years old at 5-year intervals (age 0, 1–4, 5–9, …, and over 84). As the age of participants considered in this study was 15–49 years old, it was regrouped subsequently into three groups with ages 15–24, 25–34, and 35–49. The income rank is divided into 11 groups at deciles with medical aid beneficiaries, and it was regrouped into 5 groups at 20% intervals. Variables about diagnosis were distinguished using the Korean Standard Classification of Diseases, version 6 (KCD-6), which is the Korean modified version of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10).

All methods were carried out in accordance with relevant guidelines and regulations.

Data preprocessing and case selection

The principal diagnosis and additional diagnosis of statement data were integrated into one diagnostic variable and were then merged with the type of disease data according to claim number. Based on the merged diagnosis data, details regarding delivery and age of the participants (15–49 years old) at the year of delivery date were extracted. Then, the pregnancy records of patients who had data about delivery were collected. In cases in which treatment for neonatal jaundice were provided before birth registration, when insurance claims were made by the mother, the diagnosis of neonatal jaundice is included in the mother’s record. Hence, these cases were included in the jaundice group. Cases with diagnostic codes correlated with neonatal jaundice within 4 weeks after the delivery date were included in the jaundice group. Meanwhile, the control group included cases in which the diagnosis of neonatal jaundice was not attached to the mother.

In this study, KCD-6 codes related to delivery [ 19 , 20 , 21 ], pregnancy [ 19 , 22 , 23 ] and neonatal jaundice were selected to identify each event. Preterm delivery and multiple gestation were defined as at least one record of the related codes within 4 weeks before and after the delivery date.

As the NHIS-NSC included a sample established from the claims data, but not designed for the study, the diagnoses entered in the records did not always indicate new-onset diseases. The same diagnosis codes might have been recorded repeatedly. In such a case, it was counted as one. If the same person delivered several times, each delivery was considered an independent case. The minimum interval from delivery to diagnosis of the next pregnancy was 4 weeks. Considering that periviable birth is defined as delivery during at least 20 weeks of gestation [ 24 ], the minimum interval from the previous to the next delivery was 24 weeks. The maximum duration from the diagnosis of pregnancy to delivery was 44 weeks [ 25 ]. After cross-joining pregnancy and delivery records, the joint records were listed chronologically. The date of pregnancy diagnosis was defined as the visit date of the first pregnancy record among all pregnancy records. Cases with diagnostic codes related to abortion (O00-O08, pregnancy with abortive outcome) [ 22 , 23 , 26 ] or stillbirths (O36.4, maternal care for intrauterine death; Z37.1, single stillbirth; Z37.4, twins, both stillborn; and Z37.7, other multiple births, all stillborn) [ 19 , 22 , 26 ] up to 4 weeks after the delivery date were excluded. Deliveries assigned with codes including O82 and O84.2 (multiple delivery, all via cesarean section) were considered as cesarean section. Further, deliveries assigned with codes such as O80, O81, O83, and O84.0 (multiple delivery, all spontaneous) and O84.1 (multiple delivery, all using forceps and vacuum extractor) were considered as vaginal. If the two types of delivery were present, cesarean section (O82, O84.2) was prioritized. Cases in which the type of delivery was not identified were excluded.

In this study, two studies, study A and B, were conducted. One was about diseases during ANC (study A), and the second was about diseases 1 year before ANC (study B). In study A, claims data from each pregnancy diagnosis date to day 1 before the delivery date were extracted. Cases that had no record in the ANC period, other than diagnostic codes correlated with pregnancy, were excluded to identify possible maternal risk factors. In study B, claims data from 1 year before each pregnancy diagnosis date to day 1 before the pregnancy diagnosis date were extracted. In the analyses of both two studies, the only first three characters of the diagnosis codes were used.

Statistical analysis

The two-sided Fisher’s exact test with 95% CI for the categorical variables was performed. The t -test was used to assess continuous variables. To decrease the effect of confounding variables, the jaundice and control groups were matched at a ratio of 1:10 via propensity score matching (PSM) with nearest neighbor matching. Age at the time of delivery and income at the time of pregnancy diagnosis were considered covariates. MatchIt package [ 27 ] was used to perform PSM. The results obtained by repeating PSM 1,000 times by randomly shuffling the order of records were used for the analysis of matched samples. The average number of cases, odds ratio, and p -value were calculated only for significant findings from the 1,000 results obtained using PSM. If the odds ratio was infinite, it was excluded from the average. Diseases that have more than 900 significant results, with a mean odds ratio of > 1 and a mean p -value of < 0.05, were considered a risk factor. Moreover, those with a mean odds ratio of < 1 and a mean p -value of < 0.05 were considered a protective factor. Conditional logistic regression analyses, adjusted for preterm delivery, delivery mode, multiple gestation and ANC duration, were performed for the diseases which have more than 900 significant results in the univariable analyses. Survival package [ 28 ] was used to perform conditional logistic regression analyses.

Results with a lower bound of > 1 or an upper bound of < 1 and a p -value of < 0.05 were considered significant. igraph package [ 29 ] was used to make a network image for the identified risk/protective factors. R (version 3.6.2) [ 30 ] was used in all analyses.

Demographic characteristics of the participants

Figure  1 shows the flowchart of the case selection process. 555,474 of 560,645 women, included in NHIS-NSC from 2002 to 2013, had significant claims data about diagnoses. 67,967 of those 555,474 women had claims data related to diagnosis of delivery and were 15 to 49 years old at the time of the delivery. 65,442 participants of them, who had delivery records, had claims data related to the diagnosis of pregnancy. With pairing the delivery and pregnancy records, 91,477 delivery cases (64,723 women), satisfied with the time intervals which were defined as inclusion criteria in this study, were identified. 116 cases of 91,477 delivery cases were excluded as the delivery modes were not identified, and 131 cases of abortion or stillbirth were excluded subsequently. The participants with several delivery cases were included in each step unless all cases were excluded. Among 91,230 delivery cases, 5,111 cases incomplete on qualification DB around the gestation period and 7,800 cases that had no diagnosis records except pregnancy or delivery during ANC were excluded to consist of the sample for study A. For study B, 12,691 incomplete cases and 4,418 cases with no diagnosis records during ANC were excluded.

Flowchart of the inclusion and exclusion process. ANC, antenatal care; PSM, propensity score matching

The sample in study A included 78,319 cases ( n  = 57,718). Among them, 366 cases ( n  = 364) were included in the jaundice group and 77,953 cases ( n  = 57,517) in the control group. The sample in study B had 74,121 cases ( n  = 54,787). Among them, 298 cases ( n  = 296) were included in the jaundice group and 73,823 cases ( n  = 54,620) in the control group. The n value indicated the number of mothers, not delivery cases. If a mother has delivered several times, it can be included in both the jaundice and control groups. Thus, the total number of patients in the jaundice and control groups did not correspond to the total population. The jaundice group accounted for 0.47% (366 in 78,319 cases) and 0.40% (298 in 74,121 cases) of all delivery cases in studies A and B, respectively. There was a significant difference in terms of income at the time of pregnancy diagnosis, multiple gestation, and ANC duration between the two groups in study A, but not in study B. However, the Cochran–Armitage trend test result (chi-square test for trend in proportion) for income was significant in studies A and B ( p -value = 0.002 and 0.010, respectively). There was a significant difference in the mode of delivery between the two groups in studies A and B (Table 1 ).

The matched sample for study A had 4,026 cases (jaundice group: 366, control group: 3,660), and that for study B had 3,278 cases (jaundice group: 298, control group: 2,980). All the 1,000 matched samples significantly differed in terms of the type of delivery in both two studies (Table 2 ). There was also a significant difference in ANC duration in all the 1,000 matched samples of study A.

Odds ratios for each diagnosis code in the unmatched samples

Tables 3 and 4 show the unadjusted odds ratios for neonatal jaundice according to disease that showed significant results in unmatched samples for studies A and B, respectively.

In study A, obstetrical tetanus (A34) had the largest OR (212.33, 95% CI: 2.71–14,121.54). Fever of other and unknown origin (R50) had the lowest OR (0.23, 95% CI: 0.03–0.84).

In study B, polyarteritis nodosa and related conditions (M30) had the largest OR (95% CI: 6.35-infinite). However, there was only case in the jaundice group. Pain associated with micturition (R30) had the lowest OR (0, 95% CI: 0–0.92).

Acute bronchitis (J20), vasomotor and allergic rhinitis (J30), gastritis and duodenitis (K29), dyspepsia (K30), and alopecia areata (L63) showed significance in the unmatched samples of the two studies. Among them, the OR of alopecia areata (L63) was > 1.

Risk and protective factors in the matched samples

For diseases that showed significance more than 900 times in 1000 times of PSM, the average number of cases and average odds ratio are depicted in Fig.  2 (network image) and Table 5 . Adjusted ORs were calculated for the diseases which have more than 900 significant results in the univariable analyses, as the primary outcome of this study.

Disease network image about maternal risk factors and protective factors for neonatal jaundice . A Maternal diseases during ANC associated with neonatal jaundice (Study A). B Maternal diseases during 1 year before ANC associated with neonatal jaundice (Study B). C Index. Risk factors are illustrated as red lines and protective factors as blue lines. The average odds ratio is represented by number on the line and the average number of cases as the number in the circle. The major classification of diagnosis codes is represented in a different color. The circle size is proportional to the number of cases. The edge width is proportional to the odds ratio in the case of risk factors and inversely proportional to the odds ratio in the case of protective factors. ANC, antenatal care; A53, other and unspecified syphilis; D25, leiomyoma of the uterus; D62, acute posthemorrhagic anemia; J03, acute tonsillitis; J20, acute bronchitis; J30, vasomotor and allergic rhinitis; J34, other disorders of the nose and nasal sinuses; K29, gastritis and duodenitis; K30, dyspepsia; K92, other diseases of the digestive system; N70, salpingitis and oophoritis; R12, heartburn; Z48, other surgical follow-up care. * K92, 7.89; † Z48, 15.82

In study A, among the probable risk factors, the disease with the highest OR was other diseases of digestive system (K92; adjusted OR: 14.12, 95% CI: 2.70–82.26), which was present in 0.20% of all matched cases, and the incidence of leiomyoma of the uterus was the highest (D25; adjusted OR: 3.22, 95% CI: 1.59–6.52), accounting for 1.14% of all matched cases. Among the probable protective factors, gastritis and duodenitis had the lowest OR (K29; adjusted OR: 0.39, 95% CI: 0.22–0.69), accounting for 8.43% of all matched cases, and the incidence of vasomotor and allergic rhinitis was the highest (J30; adjusted OR: 0.58, 95% CI: 0.37–0.92), which accounted for 9.46% of all matched cases (Fig.  2 a).

In study B, the possible risk factor was salpingitis and oophoritis (N70; adjusted OR: 3.33, 95% CI: 1.59–6.94), which accounted for 1.26% of all matched cases. Among the probable protective factors, heartburn had lowest OR (R12; adjusted OR: 0.29, 95% CI: 0.12–0.71), which accounted for 5.29% of all cases, and the incidence of gastritis and duodenitis (K29; adjusted OR: 0.75, 95% CI: 0.58–0.95) was the highest, which accounted for 44.15% of all cases (Fig.  2 b).

There was no common risk factor in both studies. However, the common protective factors included vasomotor and allergic rhinitis (J30) and gastritis and duodenitis (K29).

Many diseases were identified as significant disease factors from unmatched samples in Table 3 and 4 . Because these results were obtained from the unmatched samples, bias should be considered to interpret results. However, diseases with a genetic factor, such as disorders of glycoprotein metabolism from the unmatched sample of study B, may be attributed to the low incidence of these diseases. Therefore, these rare diseases are needed to be verified in a larger population. Meanwhile, some diseases identified from unmatched samples showed significance in hundreds of matched samples, but less than 900. These were not considered as risk factors in this study but may have a weak association with neonatal jaundice. For example, among the disease with OR > 1, alopecia areata showed significance in more than 700 matched samples of study B, which indicates that it may be a maternal risk factor before ANC. In previous studies, alopecia areata was associated with oxidative stress [ 31 , 32 ]. A decrease in oxidative stress is associated with low serum bilirubin levels [ 33 , 34 ].

The risk factors for neonatal jaundice included syphilis, surgical follow-up care, leiomyoma of uterus, and other diseases of the digestive system during ANC. Based on previous studies [ 35 , 36 ], congenital syphilis increases the risk of neonatal jaundice. According to the significant results of surgical follow-up during pregnancy, the type, purpose, and timing of surgery should be identified to explain the relationship between surgical follow-up and neonatal jaundice, which would be limitation of this study using claims data. Leiomyoma can be an extension of the association between leiomyoma as well as preterm birth and cesarean delivery [ 37 , 38 ].

Other diseases of the digestive system (K92) include hematemesis, melena, and gastrointestinal hemorrhage. However, considering the medical practice of registering a diagnosis, different diseases of the digestive system were included, and the incidence was low. Hence, the significant was low.

Most protective factors identified in study A were associated with infection and inflammation. Recent studies have shown the inverse association between bilirubin and inflammation [ 39 , 40 , 41 ]. Thus, inflammation may be associated with the low bilirubin levels, which could decrease the levels of unconjugated bilirubin transferred to neonates.

The pre-pregnancy maternal disease associated with neonatal jaundice was salpingo-oophoritis. Gastritis, dyspepsia, and heartburn are diagnoses associated with the gastrointestinal system. Notably, the OR value for neonatal jaundice was < 1.

The proportion of neonatal jaundice to total delivery cases was 0.40%–0.47%, which was different from its known incidence (30%–80%) [ 42 , 43 , 44 , 45 , 46 ]. This finding could be attributed to the fact that this study was based on neonatal jaundice recorded in the mothers’ claims data. Although prematurity is a risk factor for neonatal jaundice, there was no significant difference in terms of its occurrence between both groups [ 4 , 12 ]. Since newborns born prematurely are admitted to the neonatal intensive care unit, the diagnosis of neonatal jaundice is rarely applied to the mother. Therefore, jaundice in premature infants may not have been well reflected in this study. Contrary to a known risk factor for neonatal jaundice, vaginal delivery was less common in the jaundice group [ 47 , 48 , 49 ]. One possible reason for that may be the differences in the gut microbiota of newborns according to the type of delivery. Infants born via cesarean section have a lower number of Bifidobacterium and Bacteroides than infants born via vaginal delivery [ 50 , 51 , 52 ]. Bacteroides reduces unconjugated bilirubin to urobilinoids [ 53 ], and an association between the decreased number of Bifidobacterium and the elevated levels of bilirubin has been reported [ 50 ]. In terms of gut microbiota, cesarean section can be a potential risk factor for neonatal jaundice. The duration of ANC in the jaundice group of study A was significantly short, thereby indicating differences in pregnancy duration or delayed pregnancy diagnosis. A previous study reported the association between the late recognition of pregnancy and adverse outcomes such as neonatal intensive care admission [ 54 ].

Identification of the maternal gestational period or pre-pregnancy disease associated with neonatal jaundice may be helpful in counseling mothers preparing for pregnancy or pregnant mothers. For mothers with risk factors, it can predict jaundice for future babies and provide useful information for things to keep in mind after birth. In addition, neonatal jaundice can be prevented through prevention and management of maternal diseases related to neonatal jaundice.

Integration with research on maternal diseases may lead to the development of prenatal care programs to prevent neonatal jaundice. Moreover, it is thought that a more detailed correlation can be derived if the study is conducted including the maternal medication (especially, folic acid and iron, which are essential to take before and during pregnancy). The possible risk factors of certain child diseases including maternal disorders must be assessed from a long-term perspective. Therefore, follow-up studies with a disease network connecting diseases (from maternal to the child disorders) must be performed to assess the association between neonatal jaundice and other pediatric and maternal diseases.

This is the first study to analyze the association between maternal disease not related to pregnancy and neonatal jaundice. Maternal risk factors suggested in this study, including syphilis, leiomyoma, and salpingo-oophoritis, are differentiated from well-known risk factors for neonatal jaundice, such as diabetes mellitus, and suggest there may be unknown pathophysiology. While machine learning-based studies on the prediction of neonatal jaundice required information of neonates such as total serum bilirubin [ 55 , 56 ], the risk factors identified from the method used in this study can be evaluated with only maternal history before pregnancy or delivery. Another strength includes a large sample size based on health insurance data that covers almost all citizens.

This study had several limitations associated with the use of claims data. The diagnostic code for insurance claims could be differ from the actual diagnosis [ 57 , 58 , 59 ]. To ensure data integrity, although mild, the study included mothers who were insured for diseases other than those associated with pregnancy and delivery. The diagnosis codes used in this study were based on KCD-6, the Korean modified version of ICD-10, and numerous medical conditions, including symptoms, are included in the codes. Therefore, statistically significant diagnosis codes about symptoms obtained in this study, such as dyspepsia and heartburn, do not represent the diagnosis of a specific disease. The details about the surgery what other surgical follow-up care referred could not be identified precisely from claims data, which was also a limitation of this study.

This study has identified that maternal risk factors for neonatal jaundice were syphilis and leiomyoma during pregnancy, and salpingo-oophoritis before pregnancy, and protective factors were infection and inflammatory diseases, and dyspepsia. This has shown significant information that can be used for risk management and the prediction and prevention of neonatal jaundice before or during pregnancy. Furthermore it is necessary to study not only maternal diseases related to neonatal jaundice, but also studies including maternal medication history and long-term prognosis.

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available due to the regulation that the National Health Insurance Service–National Sample Cohort (NHIS-NSC) data is not provided directly to researchers and can only be accessed via the NHIS analysis system.

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Acknowledgements

Not applicable.

This work was supported by grants from Institute of Information & communications Technology Planning & Evaluation (IITP) funded by the Korea government (MSIT) (No. 2019000224, Development of Information Protection Source Technology), Brain Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Science, ICT & Future Planning (No. 2019M3C7A1032262), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No.2020R1F1A1068423) and the Bio Industry Technology Development Program(No. 20015086) from the Ministry of Trade, Industry & Energy(MOTIE, Korea), Information and Communications Promotion Fund through the National IT Industry Promotion. Agency (NIPA), funded by the Ministry of Science and ICT (MSIT), Republic of Korea (No. 20002033324071212100101AU), Korea University Guro Hospital (KOREA RESEARCH-DRIVEN HOSPITAL) funded by Korea University Medicine (No. K2117371) and (HI21C1779) from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea.

Author information

Youngjae Yu and Jinwha Choi are co-first authors and contributed equally to this work.

Authors and Affiliations

Department of Biomedical Informatics, CHA University School of Medicine, CHA University, Seongnam, Korea

Youngjae Yu, Myeong Hoon Lee, KangHyun Kim & Hyun Wook Han

Institute for Biomedical Informatics, CHA University School of Medicine, CHA University, Seongnam, Republic of Korea

Department of Pediatrics, Korea University College of Medicine, Seoul, Korea

Jinwha Choi

Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea

Hyun Mee Ryu

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Contributions

YJY and JWC are co-first authors and contributed equally. They conceived and designed the study. YJY, JWC, MHL, KHK, HMR and HWH performed the data collection and curation. YJY and JWC performed data analysis. YJY and JWC conducted statistical analyses. YJY, JWC, MHL, KHK, HMR and HWH performed data interpretation and wrote the paper. All authors reviewed the final manuscript. The author(s) read and approved the final manuscript.

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Correspondence to Hyun Wook Han .

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This study was approved by the institutional review board of CHA Bundang Medical Center, CHA University (CHAMC 2021–04-049). The need for informed consent from the participants was waived by the institutional review board of CHA Bundang Medical Center, CHA University as the study used anonymized claims data.

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Yu, Y., Choi, J., Lee, M.H. et al. Maternal disease factors associated with neonatal jaundice: a case–control study. BMC Pregnancy Childbirth 22 , 247 (2022). https://doi.org/10.1186/s12884-022-04566-6

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DOI : https://doi.org/10.1186/s12884-022-04566-6

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• Maternal disease factors
• Neonatal jaundice
• Disease network
• National Health Insurance Service–National Sample Cohort

BMC Pregnancy and Childbirth

ISSN: 1471-2393

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Maternal disease factors associated with neonatal jaundice: a case-control study

Affiliations.

• 1 Department of Biomedical Informatics, CHA University School of Medicine, CHA University, Seongnam, Korea.
• 2 Institute for Biomedical Informatics, CHA University School of Medicine, CHA University, Seongnam, Republic of Korea.
• 3 Department of Pediatrics, Korea University College of Medicine, Seoul, Korea.
• 4 Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea.
• 5 Department of Biomedical Informatics, CHA University School of Medicine, CHA University, Seongnam, Korea. [email protected].
• 6 Institute for Biomedical Informatics, CHA University School of Medicine, CHA University, Seongnam, Republic of Korea. [email protected].
• PMID: 35331174
• PMCID: PMC8953140
• DOI: 10.1186/s12884-022-04566-6

Background: Neonatal jaundice is common, and despite the considerable medical costs associated with it, there are still few studies on the maternal factors associated with it. Identification of maternal factors associated with neonatal jaundice is very important in terms of prevention, screening and management of neonatal jaundice. The current study aimed to identify maternal disease factors associated with neonatal jaundice.

Methods: We compared the maternal disease diagnostic codes during pregnancy (study A) and 1 year before conception (study B) in mothers whose insurance claims data included newborns treated for neonatal jaundice before birth registration via the National Health Insurance Service-National Sample Cohort (control group). To decrease the effect of confounding variables, the neonatal jaundice and control groups were matched at a ratio of 1:10 via propensity score matching using covariates including age and income.

Results: The matched samples for studies A and B included 4,026 and 3,278 (jaundice group: 366 and 298) delivery cases, respectively. In both studies, the jaundice group had a higher proportion of patients who underwent cesarean section than the control group. In study A, other diseases of the digestive system had the highest odds ratio (OR) (K92; adjusted OR: 14.12, 95% confidence interval [CI]: 2.70-82.26). Meanwhile, gastritis and duodenitis had the lowest OR (K29; adjusted OR: 0.39, 95% CI: 0.22-0.69). In study B, salpingitis and oophoritis had the highest OR (N70; adjusted OR: 3.33, 95% CI: 1.59-6.94). Heartburn had the lowest OR (R12; adjusted OR: 0.29, 95% CI:0.12-0.71).

Conclusions: This study identified maternal disease factors correlated with neonatal jaundice during pregnancy and 1 year before conception. Maternal risk factors for neonatal jaundice included syphilis and leiomyoma during pregnancy, and salpingo-oophoritis before pregnancy. The protective factors included infection, inflammatory diseases, and dyspepsia.

Keywords: Disease network; Maternal disease factors; National Health Insurance Service–National Sample Cohort; Neonatal jaundice; Prediction; Prevention.

© 2022. The Author(s).

• Case-Control Studies
• Cesarean Section
• Cohort Studies
• Infant, Newborn
• Jaundice, Neonatal* / epidemiology
• Jaundice, Neonatal* / etiology

Children and adults are gobbling supplements. Do you know the risks?

Among some population groups, it’s not unusual to down four or more vitamins or supplements every day, new research shows.

Americans spend billions of dollars every year on dietary supplements that claim to promote almost every aspect of our health. But how much do you know about the supplements you’re taking?

A recent government study found that nearly 60 percent of adults take vitamins, minerals, fish oil, herbal capsules, melatonin, probiotics and other types of dietary supplements. While most people used just one or two supplements — multivitamins and vitamin D were the two most popular products — it was not uncommon for people to report using three, four or more supplements at a time.

Among some parts of the population, it’s not unusual to down a handful of vitamins or supplements every day. About 15 percent of adults said they used four or more dietary supplements. Among older adults, the number reporting multi-supplement use is even higher — about 25 percent of adults 60 or older use four or more. About 35 percent of children and adolescents used dietary supplements, and nearly 10 percent of children between 2 and 5 years old were given two or more dietary supplements.

Experts say that vitamin and mineral supplements are generally safe when taken in small to moderate doses, like the amounts found in a basic multivitamin. Dietary supplements can be beneficial for pregnant women and for people with nutrient deficiencies and other health conditions. A clinical trial earlier this year found that for people who are 60 and older, taking a daily multivitamin helped to slow memory loss. Other studies have found that probiotic supplements can help with gastrointestinal disorders such as irritable bowel syndrome.

But taking supplements comes with risks, and for many healthy adults, it’s not always clear from research that the benefits outweigh the risks.

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In fact, some randomized trials have found that assigning people to take supplements with large doses of beta-carotene, selenium, and vitamins A, C, and E actually increased mortality rates. Rigorous clinical trials have also failed to support the hype around vitamin D, finding that people who were assigned to take the popular supplement did not develop lower rates of cardiovascular disease, cancer or bone fractures despite widespread marketing claims to the contrary.

Supplements don’t follow the same rules as drugs

Many people assume that the Food and Drug Administration tests supplements for safety. But that’s not how it works .

“Dietary supplements enter the market before there’s any real review of them by the FDA,” said Amy B. Cadwallader, the director of regulatory and public policy development at the United States Pharmacopeia, a nonprofit organization that examines the quality of drugs, food and dietary supplements.

Under federal law, companies are allowed to operate on the honor system. The FDA’s role in regulating supplements mostly involves trying to make sure products are safe and accurately labeled after they have already entered the marketplace.

Are you getting what you paid for?

In the United States, companies sell an estimated 90,000 dietary supplements, representing a roughly $50 billion industry . As a result, some experts say, consumers who buy supplements can’t always be sure that they are getting what they paid for. Studies of melatonin , fish oil , probiotics , ginkgo biloba , and other supplements have found that the doses and compounds listed on their labels are often not what are found in their bottles.

• In one study in the journal Pediatric Research , researchers tested 16 probiotic supplements and found that only one of them contained the specific bacterial strains listed on its label.
• In another study , researchers tested 30 dietary supplements that claimed to strengthen immune health and found that 17 of the products were “misbranded.” These supplements either lacked key ingredients listed on their labels — such as vitamin B12, garlic extract, ginger root and folate — or they contained a variety of unlisted ingredients.
• One study by the FDA estimated that the agency is notified of less than 1 percent of all adverse events linked to supplement use. Another study by the federal government estimated that injuries caused by supplements are responsible for about 23,000 emergency room visits each year.

Howard Luks, an orthopedic surgeon and sports medicine specialist in New York, said he routinely encounters patients who worry about potential side effects from medications but have no problem taking 10 or 20 supplements that they heard about from health influencers on social media. He said that many people who lost trust in public health authorities during the pandemic have turned to social media influencers for health advice.

“They view supplements as being holistic, natural, and therefore not potentially harmful for them,” he said.

In one case study published in March, doctors in New Jersey described a 76-year-old woman who went to an emergency room after experiencing heart palpitations, dizziness and fainting episodes. It turned out she had been taking black cohosh, an herbal supplement often used to treat hot flashes. A few days after stopping the supplement, her heartbeat returned to normal, and her other symptoms disappeared.

In another recent case , a 47-year-old woman in Houston suffered jaundice and liver damage after taking a supplement containing a blend of probiotics and herbal extracts. The case report noted that dietary supplements account for about 20 percent of drug-induced liver injuries nationwide.

How to shop smarter for supplements

Here are some tips when buying supplements.

Look for third-party certifications: The United States Pharmacopeia, or USP, vets dietary supplements to ensure they are meeting high standards for factors such as purity and potency. USP has a voluntary program through which companies can have their supplements and facilities routinely tested and examined. Companies that meet the organizations high standards are allowed to use a black and yellow “USP Verified” logo on their products. You can find them using the product-finder search tool on USP’s website. NSF is another independent group that tests and reviews dietary supplements. You can look for the blue and white “NSF” logo on your supplements or go to the group’s website to look up products.

Do your homework. Consumerlab.com is an independent laboratory that tests dietary supplements to see if they contain the ingredients and doses listed on their labels. The company publishes reports with their findings on a wide variety of supplements, which you can access on their website for a fee.

Talk to your doctor or pharmacist . Many people don’t realize that a lot of supplements and medications use the same metabolic pathways and that they can cause dangerous side effects when you combine them, said Michael Schuh, an assistant professor of pharmacy, family medicine and palliative medicine at the Mayo Clinic in Florida.

Vitamins E and K, ginseng, ginkgo biloba, resveratrol, turmeric and CoQ10 for example can interact with blood thinning medications. Vitamin C can interact with statins, niacin, estrogen, warfarin and chemotherapy drugs. St. John’s wort can make antidepressants and birth control pills less effective.

“We see it with a lot of supplements,” Schuh said. “Even something like resveratrol from grape skins: When you take it in concentrated form, it can interact with a lot of medications.”

Do you have a question about healthy eating? Email [email protected] and we may answer your question in a future column.

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