case study on neonatal jaundice pdf

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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 Study - Nursing Assignment

Paediatrics Internship

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Neonatal jaundice.

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Last Update: February 20, 2023 .

Continuing Education Activity

Neonatal jaundice or neonatal hyperbilirubinemia results from elevated total serum bilirubin (TSB) and clinically manifests as yellowish discoloration of the skin, sclera, and mucous membrane. In most cases, it is a mild, transient, and self-limiting condition and is referred to as "physiological Jaundice." However, it is imperative to distinguish this from a more severe form called "pathological Jaundice." Failure to identify and treat this entity may result in bilirubin encephalopathy and associated neurological sequelae. This activity reviews the etiology, pathophysiology, evaluation, and management of neonatal jaundice and the role of the interprofessional team in the care of affected patients.

Identify pathological jaundice and differentiate it from physiological jaundice.
Describe various causes of neonatal jaundice.
Review evidence-based management options for neonatal jaundice.
Explain how the interprofessional team can work collaboratively to prevent the potentially profound complications of neonatal jaundice by applying knowledge about the presentation, evaluation, and management of this condition.
Introduction

Neonatal jaundice or neonatal hyperbilirubinemia results from elevated total serum bilirubin (TSB) and clinically manifests as yellowish discoloration of the skin, sclera, and mucous membrane. The term jaundice derives from the French word "jaune," which means yellow. It is the most commonly encountered medical problem in the first two weeks of life and a common cause of readmission to the hospital after birth. [1] Approximately 60% of term and 80% of preterm newborns develop clinical jaundice in the first week after birth. [2] In most cases, it is a mild, transient, and self-limiting condition and resolves without treatment referred to as "physiological jaundice." However, it is imperative to distinguish this from a more severe form called "pathological jaundice." Failure to identify and treat this entity may result in bilirubin encephalopathy and associated neurological sequelae.

Unconjugated hyperbilirubinemia (UHB) is the cause of clinical jaundice in most neonates, but some infants with jaundice have conjugated hyperbilirubinemia (CHB), which is always pathological and signifies an underlying medical or surgical cause. The etiology of pathological UHB and CHB is vast and varied. Preterm infants and those born with congenital enzyme deficiencies are particularly prone to the harmful effects of unconjugated bilirubin on the central nervous system. [3] [4] Severe hyperbilirubinemia can cause bilirubin-induced neurological dysfunction (BIND) and, if not treated adequately, may lead to acute and chronic bilirubin encephalopathy. [5] Phototherapy and exchange transfusions are the mainstay of treatment of UHB, and a subset of patients also respond to intravenous immunoglobulin (IVIG). Treatment of CHB is more complex and depends mainly on the etiology. Despite advances in care and management of hyperbilirubinemia, it remains a significant cause of morbidity and mortality. [6]

There are two distinct types of Neonatal hyperbilirubinemia.

Unconjugated Hyperbilirubinemia(UHB) or Indirect Hyperbilirubinemia

Unconjugated hyperbilirubinemia is the more common type and is either physiological or pathological. Physiological jaundice accounts for 75% of neonatal hyperbilirubinemia and results from a physiological alteration in neonatal bilirubin metabolism. Healthy adults have a normal TSB level of less than 1mg/dl in contrast to neonates, where TSB levels are physiologically higher. Even in healthy full-term newborns, there is an increased bilirubin load owing to increased red blood cells (RBC) mass and a decreased RBC lifespan. Clearance of bilirubin is also compromised due to impaired activity of uridine diphosphate glucuronosyltransferase (UGT), the enzyme needed for bilirubin conjugation. The UGT enzyme in a newborn has an activity of about 1% of the adult level. [7] Moreover, these infants also have increased enterohepatic circulation, further contributing to elevated TSB levels. Physiological jaundice typically appears after 24 hours of age, peaks at around 48-96 hours, and resolves by two to three weeks in full-term infants. [2]

Jaundice is considered pathological if it presents on the first day of life, TSB is more than the 95th centile for age based on age-specific bilirubin nomograms, levels rise by more than 5 mg/dL/day or more than 0.2 mg/dL/hour, or jaundice persists beyond 2 to 3 weeks in full-term infants. [8]

Based on the mechanism of bilirubin elevation, the etiology of unconjugated hyperbilirubinemia can be subdivided into the following three categories:

Increased Bilirubin Production

Immune-mediated hemolysis - Includes blood group incompatibilities such as ABO and Rhesus incompatibility.

Non-immune mediated hemolysis - includes RBC membrane defects like hereditary spherocytosis and elliptocytosis; RBC enzyme defects like glucose-6-phosphate dehydrogenase (G6PD) deficiency; pyruvate kinase deficiency; sequestration like cephalohematoma, subgaleal hemorrhage, Intracranial hemorrhage; polycythemia, and sepsis.

Decreased Bilirubin Clearance

Crigler-Najjar type I & II, and Gilbert syndrome.

Miscellaneous Causes

Other miscellaneous etiologies include the infant of a mother with diabetes, congenital hypothyroidism, drugs like sulfa drugs, ceftriaxone, and penicillins, Intestinal obstruction, pyloric stenosis, breast milk jaundice, breastfeeding jaundice.

Exaggerated hemolysis, either immune or non-immune mediated, is the most common cause of pathological hyperbilirubinemia in newborns. Immune-mediated hemolysis is seen with blood group incompatibility such as ABO/RH incompatibility and leads to hemolytic disease of newborns (HDN). In HDN, due to ABO incompatibility, preformed maternal anti-A and anti-B antibodies of immunoglobulin (Ig) G subclass cross the placenta and cause hemolysis and UHB in newborns with blood type A, B, or AB. Although the direct Coombs test is used to aid diagnosis, the sensitivity and positive predictive value for predicting severe UHB are low. [9] ABO incompatibility between mother and fetus exists in about 15% of pregnancies, but HDN due to ABO incompatibility is seen only in 4% of newborns with ABO incompatibility. [10]

In Rhesus (Rh) incompatibility, an Rh-negative mother who has been previously exposed to Rh-positive RBCs usually from a previous pregnancy or miscarriage, becomes sensitized and develops antibodies against Rh antigen. Initially, sensitization produces IgM antibodies that can not cross the placenta. However, during subsequent pregnancies, the antibody class switch produces IgG antibodies which can cross the placenta, causing RBC hemolysis in the fetus with Rh-positive blood. The Rh antigen is very immunogenic, and the resultant HDN is usually severe, often leading to hydrops in fetuses or severe UHB in newborns. The American College of Obstetricians and Gynecologists (ACOG) has recommended that all Rh-negative pregnant women receive anti-D immune globulin at 28 weeks of gestation and again following delivery if the infant is Rh-positive/unknown. [11]

Non-immune causes of UHB include RBC enzyme defects, RBC membrane defects, hemoglobinopathies, sepsis, sequestration, and polycythemia. The glucose-6 phosphatase dehydrogenase (G6PD) enzyme deficiency is the most common RBC enzyme defect and is transmitted as an X-linked recessive trait. G6PD protects RBCs against oxidative damage by generating NADPH (nicotinamide adenine dinucleotide phosphate hydrogenase) from NADP (nicotinamide adenine dinucleotide phosphate). When exposed to oxidant stressors like illness, certain medications, dyes, and foods like fava beans, G6PD deficient RBCs are hemolyzed, causing anemia and hyperbilirubinemia. More than 200 different types of mutations are known to cause G6PD deficiency. [12] The clinical presentation varies depending on the variant, and some newborns may develop severe hyperbilirubinemia and bilirubin encephalopathy. Pyruvate kinase deficiency(PKD) is another enzyme deficiency that causes hemolysis and may present as UHB in newborns. It is an autosomal recessive(AR) disorder caused by a defect in Adenosine triphosphate (ATP) synthesis machinery. In PKD, RBCs and, in particular, young RBCs have shortened life span resulting in anemia and UHB. [13]

UHB due to RBC membrane defects includes hereditary spherocytosis (HS) and hereditary elliptocytosis (HE). HS, also known as Minkowski Chauffard disease, is the most common RBC membrane defect caused by mutations in RBC membrane proteins. [14] Most cases are transmitted as an autosomal dominant (AD) trait and can present in the neonatal period with UHB. [15] Hereditary elliptocytosis is another type of RBC membrane defect that is mostly asymptomatic but rarely does cause UHB in the neonatal period. [16] Most cases are transmitted as AD traits caused by mutations in RBCs structural membrane protein. The elliptical-shaped RBCs in HE are trapped in the spleen leading to extravascular hemolysis and elevated TSB.

RBC sequestrations from cephalohematoma, subgaleal hemorrhage, and Intracranial hemorrhage are also important causes or risk factors for UHB in the neonatal period due to increased bilirubin load. Polycythemia is another entity associated with an increased risk of UHB in newborns. Clinical conditions associated with polycythemia are intrauterine growth restriction (IUGR), infant of diabetic mothers (IDM), large for gestational age (LGA), maternal smoking, high altitude, twin to twin transfusion, and placental transfusion (delayed cord clamping/umbilical cord milking). Studies have shown that placental transfusion reduces the incidence of postnatal anemia and leads to improved neurodevelopmental outcomes among term and preterm infants. [17] [18] This practice has gained popularity, but at the same time, it may also increase the risk of hyperbilirubinemia. [19] [20]

Indirect hyperbilirubinemia due to decreased bilirubin clearance usually results from quantitative or qualitative defects in the uridine diphosphate glucuronosyltransferase (UGT) enzyme. Gilbert syndrome, Crigler–Najjar syndrome type 1, and Crigler–Najjar syndrome type 2 are three prototype disorders resulting from an abnormality in the UGT enzyme. Gilbert syndrome is the most common of these and results from a mutation in the UGT1A1 gene resulting in decreased UGT production leading to unconjugated hyperbilirubinemia. [21] Gilbert syndrome typically presents as mild jaundice at times of stress in the absence of hemolysis or liver dysfunction. [22] Presentation in the neonatal period is rare and is usually associated with G6PD. [3] Crigler-Najjar syndrome type 1 is an AR disorder resulting from a complete absence of UGT activity. Affected patients present with severe hyperbilirubinemia in the first days of life, often leading to bilirubin encephalopathy. Patients with Crigler-Najjar syndrome type 2 retain some of the activity of UGT enzymes. As such, the TSB levels are not that high, and patients rarely develop bilirubin encephalopathy. [23]

Breast milk jaundice and breastfeeding jaundice are two other common etiologies of UHB in newborns. Breastfeeding jaundice, also known as breastfeeding failure jaundice, occurs in the first week of life and is due to inadequate intake of breast milk leading to dehydration and sometimes hypernatremia. [7] Breastfeeding failure leads to decreased intestinal motility and decreases the elimination of bilirubin in the stool or meconium. Breast milk jaundice occurs late in the first week, peaks in the second, and usually resolves by two weeks of age. It is thought to be mainly due to inhibition of the UGT enzyme by pregnanediol and deconjugation of conjugated bilirubin in the intestines by beta-glucuronidase present in breast milk. [24] [25]

Other miscellaneous causes of UHB include IDM, gastrointestinal obstruction, congenital hypothyroidism, certain medications. IDMs often have polycythemia which is mainly responsible for the increased incidence of jaundice in these infants. [26] UHB in congenital hypothyroidism is related to decreased hepatic uptake of bilirubin, impaired UGT activity, and sluggish gut motility. Gastrointestinal obstruction promotes increased bilirubin recycling by augmenting the enterohepatic circulation. When used in the neonatal period, certain medications may also worsen UHB by displacing bilirubin from albumin, affecting albumin binding. [27] Sepsis can also predispose a newborn to UHB by causing oxidative damage to RBCs, increasing bilirubin load. [28]

The majority of infants with clinical UHB have a combination of two or more factors discussed earlier. Furthermore, certain recognized risk factors predispose an infant to jaundice. These risk factors comprise prematurity, a history of jaundice in previous siblings requiring phototherapy, Asian ethnicity, male gender, and exclusive breastfeeding. [2] Lastly, UHB in premature infants presents as a special scenario. It is believed that preterm infants have an increased risk of bilirubin encephalopathy and kernicterus in addition to being at a higher of jaundice. However, at present, there is a dearth of data on the magnitude of the problem as well as consensus guidelines on the management of UHB in preterm infants. [29] [30] The TSB threshold for initiation of phototherapy and criteria for exchange transfusion is also not clear in this population. Bilirubin is an antioxidant and may have a physiological role in neonates. [31] [32] Keeping TSB levels low by aggressive treatment in preterm infants may reduce the antioxidant level and potentially worsen the retinopathy of prematurity. Reduced antioxidant status is also associated with chronic lung disease and neurological injury. As such, treatment of UHB in this population is a challenging task in the absence of evidence-based guidelines. [29]

Conjugated Hyperbilirubinemia(CHB) or Direct Hyperbilirubinemia

Conjugated hyperbilirubinemia, also referred to as neonatal cholestasis, is characterized by elevation of serum conjugated/direct) bilirubin (> 1.0 mg/dL) and is due to impaired hepatobiliary function. Distinguishing CHB from UHB is critical because cholestatic jaundice/CHB is almost always pathologic and warrants prompt evaluation and treatment. [33]

The causes of neonatal cholestasis/CHB are extensive and can be classified into the following categories:

Obstruction of biliary flow: Biliary atresia, choledochal cysts, neonatal sclerosing cholangitis, neonatal cholelithiasis

Infections: CMV, HIV, rubella, herpes virus, syphilis, toxoplasmosis, urinary tract infection (UTI), septicemia

Genetic causes : Alagille syndrome, alpha-1 anti-trypsin deficiency, galactosemia, fructosemia, Tyrosinemia type 1, cystic fibrosis, progressive familial intrahepatic cholestasis (PFIC), Aagenaes syndrome, Dubin-Johnson syndrome, Bile acid synthesis disorders(BSAD)

Miscellaneous: Idiopathic neonatal hepatitis, parenteral nutrition induced cholestasis, gestational alloimmune liver disease/neonatal hemochromatosis, hypotension,

Biliary atresia (BA) is the most common cause of conjugated hyperbilirubinemia in infants. [34] The incidence of BA varies from region to region. It is reported at a frequency of 1 in 6000 live births in Taiwan, the region with the highest incidence. In the United States, it has an incidence of around 1 in 12,000 live births. [35] The etiology of BA is not well understood, but genetic factors along with viral infection, toxins, chronic inflammatory and autoimmune injury to bile ducts seem to play a role in its pathogenesis. The disease involves both intra-hepatic and extra-hepatic bile ducts and classically presents around 2 to 4 weeks of life with pale stools and jaundice. The initial evaluation is by ultrasonography that may show an absent gallbladder and the classic "triangular cord" sign. [36] Early diagnosis is critical to maximizing the response to a Kasai operation (hepatic portoenterostomy). [37] If the surgery is delayed by 90 days of life, less than 25% of patients are reported to respond, compared to surgery performed within 60 days when more than 70% of patients will establish adequate bile flow. [38]

Choledochal cysts involve dilation of the intrahepatic and extra-hepatic bile duct. Ultrasonography can detect cysts with normal or dilated intrahepatic bile ducts as opposed to sclerosed ducts in biliary atresia. However, cystic biliary atresia may resemble choledochal cysts. [39] Neonatal sclerosing cholangitis (NSC) is a rare form of cholangiopathy that often presents in infancy with CHB, hepatosplenomegaly, pale stools, and high serum gamma-glutamyltransferase activity (GGT). [40] Neonatal cholelithiasis is also a rare entity that can cause significant direct hyperbilirubinemia in neonates. [41]

Cytomegalovirus (CMV) is the most common congenital infection that manifests in various ways. Most infected newborns are asymptomatic, but hepatomegaly and CHB are the most prominent feature of hepatic involvement. [42] Syphilis, toxoplasmosis, herpes, and rubella should be included in the differential diagnosis of neonatal cholestasis, especially when other stigmata of congenital infection like growth restriction, coagulopathy, skin rash, and thrombocytopenia are present. Careful evaluation of maternal history along with specific serologies and culture would aid the diagnosis. UTI is also a significant cause of CHB in neonates, and a urine culture should be included as part of diagnostic evaluation. Microcirculatory changes in the liver, a direct effect of bacterial products, and toxins released by bacteria are thought to be the possible mechanism of cholestasis in patients with UTI. [43]

Alagille syndrome (ALGS) is an AD disorder caused by mutations in JAG1 or NOTCH2 genes leading to a lack of interlobular bile ducts. [44] With an incidence of 1 in 30,000 live births, ALGS is the most common cause of familial intrahepatic cholestasis. [33] Characteristic clinical features in addition to cholestasis are butterfly vertebrae, congenital heart defect (most commonly peripheral pulmonic stenosis), kidney involvement, dysmorphic features (broad forehead, small pointy chin), and posterior embryotoxic of the eye. GGT levels are elevated out of proportion, often up to 20 times their normal value. Interestingly, CHB in patients with ALGS may resolve with age. [45] Few patients with cystic fibrosis (CF) can present with features of cholestasis because of abnormal bile that plugs the bile ducts. [46] In developing nations where newborn screening with immunoreactive trypsinogen is unavailable, neonatal cholestasis may be the first clue to the diagnosis.

Alpha-1-antitrypsin deficiency is the most common genetic cause of cholestatic and may mimic biliary atresia in early infancy. Accumulation of anti-trypsin polymers in the endoplasmic reticulum of hepatocytes of a patient with the PiZZ genotype leads to apoptosis of hepatocytes, ultimately resulting in cholestasis and cirrhosis later in childhood. [47] As with ALGS, cholestasis may also improve with age as with ALGS. Galactosemia, fructosemia, and tyrosinemia type 1 are a few of the inborn errors of metabolism known to cause cholestasis in neonates. Newborns with galactosemia present with cholestatic jaundice, cataracts, hepatomegaly, failure to thrive, renal tubular acidosis, and Escherichia coli sepsis after the ingestion of galactose from milk. [48] Galactose-1-phosphate uridyl transferase (GALT) deficiency leads to the accumulation of toxic galactose metabolites in multiple organs. The presence of reducing substances in urine suggests galactosemia, and GALT activity in the liver or erythrocytes confirms the diagnosis. Neonatal cholestasis may be a presenting feature in hereditary tyrosinemia type 1, another AR disorder caused by deficiency of enzyme fumarylacetoacetate hydroxylase. Other features of this disorder are renal Fanconi syndrome, hepatomegaly, coagulation abnormality, and the risk of hepatocellular carcinoma in untreated patients. [49]

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of three genetic disorders that present with cholestasis. They are related to mutations in one of the genes involved in canalicular hepatobiliary transport. [50] Types 1 and 2 usually manifest in the neonatal period, while type 3 presents later in infancy. Affected patients frequently develop cirrhosis and end-stage liver disease during childhood. GGT level is normal in types 1 and 2 and elevated in type 3 patients. PFIC1 is caused by a mutation in the ATP8B1 gene, which encodes FIC1 protein, whereas PFIC2 is caused by a mutation in the ABCB11 gene, which encodes for the bile salt excretory protein (BSEP). PFIC 3 is caused by a mutation in the ABCB4 gene, which encodes for the multi-drug resistant-3 protein (MDR3). [51] Aagenaes syndrome, also known as lymphedema cholestasis syndrome (LCS), is another type of idiopathic familial intrahepatic cholestasis syndrome characterized by neonatal cholestasis and lymphedema in lower extremities. It is transmitted as an AR trait and is mostly seen in individuals of Norwegian descent. [52] Dubin-Johnson syndrome (DJS) is a rare AR disorder caused by a mutation in the ABCC2 gene, which codes for a non-biliary ion transporter in the liver. A unique feature of DJS is the presence of black liver and excretion of coproporphyrin 1 in urine. [53] Bile acid synthesis disorder (BASD) results from a deficiency of one of the enzymes involved in synthesizing bile acids from cholesterol. BASDs are an uncommon cause of cholestasis, but many of these are curable with medical therapy alone.

Parenteral nutrition-associated cholestasis (PNAC) is an important iatrogenic cause of cholestasis recognized most commonly in preterm infants managed with parenteral nutrition (PN). PNAC is present in about 20% of neonates who have received PN for more than two weeks. [54] Duration of PN use and intestinal failure are two independent risk factors for PNAC. The mechanism is not entirely clear and is probably multifactorial. [55] Abnormal bile salt metabolisms due to prematurity and harmful effects of components of PN are thought to be the main culprit. Other factors such as sepsis, and necrotizing enterocolitis, appear to potentiate liver injury. [56] Gestational alloimmune liver disease (GALD), which causes almost all neonatal hemochromatosis cases, is a fulminant alloimmune disorder and results from intra-hepatic and extra-hepatic iron deposition resulting in liver failure. [57]

In GALD, maternal IgG immunoglobulin against fetal hepatocytes crosses the placenta causing complement-mediated damage to fetal hepatocytes. Patients present with signs of liver failure in the form of hypoglycemic, coagulopathy, hypoalbuminemia, cholestatic jaundice, edema, and elevated liver enzymes. The risk of recurrence in subsequent pregnancies is almost 90%, and GALD can result in fetal or neonatal deaths. [58] The term idiopathic neonatal hepatitis is used when the etiology of neonatal cholestasis cannot be ascertained after an extensive diagnostic workup. The size of this entity is shrinking with advancements in newer diagnostic tools, with more and more causes of neonatal cholestasis being identified that were originally labeled as idiopathic neonatal hepatitis. [38]

Epidemiology

Unconjugated hyperbilirubinemia is a commonly encountered problem in the neonatal period. It is estimated that about 60% of term and 80% of preterm newborns will present with clinical jaundice with TSB >5 mg/dl. [2] However, only about 10% of newborns are estimated to require phototherapy for jaundice. [59] Physiological jaundice is considered the most frequent cause of clinical jaundice after the first day of life, accounting for approximately 50% of cases. [60] Around 15% of breast-fed infants will develop UCH lasting for more than three weeks. [61]

Only a minority of infants with neonatal jaundice have a pathological cause of jaundice. The incidence of severe hyperbilirubinemia, defined as TSB>25 mg/dl, is about 1 in 2500 live birth. Among these, ABO incompatibility followed by G6PD deficiency is the most frequently identified cause identified. [62] Newborns with Southeast and Far East Asian ancestry have higher recorded TSB levels than their White and African counterparts. [63] [64] Neonatal jaundice also appears to be more common in people living at high altitudes and those living around the mediterranean sea, especially in Greece. [65] [66]

The incidence of acute bilirubin encephalopathy is seen at a rate of approximately 1 in 10,000 live births, whereas the incidence of chronic bilirubin encephalopathy is lower, with an estimated incidence of 1 in 50,000 to 100,000 live births. [67] However, in developing nations, the estimated occurrence of kernicterus is much higher. [68]

Conjugated hyperbilirubinemia is much less common compared to UCH, with a frequency of around 1 in 2500 term infants. [69] The most common identifiable cause of cholestatic jaundice in the neonatal period is Biliary atresia accounting for about 25% to 40% of all cases, followed by infections and TPN-induced cholestasis. [33] [70] [33] It is estimated that 60% to 70% of patients with BA will eventually require liver transplantation in childhood, and BA remains the most common indication for a pediatric liver transplant. [71]

Pathophysiology

Bilirubin is produced from the catabolism of heme, a breakdown product of hemoglobin, in the reticuloendothelial system (RES). First, heme is converted to biliverdin, releasing iron and carbon monoxide via the action of enzyme heme oxygenase. [72] Biliverdin is then converted to bilirubin by the enzyme biliverdin reductase. This unconjugated bilirubin is hydrophobic and is transported in circulation to the liver bound to albumin, where it is conjugated with glucuronic acid in the smooth endoplasmic reticulum by the enzyme uridine diphosphate-glucuronosyltransferase (UGT). Conjugated bilirubin is water-soluble and is then excreted in bile and into the gastrointestinal (GI) tract, where it is mostly excreted in feces after being metabolized by intestinal bacterial flora. Some of the conjugated bilirubin is deconjugated in the GI tract by the action of beta-glucuronidase and is reabsorbed through the enterohepatic circulation. [73]

Newborn infants have higher TSB levels than adults owing to higher hemoglobin levels at birth, along with a shorter RBC life span and limited conjugating ability of the newborn liver. [74] As such, full-term newborns normally have peak serum bilirubin concentrations of 5 to 6 mg/dl compared to adult levels of <1 mg/dl. Pathological jaundice in neonates is related to increased production of bilirubin in RES, impaired hepatic uptake, deficient conjugation of bilirubin, and/or enhanced enterohepatic circulation of bilirubin. [72]

In severe hyperbilirubinemia, unbound and unconjugated bilirubin crosses the blood-brain barrier and binds to the brainstem, hippocampus, cerebellum, globus pallidus, and subthalamic nuclei. [2] At the cellular level, bilirubin inhibits certain mitochondrial enzymes, inhibits DNA and protein synthesis, induces breaks in DNA strands, and hampers phosphorylation. [75] Bilirubin also impairs tyrosine uptake and alters the normal functioning of N-methyl-D-aspartate–receptor ion channels. [76] [77] These mechanisms are implicated in the pathogenesis of bilirubin toxicity that clinically manifests as bilirubin-induced neurologic dysfunction (BIND) and bilirubin encephalopathy. The duration of exposure to bilirubin and the amount of bilirubin in the brain determines the severity of brain damage. However, the TSB level does not correlate well with bilirubin toxicity in the absence of hemolysis. [72] Preterm infants are even more vulnerable to the toxic effects of free unconjugated bilirubin. This is in part related to comparatively lower serum albumin level, CNS immaturity, and concurrent comorbidities like intraventricular hemorrhage, periventricular leukomalacia, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. [68]

Conjugated hyperbilirubinemia results from abnormalities in the uptake, metabolism, transport, and/or excretion of bile salts and bilirubin. [78] These abnormalities increase bile acid in the liver that promotes the proliferation of bile ducts and fibrosis. Bile acid is also responsible for inflammation and apoptosis of hepatocytes culminating in hepatocellular injury and cirrhosis. [79] Deficient bile secretion in cholestasis results in malabsorption of fat and fat-soluble vitamins that often leads to failure to thrive with vitamin A, D, E, and K deficiencies. [80]

Histopathology

The term Kernicterus denotes yellow staining of deeper brain nuclei seen on autopsy specimens on infants with severe unconjugated hyperbilirubinemia. The histopathologic features seen on these autopsies include nuclei that have undergone pyknosis, the presence of vacuolation in the cytoplasm, and fading of the Nissl substance. [81]

A liver biopsy is often needed for making a definitive diagnosis of cholestasis. It may help differentiate Biliary atresia from idiopathic neonatal hepatitis. Histopathological features of BA include the expansion of the hepatic portal tracts with edema, fibro-dysplasia, bile ductular proliferation, and bile plugs in the ductal lumen. Multinucleate giant cells and hemopoiesis are other features often seen on histopathologic exams of cholestatic liver samples. [82] Although not diagnostic of any disorder, the prominence of hepatic erythropoiesis is seen more frequently in cholestasis of infectious etiology. The pathognomonic histopathological features of other cholestatic disorders include periodic acid- Schiff (PAS)-positive granules in alpha-1 antitrypsin deficiency, paucity of bile ducts in Alagille syndrome, necrosis, and inflammation around duct seen in sclerosing cholangitis. [83]

Among familial causes of cholestasis, canalicular cholestasis with a marked absence of ductular proliferation and isolated periportal biliary metaplasia of the hepatocytes is commonly seen in PFIC1 patients. In PFIC2 patients, the histopathology is similar except that altered liver architecture and extensive lobular and portal fibrosis with inflammation are more common. [51]

History and Physical

The evaluation of the neonate with jaundice starts with a detailed history, including birth history, family history, the onset of jaundice, and maternal serologies. Color of stool and urine presence of pruritis should be assessed for infants evaluated for jaundice and may provide a clue to the type of jaundice. The American Academy recommends universal screening of all newborns for jaundice and identifying risk factors for developing severe hyperbilirubinemia. [8] Major risk factors in newborns over 35 weeks gestation include pre-discharge bilirubin in the high-risk zone, jaundice observed in the first 24 hours, blood group incompatibility, gestational age 35 to 36 weeks, a previous sibling who received phototherapy, cephalhematoma or significant bruising, exclusive breastfeeding and east Asian race. Prematurity is also a known risk factor for developing severe hyperbilirubinemia. [84] Minor risk factors are serum bilirubin in the high intermediate-range, macrosomic infant of a diabetic mother, polycythemia, male gender, and maternal age older than 25 years. [8]

To assess for jaundice, newborns should ideally be examined in daylight. However, the clinical assessment may be unreliable, especially if a newborn has received phototherapy or has dark skin. [85] Therefore clinically significant jaundice should always be confirmed with a TSB or transcutaneous bilirubin. A focused physical examination to identify the cause of pathologic jaundice should be performed. Evaluation for pallor, petechiae, cephalhematoma, subgaleal bleed, extensive bruising, hepatosplenomegaly, weight loss, signs of dehydration needs to be done. All infants with jaundice should also be assessed for signs and symptoms of bilirubin encephalopathy that includes poor feeding lethargy, altered sleep, abnormal tone, or seizures. It is, however, important to note that up to 15% of neonates with kernicterus are clinically asymptomatic in the newborn period. [72] As discussed in prior sections, certain etiologies of neonatal cholestasis have multi-system involvement. These signs should be looked for during physical exams that may often provide a clue to diagnosis and aid in directing specific work-up.

Diagnosis of Unconjugated Hyperbilirubinemia

Bilirubin levels can be assessed using a transcutaneous measurement device or blood samples for total serum bilirubin. Transcutaneous estimation of bilirubin reduces the frequency of blood tests, but its utility is limited in infants with dark skin and following phototherapy use. [86] [87] The serum level should be measured when the transcutaneous bilirubin (TcB) level exceeds the 95th percentile on the transcutaneous nomogram or 75% of the TSB nomogram for phototherapy. Another limitation of relying on TcB is the inability to detect the direct fraction of bilirubin required for diagnosing neonatal cholestasis.

Recommended workup for identifying a hemolytic disease as the cause of unconjugated hyperbilirubinemia include maternal/neonatal blood type, Coombs test, complete blood cell (CBC), reticulocyte count, blood smear, and G6PD. Serum albumin should always be checked, especially if TSB level approaches near the exchange transfusion levels, as it is considered a surrogate marker for free bilirubin. Free bilirubin is the fraction responsible for bilirubin-induced toxicity. [88] Bilirubin-albumin ratio(B/A) ratio is, therefore, an additional tool that may predict the risk of kernicterus and may serve as an alternative guide to exchange transfusion.

Radiographic imaging is usually not required for most cases of UCH. Magnetic resonance imaging (MRI) findings have high sensitivity for bilirubin encephalopathy, with posteromedial borders of the globus pallidus being the most sensitive brain region for detecting signal changes. Infants with bilirubin encephalopathy demonstrate hyperintense signals on T1-weighted sequences in the acute stage that eventually becomes hyperintense on T2-weighted sequences as the disease evolves. Magnetic resonance spectroscopy(MRS) shows increased levels of glutamate and decreased levels of N-acetyl-aspartate and choline. [89] However, the absence of these findings does not exclude the risk of chronic bilirubin encephalopathy.

Diagnosis of Conjugated Hyperbilirubinemia

In patients with conjugated hyperbilirubinemia, the serum aminotransferases should be ordered for evidence of hepatocellular injury, alkaline phosphatase, and GGT levels for evidence of obstruction in biliary channels, prothrombin time/INR, and serum albumin to evaluate for hepatic synthetic function. Additional tests like TORCH titers, urine cultures, viral cultures, serologic titers, Newborn screening results, specific tests for inborn errors of metabolism, alpha-1 antitrypsin phenotype, and specific genetics tests may be needed depending on the scenario.

Radiology is often necessary as part of the workup of neonatal cholestasis. Hepatic ultrasonography may help identify sludging in the biliary tree, gallstones, inspissated bile, and choledochal cysts. Triangular cord sign seen on hepatic ultrasound has high sensitivity and almost 100% specificity for biliary atresia. [78] Hepatobiliary scintigraphy is another tool increasingly used in evaluating neonatal cholestasis. Decreased excretion of tracer 24 hours after introduction suggests obstruction and further helps in excluding nonobstructive causes of cholestasis. [90] Prior treatment with phenobarbitone has been shown to improve the sensitivity for this imaging. Finally, liver biopsy is usually considered the gold standard for diagnosing neonatal cholestasis. Histopathological interpretation by an experienced pathologist will help to identify the correct diagnosis in 90% to 95% of cases and may prevent unnecessary interventions in patients with intrahepatic cholestasis. [91]

Treatment / Management

Treatment of Unconjugated Hyperbilirubinemia

Phototherapy and exchange transfusion are the mainstay of treatment for patients with unconjugated hyperbilirubinemia.

Phototherapy

Phototherapy (PT) remains the first-line treatment for managing pathological unconjugated hyperbilirubinemia. PT is very effective in reducing TSB to safe levels and reduces the risk of bilirubin toxicity and the need for exchange transfusion. Phototherapy is started based on risk factors and the TSB levels on the bilirubin nomogram. [8] However, guidelines on the indications for PT in preterm infants are lacking, especially in the United States, because of a lack of evidence. As such most hospitals in the U.S have instituted their own guidelines for the use of phototherapy and exchange transfusion in preterm infants based on birth weight or gestational age. [30] The efficacy of phototherapy depends on the dose and wavelength of light used as well as the surface area of the infant's body exposed to it. Increasing the dose of PT can be achieved by placing phototherapy units at the minimum safe distance from the infant and increasing the number of units used.

Bilirubin absorbs light optimally in the blue-green range (460 to 490 nm). PT works by inducing bilirubin photoisomerization and converting bilirubin into lumirubin, which is the rate-limiting step for bilirubin excretion. [92] During phototherapy, the eyes of the newborn must be covered to avoid retinal injury. Measures are necessary to expose maximum body surface area to the light and avoid interruptions in PT. It is important to maintain adequate hydration and ensure normal urine output as most bilirubin is excreted in the urine as lumirubin. After phototherapy is discontinued, there is an increase in the total serum bilirubin level known as the" rebound bilirubin." The "rebound bilirubin" level is usually lower than the level at the initiation of phototherapy and usually does not require reinitiation of phototherapy. [93] PT has been considered relatively safe, but recent evidence points towards possible long-term side effects. Reported side-effects with PT use include rash, dehydration, hypocalcemia, retinal damage, hemolysis due to oxidative damage, delay in PDA closure in preterm infants, and allergic reactions. [94]

Few studies have also reported an increased incidence of solid organ tumors and non-lymphocytic leukemias in children treated with phototherapy. [95] [96] The bronze baby syndrome is another commonly described phenomenon associated with PT and results in irregular pigmentation of the skin, mucous membranes, and urine. It is usually seen in neonates with elevated serum conjugated bilirubin levels. The mechanism is not clear but appears to be related to the accumulation of photoisomers of bilirubin and biliverdin deposition. [97] [98]

Exchange Transfusion

Exchange transfusion (ET), the first successful treatment ever used for jaundice, is currently the second-line treatment for severe unconjugated hyperbilirubinemia. [99] It is indicated when there is a failure of response to PT, or the initial TSB levels are in the exchange range based on the nomogram. ET rapidly removes bilirubin as well as hemolysis, causing antibodies from circulation. A double volume exchange blood transfusion (160 to 180 ml/kg) is performed, replacing the neonate's blood in aliquots with crossed-matched blood. Since most of the total body bilirubin lies in the extravascular compartment complications, TSB levels immediately following ET is about 60% of the pre-exchange level that later increase to 70 to 80% of pre-exchange levels as a result of equilibrium with an extravascular moiety of bilirubin. During ET, vitals should be monitored closely, and TSB, CBC, serum calcium, glucose, and electrolytes need to be checked following procedure. Complications of ET include electrolyte abnormalities like hypocalcemia and hyperkalemia, cardiac arrhythmias, thrombocytopenia, blood-borne infections, portal vein thrombosis, graft versus host disease, and necrotizing enterocolitis (NEC). [100] [101] Phototherapy should resume after exchange transfusion until the bilirubin reaches a level where it can be safely discontinued.

Intravenous Immunoglobulin (IVIG)

IVIG is used when immune-mediated hemolysis is the cause of UHB jaundice and prevents RBC hemolysis by coating Fc receptors on RBCs.The AAP recommends IVIG infusion in immune-mediated hemolysis if TSB remains within 2 to 3 mg/dl of exchange level despite intensive phototherapy. [102] [103] However, the evidence that the use of IVIG reduces the need for ET is not very clear. Nonetheless, IVIG is often used in clinical practice to manage unconjugated hyperbilirubinemia.

Treatment of Conjugated Hyperbilirubinemia

Treatment of conjugated hyperbilirubinemia is tailored to the specific etiology. Patients diagnosed with biliary atresia require a Kasai operation (hepatic portoenterostomy) preferably within two months of life for best outcomes. [37] The Kasai operation involves removing the atretic biliary ducts and fibrous plate and Roux-en-Y anastomosis of jejunum with the remaining ducts to provide an alternative pathway for biliary drainage. [104] Infectious causes of cholestasis would be treated with specific anti-microbial, whereas treatment with cholic acid and chenodeoxycholic acid is often curative for many BASDs. Metabolic causes of cholestasis would typically respond to the improvement of the primary disorder and liver functions. Patients with GALD appear to respond well to IVIG and double volume exchange transfusion. Liver transplant, when available, is curative but is technically challenging in this age group. [58] Parenteral nutrition-induced cholestasis is managed with cyclic PN, reducing the duration of exposure and initiating enteral feeds as early as possible. Manganese and copper content of PN should be reduced to minimize liver injury.

Differential Diagnosis

The differential diagnosis for neonatal jaundice is quite limited as it can easily be diagnosed by a physical exam in a newborn. In a rare situation, high carotene levels may cause yellowish discoloration of the skin and may be mistaken to be hyperbilirubinemia. [34] There is, however, no involvement of the sclera or mucosa in carotenemia. Carotenemia arises from the ingestion of carotenoid-containing foods like carrots, mangos, green leafy vegetables, sweet potatoes, apricots, and melons, which is why it is unlikely that a newborn will present with this. However, as discussed in previous sections, the etiology of the two types of neonatal hyperbilirubinemia is quite extensive. Thorough knowledge of these conditions is required for timely diagnosis and appropriate treatment.

Bilirubin encephalopathy in patients with severe unconjugated hyperbilirubinemia has different manifestations depending on the time of presentation. The level at which unconjugated bilirubin becomes neurotoxic is unclear, and kernicterus has been reported in infants in the absence of markedly elevated levels of bilirubin on autopsy.

Acute bilirubin encephalopathy: has been described to evolve through three stages:

Phase 1: The symptoms of phase 1 are seen during the first one-two days of illness and are marked by poor feeding, lethargy, hypotonia, or frank seizures.

Phase 2: If the infants continue to deteriorate, they may progress to phase 2, characterized by increased tone, especially of the extensor group of muscles leading to opisthotonus and retrocollis. These signs are typically seen during the middle of the first week of illness.

Phase 3: This phase, seen after the first week, is mainly dominated by increased tone.

Chronic Bilirubin encephalopathy: This condition is present in two forms depending on the timing of symptoms.

Chronic Bilirubin encephalopathy in the First year: These patients present with hypotonia, exaggerated deep tendon reflexes, obligatory tonic neck reflexes, delayed motor milestones

Chronic Bilirubin encephalopathy beyond the First year: Highlights of this phase include movement disorders (most commonly choreoathetosis), choreo-athetoid type of cerebral palsy, dental enamel hypoplasia, upward gaze abnormality, and sensorineural hearing loss. [72]

With treatment, the prognosis for most types of unconjugated hyperbilirubinemia is excellent. In those with delayed or inadequate treatment, bilirubin encephalopathy may ensue. The burden of bilirubin encephalopathy is significantly higher in developing and resource-limited nations. [68] Reports suggest a resurgence of kernicterus in countries where this complication had virtually disappeared in the past. This has been attributed mainly to the early discharge of newborns from the birthing hospital. Patients with Crigler-Najjar type 1 carry a poor prognosis and require liver transplantation for a definitive cure. In the absence of liver transplantation, bilirubin encephalopathy is common.

The prognosis for conjugated hyperbilirubinemia depends on the etiology. The outcome and prognosis of patients with biliary atresia are significantly improved by early diagnosis and surgery within 60 days of life. Similarly, patients with bile acid synthesis disorder (BASD) have an excellent prognosis as they respond very well to medical treatment. Historically, the prognosis for gestational alloimmune liver disease (GALD) was poor, with up to 80% mortality without liver transplantation. However, with the advent of IVIG use and double volume exchange transfusion, the prognosis for this disease has greatly improved in recent years. [105] The prognosis for most of the other types of cholestasis is often not very favorable, and many of these patients will require multidisciplinary interventions.

Complications

Newborns with severe hyperbilirubinemia are at risk for bilirubin-induced neurologic dysfunction (BIND). Bilirubin binds to globus pallidus, hippocampus, cerebellum, and subthalamic nuclear bodies, causing neurotoxicity. [106] Acutely, this manifests as acute bilirubin encephalopathy (ABE), characterized by lethargy, hypotonia, and decreased suck. At this stage, the disease is reversible. However, if ABE were to progress, patients can develop chronic bilirubin encephalopathy/kernicterus, which is then irreversible. It manifests as choreo-athetoid cerebral palsy, seizures, arching, posturing, gaze abnormality, and sensorineural hearing loss. Patients with neonatal cholestasis are at risk of developing liver failure, cirrhosis, and even hepatocellular carcinoma in a few cases. Long-standing cholestasis may also lead to failure to thrive and fat-soluble vitamin deficiencies.

Consultations

A pediatric or neonatal provider can manage most patients with unconjugated hyperbilirubinemia. However, patients suspected of genetic causes of hyperbilirubinemia may need consultations and follow-ups with a pediatric gastroenterologist, hematologist, and medical geneticist.

Patients suspected of neonatal cholestasis should be referred to a pediatric gastroenterologist at the earliest. Most of these patients will need a battery of investigation, and once a cause of cholestasis is identified, more referrals would be warranted. Infants diagnosed with biliary atresia also need a referral to a pediatric gastrointestinal surgeon for corrective surgery. Likewise, patients with inborn errors of metabolism would need a consultation with a metabolic specialist as well as a medical geneticist and a Dietician experienced in metabolic disorders.

Deterrence and Patient Education

Detailed counseling, depending on the etiology of neonatal jaundice, is vital to improving the long-term outcome. Most patients with the common causes of unconjugated hyperbilirubinemia have an excellent prognosis, and parents need to be educated to alleviate fear and anxiety. Jaundice from etiologies that carry poor prognosis often requires multidisciplinary interventions, and parents should be adequately counseled and educated. Genetic counseling and referrals to medical geneticists should also be offered to parents whenever a child is diagnosed with hereditary hyperbilirubinemias.

Enhancing Healthcare Team Outcomes

Neonatal jaundice is a common condition with varied etiologies. Most cases are benign with an excellent prognosis and resolve with or without treatment. However, bilirubin encephalopathy can complicate clinical course in a few. Health care professionals taking care of newborn needs to be aware of this. While many conditions that cause jaundice cannot be diagnosed right away, education about the disease is critical. Nurses and parents are often the first to notice jaundice in a newborn. After discharge from the birth hospital, parents need to be educated by the nurses, pediatricians, obstetricians, and the family practice providers to monitor for jaundice and seek medical care if it worsens.

The availability of a 2-color icterometer can help parents identify jaundice earlier for prompt medical intervention. Nurses can also train mothers on how to examine the skin and eyes of neonates for jaundice. In addition, a smartphone app can also help parents assess jaundice. An interprofessional team approach including nurses, lab-technician, providers from various sub-specialties, and nutritionists is necessary for the best outcome. Every health care provider involved in the care of a jaundiced newborn needs to be updated on current evidence-based management approaches. Nurses play a vital role by monitoring treatments, educating parents, and keeping the team apprised about changes in the patient's condition. [Level 5] As per the American Academy of Pediatrics, every newborn must have a predischarge bilirubin check and should also be assessed for risk factors associated with the development of severe hyperbilirubinemia to improve patient outcomes. [8] [Level 3]

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Metabolic Pathway for Bilirubin in the Hepatocyte. Bilirubin-G corresponds to bilirubin glucuronate, where the donor is uridine diphosphate glucuronic acid (UDP-GA). This is catalyzed by the enzyme uridine diphosphate-glucuronyltransferase (UGT1A1). Gilbert (more...)

Disclosure: Betty Ansong-Assoku declares no relevant financial relationships with ineligible companies.

Disclosure: Sanket Shah declares no relevant financial relationships with ineligible companies.

Disclosure: Mohammad Adnan declares no relevant financial relationships with ineligible companies.

Disclosure: Pratibha Ankola declares no relevant financial relationships with ineligible companies.

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Cite this Page Ansong-Assoku B, Shah SD, Adnan M, et al. Neonatal Jaundice. [Updated 2023 Feb 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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Systematic Review
Open access
Published: 13 April 2024

Risk of childhood neoplasms related to neonatal phototherapy- a systematic review and meta-analysis

Ilari Kuitunen ORCID: orcid.org/0000-0001-8178-9610 1 , 2 ,
Atte Nikkilä 3 , 4 ,
Panu Kiviranta 1 , 2 , 5 ,
Johanna Jääskeläinen 1 &
Anssi Auvinen 6

Pediatric Research ( 2024 ) Cite this article

Metrics details

Observational studies have shown conflicting results as to whether exposure to neonatal phototherapy is associated with increased rates of childhood cancer.

To describe the rates of childhood neoplasms and cancer after neonatal phototherapy.

Data sources

The CENTRAL, PubMed, Scopus, and Web of Science databases.

Study selection

Observational studies regardless of design were included.

Data extraction

The data were extracted by one author and validated by another. The risk-of-bias assessment was performed using the ROBINS-E and Joanna Briggs Institute critical appraisal tools.

Six cohort and 10 case-control studies were included. The overall risk of bias was high in seven and low in nine studies. In cohort studies, the odds ratio (OR) was increased for hematopoietic cancer (1.44; confidence interval [CI]: 1.16–1.80) and solid tumors (OR: 1.18; CI: 1.00–1.40). In case-control studies, the OR was 1.63 (CI: 0.99–2.67) for hematopoietic cancers and 1.18 (CI: 1.04–1.34) for solid tumors.

Conclusions

Children with a history of neonatal phototherapy had increased risk of hematopoietic cancer and solid tumors. The evidence quality was limited due to the high risk of bias and potential residual confounding.

Impact statement

Exposure to neonatal phototherapy increased later risk of hematopoietic cancer and solid tumors.

This is the most comprehensive study on the association between phototherapy and cancer, but the evidence quality was limited due risk of bias and residual confounding.

Future large scale well conducted studies are still needed to better estimate the association and.

Introduction

Neonatal jaundice is a common condition during the first month of life, as approximately 70% of neonates have some level of jaundice, and 5% to 10% require phototherapy for treatment of unconjugated hyperbilirubinemia. 1 , 2 , 3 Phototherapy is commonly used to decrease bilirubin levels in order to avoid the neurotoxic effects of high bilirubin levels. Some of the known risk factors for unconjugated hyperbilirubinemia requiring phototherapy are maternal red blood cell antibodies, prematurity, birth injuries, hereditary factors (ethnicity and a history of phototherapy in older siblings), and maternal obesity. 3 , 4 , 5

Phototherapy has been associated with some short-term adverse events, such as rash, dehydration, and difficulties with breastfeeding, 6 , 7 as well as with long-term risks, such as allergies and seizure disorders. 8 , 9 , 10 Phototherapy has been suggested to cause DNA damage and promote reactive oxygen species and proinflammatory cytokines, which could lead to an increased cancer risk. 11 In addition, phototherapy has been associated with increased incidence of café-au-lait macules in children but not with melanocytic nevi. 12 , 13 Previous studies have shown conflicting results regarding the possible increased incidence of childhood cancers following neonatal phototherapy. In some cohort studies, children exposed to phototherapy had an increased risk of all childhood cancers, 14 , 15 whereas no such excess was reported in other studies. 16 , 17 It has also been speculated that there may be an association between hyperbilirubinemia and malignancies. Therefore, the association between phototherapy may be due to higher bilirubin levels or other maternal/neonatal factors that increase the risk for both hyperbilirubinemia and neoplasms. As phototherapy is an effective and frequently used therapy for neonatal unconjugated hyperbilirubinemia, 18 evidence summaries on possible long-term risk are of clinical relevance. A recent meta-analysis reported an increased risk for solid cancers among children treated with phototherapy, but the authors included benign nevi in their analysis and pooled case-control and cohort studies together, which caused a notable heterogeneity in their results. 19 The aim of this systematic review was to provide a systematic assessment of the incidence of cancer and neoplasms after neonatal phototherapy.

Search process

The literature search was performed on June 28, 2022. We searched the PubMed (MEDLINE), Web of Science, CENTRAL, and Scopus databases for these search terms: (neonat* OR newborn* OR infant*) AND (phototherapy OR hyperbilirubinemia OR jaundice) AND (cancer or malign* OR leukemia OR leukaemia OR lymphoma* OR tumor* or neoplasm*). Additional articles were included if found in the references of the included articles and assessed suitable for the review and analysis. We did not search other sources and decided not to include gray literature. The full search strategy is presented in the appendix (Supplementary file 1 ).

Inclusion criteria

We included only human studies published in peer-reviewed journals in English. Retrospective and prospective observational studies with control groups, regardless of the design (cohort, case-control, etc.) were included. Studies focusing on benign and/or malignant neoplasms, leukemia, and lymphomas were included.

Exclusion criteria

We excluded studies focusing only on nevi or other benign tumors (including hemangiomas). All animal studies were also excluded. Studies without original data or reported in languages other than English were excluded as well.

Main outcome

Our main outcome was neoplasm and cancer risk estimates stratified by anatomic site and the cell type of the neoplasm. We aimed to collect the mortality due to cancers.

Two authors screened the abstracts and full texts using Covidence software. 20 A third party was consulted in cases of disagreement if mutual consensus was not achieved. Data extraction was performed by one author and validated by another. The following information was extracted to a pre-designed spreadsheet: authors, year of publication, country where the study was conducted, study period, study design, original inclusion criteria, exposure and control, total number of people included in the study, number of exposed and unexposed or number of cases and controls (depending on the study design), follow-up duration, and overall person-years of follow-up. The effect estimates from both adjusted and unadjusted analyses (hazard ratios [HRs], incidence rates, odds ratio [ORs], and risk ratios [RRs]) with uncertainty estimates (95% confidence intervals [CIs]) were abstracted as well.

Risk-of-bias assessment

Risk of bias was assessed for all the included studies. We used the Risk of Bias in Non-randomized Studies of Exposures (ROBINS-E) tool to assess risk of bias. 21 If the study did not attempt to adjust for confounding, it was immediately labeled as high risk for bias, and other domains were not assessed. The scale used in the judgment was low , some concerns , and high . We also utilized a secondary risk-of-bias assessment strategy. We analyzed the cohort studies’ risk of bias according to the Joanna Briggs Institute critical appraisal tool for cohort studies and the case-control studies’ according to the Joanna Briggs Institute critical appraisal tool for case-control studies. 22 These were labeled as with concerns or no concerns . We decided not to exclude any reports from the synthesis due to risk of bias but performed sensitivity analyses where these were excluded.

Statistical methods

RevMan version 5.4 and R statistical software version 4.2.2 (metafor package) were used for the meta-analysis. Data analysis was performed according to Cochrane Handbook for Systematic Reviews guidelines. Forest plots are presented for all outcomes.

We decided not to pool case-control studies with cohort studies, as these have different inclusion strategies and are thus problematic to combine. Overall, we expected heterogeneity in the populations between the studies, and therefore we decided to use the random-effects Mantel-Haenszel model. 23 Pooled ORs with 95% CIs were calculated with the Mantel-Haenszel method for cohort and case-control studies. The inconsistency index statistic I² for statistical heterogeneity was calculated, but it was not used to decide whether the fixed-effect or random-effect model was used. Some of the studies contained outcomes that could not be pooled for quantitative analysis, and these outcomes have been reported according to the Synthesis Without Meta-analysis (SWiM) guideline. 24 For example, the adjusted effect estimates in the included studies had high heterogeneity (confounder selection, statistical method, chosen effect estimate measure [OR, RR, HR]) in the reporting, and thus we decided not to force this to a single estimate and presented these in a table. We assessed publication bias by Egger’s test and the trim and fill method and provide the funnel plots. 25

We report our meta-analysis according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items in Systematic Reviews and Meta-analyses (PRISMA) guidelines and provide the checklists in the appendix. 26 , 27

Protocol registration

We registered our protocol in Prospero (ID CRD42022342273), and it can be assessed online: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022342273 .

We initially screened 2,325 abstracts and assessed 31 full reports. After exclusions (19 studies) and inclusions from hand searches (4 studies), a total 16 studies were included for systematic review and meta-analysis Figure 1 . 14 , 15 , 16 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 Six were retrospective cohort studies and 10 case-control studies (Table 1 ). Eight of the studies were from Europe, five from North America, and three from the Middle East. The study periods ranged from the 1960s to the 2010s. The main outcome used was the odds or risk of any cancer. The number of participants varied between 150 and 0.9 million (Table 2 ). Six studies did not adjust their analysis, and, furthermore, only five studies described a rationale for the selection of the covariates for adjustments (Table 2 ).

Risk of bias and publication bias

Risk of bias was assessed by ROBINS-E; nine studies were judged to have a low risk of bias, and seven studies had a high risk of bias due to lack of adjustment for potential confounders (Table 3 ). Concerns were found in nine studies with the Joanna Briggs Institute critical appraisal tool. Most issues were in confounder identification and strategies to address incomplete follow-up in cohort studies. In case-control studies, most issues were in measuring the exposure and appropriate statistical analysis (Table 3 ). We did not detect publication bias visually in funnel plots, and Egger’s test confirmed this. The trim and fill method was utilized and showed no obvious asymmetry (Fig. S 1 ).

PRISMA flowchart of the study selection process.

Cancer and tumor incidence in cohort studies

Six cohort studies with a combined follow-up of 16 million person-years were analyzed and pooled for all cancer incidence estimates. In analysis by cancer type, the risk of hematopoietic cancers (OR: 1.44; CI: 1.16–1.80) and solid tumors (OR: 1.18; CI: 1.00–1.40) was increased. Rates of solid tumors and skin cancers did not show evidence of difference in crude analysis (Fig. 2 ). In sensitivity analyses, in which studies with high risk of bias were excluded, the OR changed only for skin cancers, and risk remained highly imprecise (OR: 1.78; CI: 0.70–7.97) (Fig. S 2 ).

Forest plot of the cancer incidence between phototherapy exposed cohort and unexposed cohort stratified by the cancer type.

In adjusted analyses of the cohort studies, statistically significant associations were detected in two studies regarding all cancer incidences (Table 4 ). In stratified analysis, one study found an increased overall adjusted hazard of hematopoietic cancers and one an increased adjusted OR (aOR) for acute myeloid leukemia. One study further presented an increased aOR for kidney cancer but not for any other type of solid cancer.

Cancer and tumors in case-control studies

Ten case-control studies were included for a pooled analysis with 10,799 cancer cases, of whom 734 (7.0%) had been exposed to phototherapy. The control group consisted of 219,364 children, of whom 11,262 (5.1%) were exposed to phototherapy. In the analysis by tumor type, solid tumors were the only group with increased risk associated with phototherapy (OR: 1.18; CI: 1.04–1.34) (Fig. 3 ). This estimate remained unchanged in sensitivity analysis (Fig. S 3 ). The OR for hematopoietic cancers was 1.63 (CI: 0.99–2.67). In the sensitivity analysis, the OR for hematopoietic cancers was 1.70 (CI: 1.14–2.55) (Fig. S 3 ), indicating increased odds, when only studies with a low risk of bias were included.

Forest plot of the crude overall cancer/ tumor rates of exposed and unexposed between case and control groups in case-control studies stratified by the tumor/cancer type.

Four case-control studies presented adjusted analyses. In the adjusted analyses, the aOR was statistically significant in one study and for only one outcome. The acute lymphatic leukemia aOR was 1.69 (CI: 1.37–2.08). Other adjusted estimates had CIs overlapping 1 (Table 4 ).

Main findings

Based on this systematic review and meta-analysis, children with a history of neonatal phototherapy have a 1.2- to 1.6-fold increased risk of hematopoietic cancers and solid tumors. However, several factors need to be considered in interpretation, including issues with the quality of reporting in the original studies, potential causal pathways, and confounding factors.

Some studies have speculated that the increased cancer risk could be at least partly attributable to hyperbilirubinemia instead of phototherapy, i.e., confounding by indication. This could be related to oxidative stress caused by bilirubin at the cellular level, which could promote carcinogenesis. 41 This is consistent with findings showing that cancer incidence among children with hyperbilirubinemia who did not receive phototherapy was between that of children without hyperbilirubinemia and that of those treated with phototherapy. 15 , 40

We originally intended to analyze cancer risk by duration and intensity of phototherapy, as it could be hypothesized that longer treatment duration could lead to higher risk. However, it turned out that most studies did not report the phototherapy duration.

Prematurity has been associated with both phototherapy and cancer risk. One of the included studies analyzed term and preterm infants separately and found that incidence did not differ between the treated and non-treated individuals who were born prematurely, whereas among full-term infants phototherapy was associated with a slightly increased risk of hematopoietic cancers. 33

Comparison to previous meta-analyses

During our initial search process, we identified a previous meta-analysis, and later another one was identified. 19 , 42 Their results were generally similar to ours, but there were some key differences and issues in the previous meta-analyses. Both previous meta-analyses pooled case-control and cohort studies and reported their combined results. Although this is technically possible, it increases variability in study populations and adds to heterogeneity. Furthermore, the meta-analysis by Hemati et al. also included benign nevi count as an outcome and did not present any sensitivity analysis to assess the impact of risk of bias or reasons for high heterogeneity. Furthermore, we were able to include one additional study to the meta-analysis by Abdellatif et al.

We performed our systematic review according to a pre-registered protocol without major deviations. In contrast to previous studies, we did not pool results from case-control and cohort studies, which reduces the heterogeneity in our reporting. The results from case-control studies exhibited high variability, including both increased and decreased odds. Furthermore, the measured inconsistency was high. The effect estimates from cohort studies had lower heterogeneity, which was also seen as higher statistical consistency. It must be noted that, based on the wide CIs, nearly all the included studies seemed to be underpowered to detect meaningful risk increases.

Limitations

Most of the limitations of this work come from the limitations of the included studies. Several studies had a high risk of bias due to lack of adjustment for possible confounders. The studies that did adjust for confounders rarely presented the rationale for the covariate selection. None of the studies discussed causal pathways or visualized them, e.g., as directed acyclic graphs. To overcome this issue, we have visualized the potential causal pathways in Figure S 4 to better illustrate the possible causality and alternative backdoor paths causing bias to estimates.

We were unable to perform two analyses planned in the protocol: mortality and exposure-outcome gradient (dose dependency). As the studies did not report mortality, we were unable to assess it. Furthermore, we aimed to examine the exposure gradient (higher risk with higher exposure level) in the potential association, as it could have strengthened the plausibility of a potential effect. Dose dependency would have been addressed by examining the duration and intensity of the phototherapy, but only two studies presented information on duration and none on the intensity (number of lamps). Furthermore, we were unable to find information on the phototherapy practices in the included countries during the study periods, as there may have been variations in the bilirubin levels for phototherapy initiation and ending. Thus, this causes additional heterogeneity in our estimates.

Implications for clinical practice and future research

Future studies are still needed. Although our systematic review identified 16 studies, the overall quality had clear limitations. Furthermore, due to the rare outcome, estimates in our meta-analysis have notable imprecision, and further large-scale studies are needed. Future studies should focus more on potential causal pathways in selecting the covariates for their analyses. We have illustrated the potential causal pathways and modifiers, which could partly explain the observed differences (Fig. S 4 ). Some maternal and neonatal conditions, such as prematurity, congenital anomalies, hereditary syndromes, and intrauterine growth restrictions, may increase the rates of phototherapy and cancers. Inability to control for these creates a potential source of bias due to confounding by indication and shared risk factors. Mortality in cancer patients with and without prior phototherapy would be an interesting topic to address in the future.

While our results suggest that neonatal phototherapy may increase the risk of hematopoietic cancers and solid tumors, they do not justify changes in the use of phototherapy. As high bilirubin levels are neurotoxic, it is important to treat hyperbilirubinemia appropriately. However, guidelines should be followed and unnecessary therapy avoided, as it may have harmful effects. 43 Currently, we cannot conclude whether the phototherapy, high bilirubin, or shared risk factors for prematurity and childhood cancer underlie the observed association with cancer risk.

Neonates receiving phototherapy have a 1.2- to 1.6-fold increased risk of hematopoietic cancers and solid tumors. Quality concerns in the reporting of the original studies limited the evidence. More high-quality studies are needed to further elucidate the observed association between phototherapy and neoplasia and improve understanding of the potential causal pathways.

Data availability

All the data generated during the review process are available from the corresponding author upon request.

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Ilari Kuitunen, Panu Kiviranta & Johanna Jääskeläinen

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Tampere University, Faculty of Medicine and Health Technologies, Tampere, Finland

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Tampere University, Faculty of Social Sciences, Department of Epidemiology, Tampere, Finland

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Dr. Ilari Kuitunen had the original idea and conceptualized the study design, participated in screening process and data extraction process, was in charge of the statistical analyses, and wrote the initial draft. Dr. Atte Nikkilä participated in the conceptualization and provided methodological assistant for analyses and conducted some parts of the analyses, participated in the screening and data extraction process, and also provided important revisions to the manuscript. Dr. Johanna Jääskeläinen and Dr. Panu Kiviranta both participated in the screening process and data extraction process and provided important revisions to the manuscript. Prof. Anssi Auvinen participated in the conceptualization and supervised the whole process, provided methodological knowledge and have revised important intellectual content to the manuscript. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

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Kuitunen, I., Nikkilä, A., Kiviranta, P. et al. Risk of childhood neoplasms related to neonatal phototherapy- a systematic review and meta-analysis. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03191-7

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Notes from the Field: Neonatal Salmonellosis Associated with Backyard Poultry — Oregon, November 2023

Weekly / April 11, 2024 / 73(14);321–322

Stephen G. Ladd-Wilson, MS 1 ; Karen Yeargain 2 ; Samuel P. Myoda, PhD 3 ; Mansour Samadpour, PhD 3 ; Karim Morey, MS 4 ; Paul R. Cieslak, MD 1 ( View author affiliations )

What is already known about this topic?

Salmonellosis outbreaks associated with backyard poultry involving young children have been well documented.

What is added by this report?

A case of backyard poultry–associated salmonellosis was identified in a newborn who was infected during the first week of life, despite living >150 miles (>241 km) from the location of the backyard flock, suggesting that even in the absence of direct exposure, backyard poultry might present a risk for salmonellosis to newborns and infants via fomites.

What are the implications for public health practice?

Investigation of salmonellosis outbreaks should include detailed epidemiologic inquiry regarding any potential backyard poultry exposures and follow-up environmental testing where indicated. Families with newborns and infants should be aware of the potential risks associated with owning backyard poultry.

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Outbreaks of salmonellosis (infection with non-typhoidal Salmonella ) involving young children associated with keeping backyard poultry,* including descriptions of high-risk practices such as keeping poultry inside households and kissing birds, have been well documented ( 1 ). During 2023 (as of October 19), backyard poultry–associated salmonellosis outbreaks were reported to CDC from 48 States and Puerto Rico; these outbreaks accounted for 1,072 cases of illness, including 247 hospitalizations ( 2 ). Several of these outbreaks involved multiple states and included serotypes Braenderup, Enteritidis, Indiana, Infantis, Mbandaka, and Typhimurium ( 3 ). During a salmonellosis outbreak investigation across multiple states (A. Lodato, CDC, unpublished data, 2023), the Oregon Health Authority, in collaboration with a local health department, investigated a case of salmonellosis in a newborn whose parents had kept backyard poultry. This activity was deemed to be routine public health surveillance by the Public Health Division of the Oregon Health Authority and did not require human subjects review.

Investigation and Outcomes

The Oregon patient was an exclusively breastfed male newborn who was born during October 2023 at hospital A, approximately 150 miles (241 km) from the parents’ home. The Salmonella Thompson whole genome sequencing (WGS) pattern of the isolate from the patient matched that of the unpublished outbreak strain. The newborn was discharged with his mother to a relative’s home the day after his birth. Four days later, he was readmitted to hospital B with bloody stools and lethargy, at which time a stool sample was collected for analysis and subsequently tested positive for S. Thompson; the WGS pattern matched the unpublished outbreak strain. Neither parent had been symptomatic, and neither had received a diagnosis of salmonellosis. The baby’s father, who tended the family’s backyard poultry approximately 150 miles (241 km) away, had been present at hospital A during the child’s birth and stayed with the child and the child’s mother at the relative’s home through the time of illness onset. The newborn had not traveled to the home where the backyard poultry were kept during the interval from his birth until his hospital admission. Twenty-seven days after this admission, nine environmental samples from the chicken bedding in the family’s backyard poultry coop (where the child’s father also had had contact) and one cloacal sample from a chicken were collected. The samples were sent to the Institute for Environmental Health Laboratories in Seattle, Washington, for Salmonella spp. serotyping and WGS analyses. Two of the environmental samples matched the newborn’s isolate within three single nucleotide polymorphisms † : clinical PNUSAS396258, and environmental CFSAN1435603 and CFSAN1435604. Samples were not collected from the parents.

Preliminary Conclusions and Actions

The mechanism by which this newborn was exposed to this strain of Salmonella is not known. The newborn’s family had recently started keeping backyard poultry, having purchased the chicks in September 2023, approximately 1 month before the child’s birth. It is possible that one of the parents was asymptomatically shedding the organism and exposed the newborn during or after birth; alternatively, the organism might have been carried from the backyard farm to the newborn by fomites.

This case of neonatal salmonellosis linked to environmental isolates from a backyard poultry coop to which the newborn had not been directly exposed highlights the importance of hygiene when tending backyard poultry, especially when persons at risk for exposure are newborns and young infants whose intestinal flora and immune systems are still developing ( 4 , 5 ). In addition to adhering to recommended hygiene practices ( 2 ), families contemplating raising backyard poultry should consider the potential risk to newborns and young infants living in the household. To better understand the breadth of backyard poultry–associated salmonellosis outbreaks, state and local public health officials can conduct detailed epidemiologic inquiry around potential backyard poultry exposures, not limited to those where the patient lives, and perform follow-up environmental testing where indicated.

Acknowledgments

Angelo Lodato, Outbreak Response and Prevention Branch, Division of Foodborne, Waterborne, and Environmental Diseases, National Center for Emerging and Zoonotic Infectious Diseases, CDC.

Corresponding author: Stephen G. Ladd-Wilson, [email protected] .

1 Public Health Division, Oregon Health Authority; 2 Crook County Health Department, Prineville, Oregon; 3 Institute for Environmental Health Laboratories, Seattle, Washington; 4 Oregon State Public Health Laboratory, Oregon Health Authority.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

* https://www.cdc.gov/healthypets/pets/farm-animals/backyard-poultry.html

† https://www.ncbi.nlm.nih.gov/

Basler C, Nguyen TA, Anderson TC, Hancock T, Behravesh CB. Outbreaks of human Salmonella infections associated with live poultry, United States, 1990–2014. Emerg Infect Dis 2016;22:1705–11. https://doi.org/10.3201/eid2210.150765 PMID:27649489
CDC. Investigation notice: Salmonella outbreaks linked to backyard poultry. Atlanta, GA: US Department of Health and Human Services, CDC; 2023. https://www.cdc.gov/salmonella/backyardpoultry-05-23/index.html
CDC. Investigation details: Salmonella outbreaks linked to backyard poultry. Atlanta, GA: US Department of Health and Human Services, CDC; 2023. https://www.cdc.gov/salmonella/backyardpoultry-05-23/details.html
Bula-Rudas FJ, Rathore MH, Maraqa NF. Salmonella infections in childhood. Adv Pediatr 2015;62:29–58. https://doi.org/10.1016/j.yapd.2015.04.005 PMID:26205108
Varela K, Brown JA, Lipton B, et al. A review of zoonotic disease threats to pet owners: a compendium of measures to prevent zoonotic diseases associated with non-traditional pets such as rodents and other small mammals, reptiles, amphibians, backyard poultry, and other selected animals. Vector Borne Zoonotic Dis 2022;22:303–60. https://doi.org/10.1089/vbz.2022.0022 PMID:35724316

Suggested citation for this article: Ladd-Wilson SG, Yeargain K, Myoda SP, Samadpour M, Morey K, Cieslak PR. Notes from the Field: Neonatal Salmonellosis Associated with Backyard Poultry — Oregon, November 2023. MMWR Morb Mortal Wkly Rep 2024;73:321–322. DOI: http://dx.doi.org/10.15585/mmwr.mm7314a6 .

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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.

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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

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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.

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

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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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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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Case 1: Severe Jaundice in a 2-day-old Term Neonate
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 ...
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management of neonatal jaundice. CONCLUSION The present study "A Critical clinical study of neonatal jaundice and its treatment modalities through ayurveda" draws to following conclusions- Rise in the serum bilirubin level is a physiological phenomenon in the early neonatal age. In this study, the yellowish
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The odds of having neonatal jaundice among neonates who had the O blood group was 3 times higher than neonates who had the A blood group (AOR = 2.99; 95% CI 1.04-8.59), similarly, the odds of developing neonatal jaundice among neonates admitted for more than 7 days in the hospital, was almost 10 times higher than their counterparts who stayed ...
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Jaundice caused by hyperbilirubinaemia is a common phenomenon during the neonatal period. Population-based studies evaluating assessment, management, and incidence of jaundice and need for ...
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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.
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The study is a retrospective study where data were retrieved from neonates' case notes frommedical records unit of the University College Hospital, Ibadan.A total of 232 neonatal jaundice cases ...
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This study aims to investigate the association between maternal blood parameters and the risk of neonatal pathological jaundice. A retrospective case-control study of 1309 newborns and their ...
Burden of severe neonatal jaundice: a systematic review and meta
Introduction. Newborn jaundice occurs in up to 85% of all live births. 1-3 In the absence of haemolysis, sepsis, birth trauma or prematurity, it usually resolves within 3-5 days without significant complications. 1 However, epidemiological evidence suggests that severe neonatal jaundice (SNJ) results in substantial morbidity and mortality. 4 SNJ has been recognised as a significant cause ...
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Jaundice is a marker used to identify those infants who may be at risk for developing severe hyperbilirubinemia. Severe hyperbilirubinemia can be toxic to the nervous system of infants, potentially causing brain damage. (Stanford Children's Health, 2016) Neonatal Jaundice can be considered physiological and pathological.
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Introduction. of in bilirubin Jaundice is when clinically there is an increase in the amount in the serum rising above 85mmol/l (5mg/dl). produce cord serum bilirubin unconjugated bilirubin of approximately is in 35mmol/L dl). After birth, jaundice is a reflection of the bilirubin present. to in to of Many variations in individual responses to ...
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related, and there has been no study to identify risk fac-tors 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 jaun-dice requiring the treatment in clinical situation has not been done well. In Korea, all citizens are covered by the
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Neonatal Jaundice
Neonatal jaundice or neonatal hyperbilirubinemia results from elevated total serum bilirubin (TSB) and clinically manifests as yellowish discoloration of the skin, sclera, and mucous membrane. The term jaundice derives from the French word "jaune," which means yellow. It is the most commonly encountered medical problem in the first two weeks of life and a common cause of readmission to the ...
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Stony Brook University Hospital
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Neonatal jaundice or neonatal hyperbilirubinemia results from elevated total serum bilirubin (TSB) and clinically. manifests as yellowish discoloration of the skin, sclera, and mucous membrane. In ...
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PDF NEONATAL JAUNDICE
Jaundice: yellowing of the skin, scleral, and mucous membranes from a build up of bilirubin. 60% of term infantsand 80% ofpreterm infants develop jaundice in the 1stweek of life, typically an unconjugated hyperbilirubinemia.
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Neonatal jaundice is a common disease [].In Korea, it is the most common cause of admission among newborns [], and medical expenses correlated with jaundice exceeded $10 million in 2012 [].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].
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