US Collaborative Perinatal Research Articles

In utero aspirin exposure and child neurocognitive development: A propensity score-matched analysis.

To evaluate the association between a short-period, high-dose in utero aspirin exposure and child neurocognitive development. A propensity score-matched analysis of a multicentre prospective cohort study. The US Collaborative Perinatal Project (1959-1976). A total of 50 565 singleton live births with maternal information. We performed a propensity score matching to balance maternal characteristics between women with and without aspirin exposure. Inverse probability-weighted marginal structural models were used to estimate associations between aspirin exposure and child neurocognitive assessments. Child neurocognitive development was assessed using the Bayley Scales at 8 months, the Stanford Binet Intelligence Scale at 4 years, and the Wechsler Intelligence Scale and Wide-Range Achievement Test (WRAT) at 7 years. Children exposed to aspirin in utero were associated with an 8%-16% reduced risk of having suspect/abnormal or below-average scores in most neurocognitive assessments. A trend of lower risks of having suspect/abnormal or below-average scores was further observed in children with in utero aspirin exposure for more than 7 days, particularly on Bayley Mental (relative risk [RR] 0.82, 95% CI 0.74-0.92), WRAT Reading (RR 0.88, 95% CI 0.78-0.98) and WRAT Arithmetic tests (RR 0.76, 95% CI 0.66-0.86). This association was mainly observed in the second trimester of pregnancy. In utero aspirin exposure was associated with improved child neurocognitive development in a prospective cohort study. Further studies are warranted to evaluate the impact of long-period and low-dose in utero aspirin exposure on child short- and long-term neurodevelopment.

Associations between maternal exposure to surgery or pregnancy exposure to fluorinated anesthetics and children's cognitive development and educational outcomes.

A transgenerational, epigenetic effect of anesthesia, particularly fluorinated agents, has been examined in rat models, but translation to humans is unclear. This study examined associations of maternal lifetime exposure to anesthesia and pregnancy exposure to fluorinated anesthetics with child cognitive and educational outcomes. Women in the US Collaborative Perinatal Project (1959-1963) reported lifetime history of surgeries, and the obstetric record captured pregnancy exposure to anesthetics. Children were followed to age 7 for global cognitive ability and educational outcomes (n=47,977). Logistic and linear regressions were adjusted for maternal and child birth years, race and ethnicity, smoking, education, parity, study site. Many outcomes were not associated with exposure to maternal surgery that occurred at various life stages. However, maternal surgery in early childhood was associated both with being in a special school or not in school (adj OR=1.42; 95% CI 1.02, 1.98) and with slightly better cognitive ability across childhood (e.g., WISC IQ (adj β=0.59; CI 0.13, 1.04) (especially among boys)). Maternal surgery in puberty was associated with slightly lower IQ (adj β= -0.42; CI -0.79, -0.05) and poorer spelling at age 7. Children's prenatal exposure to fluorinated anesthetics was associated with slightly better spelling ability (adj β = 1.20; CI 0.02, 2.38) but lower performance IQ at age 7 (only among boys, adj β=-1.97; CI -3.88, -0.06). This study shows inconsistent evidence of effects of maternal exposure to surgery or prenatal exposure to fluorinated agents on child developmental and educational outcomes Residual confounding by indication and socioeconomic status may explain observed associations.

High-risk Growth Trajectory Related to Childhood Overweight/Obesity and Its Predictive Model at Birth.

Childhood obesity increases the risk of chronic disease in adulthood. To construct an early predictive model for a growth trajectory that is highly related to childhood overweight/obesity. Prospective cohort study. Shanghai Birth Cohort (SBC) and US Collaborative Perinatal Project (CPP). A total of 848 mother-child pairs in the SBC (2013-2016) and 22 691 pairs in the CPP (1959-1965) with 2- and 7-year follow-up, respectively. A high-risk postnatal growth trajectory intimately associated with childhood overweight/obesity and its predictive model. We demonstrated that the shifts of postnatal body mass index (BMI) percentile had been completed around 1 year of age and identified a high-risk growth trajectory that was closely related to overweight/obesity [odds ratio 6.5 (95% CI 5.9, 7.2)] at 7 years old. Children with this trajectory presented with a consistent BMI around the 85th percentile after the age of 1 year. It could be recognized early after birth using a predictive model with 4 metabolites (tyrosine, glycine, octenoylcarnitine, and stearoylcarnitine), combined with sex, birth weight, and maternal prepregnancy BMI. The model had an area under the receiver operating characteristic curve of 0.869 (95% CI 0.779, 0.932), a sensitivity of 83.3% (95% CI 51.6%, 97.9%), and a specificity of 81.1% (95% CI 70.3%, 89.3%) in the validation data set. Children with postnatal high-risk growth trajectories were significantly associated with subsequent overweight/obesity at 7 years old. Metabolite profiles at birth combined with clinical measures were able to predict at-risk children before overweight/obesity occurrence.

Gestational age at term delivery and children's neurocognitive development.

Preterm birth is associated with lower neurocognitive performance. However, whether children's neurodevelopment improves with longer gestations within the full-term range (37-41 weeks) is unclear. Given the high rate of obstetric intervention in the USA, it is critical to determine whether long-term outcomes differ for children delivered at each week of term. This secondary analysis included 39199 live-born singleton children of women who were admitted to the hospital in spontaneous labour from the US Collaborative Perinatal Project (1959-76). At each week of term gestation, we evaluated development at 8 months using the Bayley Scales of Infant Development, 4 years using the Stanford-Binet IQ (SBIQ) domains and 7 years using the Wechsler Intelligence Scales for Children (WISC) and Wide-Range Achievement Tests (WRAT). Children's neurocognitive performance improved with each week of gestation from 37 weeks, peaking at 40 or 41 weeks. Relative to those delivered at 40 weeks, children had lower neurocognitive scores at 37 and 38 weeks for all assessments except SBIQ and WISC Performance IQ. Children delivered at 39 weeks had lower Bayley Mental (β = -1.18; confidence interval -1.77, -0.58) and Psychomotor (β = -1.18; confidence interval -1.90, -0.46) scores. Results were similar for within-family analyses comparing siblings, with the addition of lower WRAT scores at 39 weeks. The improvement in development scores across assessment periods indicates that each week up to 40 or 41 weeks of gestation is important for short- and long-term cognitive development, suggesting 40-41 weeks may be the ideal delivery window for optimal neurodevelopmental outcomes.

Developmental Origins of Suicide Mortality in the US Collaborative Perinatal Project (CPP) Cohort

Developmental Origins of Suicide Mortality in the US Collaborative Perinatal Project (CPP) Cohort

Association between Placental Inflammatory Pathology and Offspring Neurodevelopment at 8 Months and 4 and 7 Years of Age

To examine whether placental inflammatory pathology is associated with subsequent child neurodevelopment. We used the data of US Collaborative Perinatal Project cohort study. Placentas were examined by pathologists and child neurodevelopment was evaluated at 8months and 4 and 7years of age. Multivariable logistic regression modelling was used to assess the association. A mediation analysis was used to evaluate whether the association was mediated through shorter gestational age. Multivariable analysis after adjusting for confounders showed that placental inflammatory pathology was significantly associated with low Bayley motor (adjusted OR (aOR), 2.15; 95% CI, 1.50-3.06) and mental scales (aOR, 1.51; 95% CI, 1.05-2.17) at 8months and an IQ of 70-84 (aOR, 1.13; 95% CI, 1.01-1.26) at 4years of age. The association diminished at 7years of age (IQ of <70, aOR 1.20 [95% CI, 0.97-1.48]; IQ of 70-79, aOR 1.03 [95% CI, 0.89-1.18]). The mediation analysis demonstrated that associations between placental inflammatory pathology and development were primarily due to direct effects of placental inflammatory pathology rather than indirect effects of shorter gestational age. Placental inflammation was associated with adverse offspring neurodevelopment up to 4years of age.

Association between neonatal serum bilirubin and childhood obesity in preterm infants.

Serum bilirubin levels are inversely associated with obesity in adults. We are interested in whether neonatal jaundice is associated with childhood obesity in preterm infants. Data were obtained from the US Collaborative Perinatal Project. Neonatal bilirubin levels were used as exposure factors for obesity at age 7 years. Logistic regression models were used to control for potential confounders and calculate odds ratios (ORs). A generalized estimating equation (GEE) model was used to correct for intracluster correlation coefficient. SAS was used for all statistical analyses. In the study subjects, 865 of 5019 preterm infants were obese at age 7 years. While neonatal total serum bilirubin (TSB) rose 1 mg/dl, body mass index (BMI) increased 0.03 kg/m2 (95% confidence interval (CI) 0.02, 0.04). Compared with infants with TSB <3 mg/dl, the ORs (95% CIs) for obesity in infants with 3 mg/dl≤ TSB <6 mg/dl, 6 mg/dl≤ TSB <9 mg/dl, 9 mg/dl≤ TSB <12 mg/dl and TSB ≥12 mg/dl were, respectively, 1.18 (0.87, 1.59), 1.25 (0.93, 1.67), 1.52 (1.11, 2.09), and 1.67 (1.22, 2.07). By using subtypes of bilirubin as exposure factors and the GEE model to correct for intracluster correlation coefficient, similar trends of associations were observed. Neonatal bilirubin levels have positive trends of associations with childhood obesity in preterm infants.

Prenatal Exposure to Antibiotics and Risk of Childhood Obesity in a Multicenter Cohort Study.

Mounting evidence has linked postnatal antibiotic use with body mass index (BMI) in children, but the influence of prenatal antibiotic use on offspring obesity risk remains unclear. We aimed to assess the association between fetal exposure to antibiotics and obesity at ages 4 and 7 years among 43,332 children using a multicenter prospective cohort of the US Collaborative Perinatal Project (1959-1976). Antibiotic use was ascertained for mothers during pregnancy. Modified Poisson regression models were used to estimate risk ratios for obesity (BMI >95th percentile), and linear mixed models were applied to assess the association with BMI z score. Repeated prenatal exposure to antibiotics was associated with childhood obesity at age 7 years, and risk of obesity tended to increase with an increasing number of antibiotic exposures (for 2-3 exposures, risk ratio (RR) = 1.22, 95% confidence interval (CI): 1.04, 1.44; for ≥4 exposures, RR = 1.34, 95% CI: 1.03, 1.73). The magnitude of association was strongest for repeated exposures in the second trimester (RR = 1.40, 95% CI: 1.16, 1.71). Prenatal antibiotic use was not associated with obesity or BMI z score at age 4 years. These findings support an increased risk of mid-childhood obesity with repeated use of antibiotics during pregnancy.

The importance of cohort research starting early in life to understanding child health.

The current review addresses the importance of the prospective cohort design in large, unselected populations starting early in life for understanding the origins of childhood health disorders. Cohort studies originating in healthy populations have contributed to great advances in health, especially in cardiovascular diseases, but have only recently been applied systematically to study the origins of childhood disorders. Several large population-based pregnancy and/or birth cohorts have been developed in different parts of the world, and these are beginning to contribute to better understanding of the underlying causes of rare but important childhood disorders, such as autism. The environmental influences on child health outcomes (ECHO) Program is distinct in leveraging and building upon 84 existing cohorts to prospectively investigate the role of early-life exposures and underlying biological mechanisms in childhood health and disease, specifically perinatal conditions, obesity, neurodevelopmental disorders, asthma and related pulmonary disorders as well as optimum child health. ECHO is expected to comprise approximately 50 000 children. It is the first US study of this size and scope since the US Collaborative Perinatal Project of 1959-1966. The ECHO project represents a new approach to cohort studies in childhood, efficiently making use of extant cohorts while adding new data collection elements that should permit novel insights into the underlying causes of several important pediatric conditions.

Childhood Health Outcomes in Term, Large-for-Gestational-Age Babies With Different Postnatal Growth Patterns.

Large-for-gestational-age (LGA) babies have a higher risk of metabolic disease later in life, and their postnatal growth in early childhood may be associated with long-term adverse outcomes. This study aimed to determine childhood health outcomes of term LGA babies with different growth patterns. Data were obtained from the US Collaborative Perinatal Project for the years between 1959 and 1976. The growth trajectories of 3,316 term LGA babies were identified and odds ratios of obesity, growth restriction, low intelligence quotient (IQ), and high blood pressure (HBP) were calculated by logistic regression. Compared with term appropriate-for-gestational-age infants, term LGA babies without catch-down growth had increased risks of obesity (adjusted odds ratio (aOR) = 6.37, 95% confidence interval (CI): 5.24, 7.73) and HBP (aOR = 1.67, 95% CI: 1.37, 2.03). Those with high catch-down growth had higher risks of growth restriction (aOR = 2.21, 95% CI: 1.66, 2.95) and low IQ (aOR = 1.61, 95% CI: 1.04, 2.49). Nevertheless, infants with small catch-down growth had lower risks of obesity (aOR = 0.78, 95% CI: 0.63, 0.95), growth restriction (aOR = 0.28, 95% CI: 0.17, 0.46), low IQ (aOR = 0.66, 95% CI: 0.41, 1.06), and HBP (aOR = 0.89, 95% CI: 0.77, 1.04). According to our data, term LGA infants with small catch-down growth had no increased risks of adverse outcomes.

Creating a placental inflammatory composite index that has a high prognostic relevance to child morbidity.

Selecting pathologic measures of placental inflammation that affect pregnancy and childhood health is largely empirical. We aimed to systematically select several core inflammation-related placental measures to construct a novel placental inflammatory evaluation criterion with a high prognostic relevance to child morbidity. We used data from the US Collaborative Perinatal Project (1959-1976), a longitudinal birth cohort study that recruited women during pregnancy and followed the children until 7 years of age. Bootstrap resampling, least absolute shrinkage and selection operator, and receiver-operator curve were used to select placental pathologic measures that were closely related to child morbidity to form a placental inflammatory composite index. Twenty-six candidate placental inflammation-related measures were ranked based on their close association with adverse neonatal outcomes. The top five placental measures were: (i) neutrophilic infiltration in umbilical artery; (ii) placental weight-birthweight ratio; (iii) necrosis in decidua capsularis; (iv) bacterial colony in epithelium of amnion; and (v) opacity of membranes and fetal surface. Several composite indexes were constructed. A five-measure composite index that had the highest prognostic relevance was chosen. Compared with subjects without any of the five abnormal measures, those with any lesion ranging from 1 to 5 had a 1.2- to 4.6-fold risk of adverse child outcomes, respectively. Our composite index is simple, evidence-based, and has predictive value for child morbidity. It may be used as a novel placental inflammatory evaluation criterion.

Placental pathology and hypospadias.

Studies have shown that hypospadias is associated with placenta-mediated pregnancy complication (PMPC). The role of placental lesions is still unclear. We aimed to examine the association between hyposadias and placental pathology, and the effect of PMPC. Using data from the US Collaborative Perinatal Project in 1959-1966, we identified 15,780 male subjects (167 hypospadias) for analysis. Detailed placental examinations were conducted following a standard protocol. Subjects were divided into two groups according to whether they had PMPC, including small-for-gestational-age, pre-eclampsia/eclampsia or placental abruption. Logistic regression models were used to explore the association. The prevalence of hypospadias was two times higher in subjects with PMPC than those without. Compared to pregnancies with PMPC but no hypospadias, those with both PMPC and hypospadias had significant higher prevalence of placental lesions, such as low placental weight, vascular lesions, villous lesions, and membranous insertion of cord (adjusted odds ratio (OR) ranging from 2.6 to 5.2) after adjusting for potential confounders. In subjects without PMPC, no significant difference of placental pathology was found between those with or without hypospadias. About one third of hypospadias cases were complicated with PMPC and had a higher risk of placental lesions, suggesting heterogeneity of hypospadias etiology and mechanisms.

What mom and dad’s match means for junior: Marital sorting and child outcomes

This paper employs recently developed marital matching models to examine empirically the role played by marital sorting in observed measures of marital production. Using the US Collaborative Perinatal Project (CPP), a large-scale study from the 1960s, and the National Longitudinal Survey of Youth 1979 (NLSY), we find that marital surplus is strongly correlated with indices of child quality, as measured by cognitive test scores, and with the durability of the marital union. At ages beyond infancy, the correlation between cognitive outcomes and marital surplus is robust to the inclusion of the parental characteristics that generate the match, suggesting that the correlation represents effects of the match itself. High marital surplus is associated with assortative mating on education and age, suggesting complementarity in parental inputs in child production. Our results suggest that marital surplus is an important input for child quality above and beyond its indirect effects on marital stability.

Exposure to Tobacco Metabolites via Breast Milk and Infant Weight Gain: A Population-Based Study.

Although the immutable benefits of breastfeeding are well documented, information on the potential consequences of exposure to tobacco metabolites specifically via breastfeeding is sparse. The aim was to conduct the first study of the association between exposure to tobacco metabolites specifically through breastfeeding and infant weight gain. We used historical data from the US Collaborative Perinatal Project. Mothers were classified as nonsmokers, light smokers (1-19 cigarettes/day), and heavy (20+ cigarettes/day) smokers. In-hospital feeding type was observed during a nursery stay after delivery. We conducted stratified analyses among average-for-gestational-age (AGA; N = 23 571) and small-for-gestational-age (SGA; N = 2552) infants. We isolated the effect of exposure to tobacco metabolites specifically through breastfeeding. Overall, maternal smoking was associated with change in weight-for-length z-score in a dose-response manner. Change in weight z-score was most pronounced among SGA infants of heavy smokers (breastfed: 0.53; 95% confidence interval [CI], 0.12-0.94; formula fed: 0.17; 95% CI, 0.03-0.30). Exposure to tobacco metabolites specifically through breastfeeding was not associated with additional weight gain among AGA infants. Among the much smaller sample of SGA infants, exposure specifically through breastfeeding was associated with marginally significant additional weight gain (0.46; 95% CI, 0.00-0.91) among infants of heavy smokers. Our findings are in accord with recommendations by health agencies for smokers to breastfeed. However, SGA infants exposed to tobacco metabolites via breastfeeding by heavy smokers appear to gain weight more rapidly than other infants. Practical implications of our findings are discussed.

Maternal vitamin D status and infant anthropometry in a US multi-centre cohort study

Background: Maternal vitamin D status in pregnancy is linked to foetal growth and may impact infant growth.Aim: This study examined the association between maternal vitamin D status and infant anthropometry.Subjects and methods: Data came from n = 2473 mother–child pairs from the 12-site US Collaborative Perinatal Project (1959–1965). Maternal serum 25-hydroxyvitamin D (25(OH)D) was measured at ≤ 26 weeks gestation. Multivariate-adjusted linear mixed models were used to relate maternal vitamin D status to infant z-scores for length (LAZ), head circumference (HCZ), weight (WAZ) and BMI (BMIZ), measured at birth and 4, 8 and 12 months.Results: Infants with maternal 25(OH)D ≥30 nmol/L vs <30 nmol/L had LAZ and HCZ measures 0.13 (95% CI = 0.03–0.23) and 0.20 (95% CI = 0.11–0.28) units higher, respectively, across the first year of life. Similar differences in WAZ and BMIZ at birth were resolved by 12 months of age due to interactions indicating steeper age slopes in infants with maternal 25(OH)D <30 nmol/L.Conclusion: Low maternal vitamin D status was associated with deficits at birth in infant weight and BMI that were recouped across the first year of life; associations with reduced measures of linear and skeletal growth were sustained from birth to 12 months.

Maternal and cord blood 25(OH)-vitamin D concentrations in relation to child development and behaviour.

Animal studies have linked in utero vitamin D exposure to various aspects of offspring brain development. Limited research has translated these findings to humans, and none have employed cord blood to measure exposure late in gestation. Our objective was to examine the associations between maternal 25(OH)D measured at ≤26 weeks' gestation or cord blood 25(OH)D and offspring global development, IQ, achievement, and behaviour in the US Collaborative Perinatal Project (1959-73). This was a secondary analysis of data from a case-cohort study, with 3896 women and children who participated in at least one outcome assessment. Psychologists assessed global development at 8 months, IQ and behaviour at 4 and 7 years, and achievement at 7 years. Multiple linear and logistic regression was used to examine the associations between 25(OH)D and child outcomes, controlling for maternal education, age, parity, race, maternal body mass index, marital status, smoking, gestational age and month of blood draw, and study site. Positive associations for many outcomes were greatly attenuated upon adjustment for confounders and were generally null. Only IQ at age 7 was associated with both maternal and cord blood 25(OH)D, but the effect estimates were very small (β for 5 nmol/L increment of maternal 25(OH)D = 0.10; [95% CI 0.00, 0.19]). We observed very little indication that maternal or cord blood 25(OH)D are associated with cognitive development, achievement, and behaviour between 8 months and 7 years of age.

Re: "Neonatal Bilirubin Levels and Childhood Asthma in the US Collaborative Perinatal Project, 1959-1965"

We read with interest the paper by Huang et al. (1) suggesting that neonatal jaundice is associated with childhood asthma. Using data from the Collaborative Perinatal Project (CPP), Huang et al. examined whether the associations between neonatal jaundice and childhood asthma could be due to phototherapy (which was unavailable at the time of the CPP) or a high bilirubin level itself, but the accompanying commentary (2) raised the issue of a potential common cause for both childhood asthma and hyperbilirubinemia, among other possible explanations. We suggest that such a common cause is likely to be maternal asthma, based on our recent findings on the neonatal health of infants born to mothers with asthma (3). We found an increased risk of hyperbilirubinemia (odds ratio = 1.09, 95% confidence interval: 1.04, 1.14) associated with maternal asthma after adjustment for detailed demographic and clinical information from a large US cohort study of electronic medical records. Given that maternal asthma is known to increase the risk of asthma among offspring (4), maternal asthma is a plausible common cause that has not (to our knowledge) been considered in the literature. These relationships are bound to be complex, and careful attention is needed to properly model the potential confounders and mediators of maternal-infant-childhood associations (5). In this case, Huang et al. adjusted their results for maternal allergic conditions (1), but this is a poor proxy for maternal asthma, since about half of current asthma is nonallergic and perhaps 30% of nonasthmatics have a common allergy response. On the other hand, we recognize that the differences between asthma diagnosis and treatment in the 1960s and in the present day add further complexity to the interpretation of these findings. This is an intriguing area of research, and given the high prevalence of asthma in contemporary pregnancy cohorts, it merits further attention.

Maternal Vitamin D Status and Spontaneous Preterm Birth by Placental Histology in the US Collaborative Perinatal Project

The objective of this study was to determine the association between maternal 25-hydroxyvitamin D (25(OH)D) and the risk of spontaneous preterm birth (sPTB) before 35 weeks' gestation. A random subcohort from the US Collaborative Perinatal Project (1959-1965) was sampled (n = 2,629) and augmented with all remaining cases of sPTB before 35 weeks' gestation for a total of 767 cases. Banked serum samples collected at 26 weeks' gestation or earlier were assayed for 25(OH)D. Constructs for vascular histology and inflammatory histology were developed from placental pathology examinations. There was no relationship between 25(OH)D and sPTB among white women. Among nonwhite mothers, serum 25(OH)D levels of 30-<50, 50-<75, and ≥75 nmol/L were associated with reductions of 1.0-1.6 cases of sPTB per 100 live births and 20%-30% reductions in risk of sPTB compared with 25(OH)D levels less than 30 nmol/L after adjustment for prepregnancy body mass index (weight (kg)/height (m)(2)), season, and other confounders. This association was driven by inflammation-mediated cases of sPTB and sPTB cases without placental lesions. A sensitivity analysis for unmeasured confounding by exercise, fish intake, and skin color suggested some bias away from the null in the conventional results, but conclusions were generally supported. The vitamin D-sPTB relationship should be examined in modern cohorts with detailed data on skin pigmentation and other covariates.

Neonatal Bilirubin Levels and Childhood Asthma in the US Collaborative Perinatal Project, 1959–1965

Evidence shows that asthma originates in early life. Studies have found that phototherapy and/or neonatal jaundice may be associated with asthma. We investigated the association between neonatal bilirubin levels and childhood asthma without phototherapy intervention in the Collaborative Perinatal Project, a multicenter prospective cohort study conducted in the United States from 1959 to 1965. A total of 54,795 livebirths were included, and 40,063 children were followed up until 7 years of age or older. Total serum bilirubin (TSB) levels were examined at 48 hours postpartum in newborns with birthweights of 2,250 g or more. Information on asthma and other diseases through age 7 years was summarized and confirmed by a group of pediatricians and child neurologists. Among 28,807 term infants, the overall prevalence of asthma was 5.26%. Risks of asthma increased with both maximum TSB levels and TSB levels at 48 hours postpartum (P for trend < 0.01). Neonatal maximum TSB levels greater than 15 mg/dL were associated with a 61% increase in the risk of childhood asthma (odds ratio = 1.61, 95% confidence interval: 1.04, 2.08) after adjustment for confounders. In this prospective cohort study of infants born at a time when phototherapy was unavailable, neonatal hyperbilirubinemia was associated with an increased risk of childhood asthma.

Invited Commentary: Does Neonatal Hyperbilirubinemia Cause Asthma?

In an analysis of data from the US Collaborative Perinatal Project, Huang et al. (Am J Epidemiol. 2013;178(12):1691-1697) report an association between neonatal total serum bilirubin levels and childhood asthma. To consider the implications of this finding, we need to evaluate whether the association is causal. The results do not appear to be due to chance or any obvious biases. It is likely that the observed association is the result of a common cause of both hyperbilirubinemia and asthma (confounding). Polymorphisms in the glutathione S-transferase gene are a potential genetic confounder. The glutathione S-transferase M1-null phenotype has been linked to both neonatal hyperbilirubinemia and asthma in several studies. Before making any changes in practice aimed at lowering peak bilirubin levels to reduce asthma risk, it is vital to determine not only whether the association between higher bilirubin levels and asthma risk is causal, but also whether interventions to reduce peak bilirubin levels (or their duration) are associated with decreased risk of asthma (without evidence of other adverse effects). The study by Huang et al. should encourage further investigation of these questions.