Background: To examine the prospective association between multivitamin supplementation during pregnancy and biomarker measures of maternal plasma folate and vitamin B 12 levels at birth and child's Autism Spectrum Disorder (ASD) risk. Methods: This report included 1257 mother-child pairs, who were recruited at birth and prospectively followed through childhood at the Boston Medical Center. ASD was defined from diagnostic codes in electronic medical records. Maternal multivitamin supplementation was assessed via questionnaire interview; maternal plasma folate and B 12 were measured from samples taken 2-3 days after birth. Results: Moderate (3-5 times/week) self-reported supplementation during pregnancy was associated with decreased risk of ASD, consistent with previous findings. Using this as the reference group, low (≤2 times/week) and high (>5 times/week) supplementation was associated with increased risk of ASD. Very high levels of maternal plasma folate at birth (≥60.3 nmol/L) had 2.5 times increased risk of ASD [95% confidence interval (CI) 1.3, 4.6] compared to folate levels in the middle 80th percentile, after adjusting for covariates including MTHFR genotype. Similarly, very high B 12 (≥536.8 pmol/L) showed 2.5 times increased risk (95% CI 1.4, 4.5). Conclusion: There was a 'U shaped' relationship between maternal multivitamin supplementation frequency and ASD risk. Extremely high maternal plasma folate and B 12 levels at birth were associated with ASD risk. This hypothesis-generating study does not question the importance of consuming adequate folic acid and vitamin B 12 during pregnancy; rather, raises new questions about the impact of extremely elevated levels of plasma folate and B 12 exposure in-utero on early brain development.

Kabuki syndrome is a monogenic disorder caused by loss of function variants in either of two genes encoding histone-modifying enzymes. We performed targeted sequencing in a cohort of 27 probands with a clinical diagnosis of Kabuki syndrome. Of these, 12 had causative variants in the two known Kabuki syndrome genes. In 2, we identified presumptive loss of function de novo variants in KMT2A (missense and splice site variants), a gene that encodes another histone modifying enzyme previously exclusively associated with Wiedermann-Steiner syndrome. Although Kabuki syndrome is a disorder of histone modification, we also find alterations in DNA methylation among individuals with a Kabuki syndrome diagnosis relative to matched normal controls, regardless of whether they carry a variant in KMT2A or KMT2D or not. Furthermore, we observed characteristic global abnormalities of DNA methylation that distinguished patients with a loss of function variant in KMT2D or missense or splice site variants in either KMT2D or KMT2A from normal controls. Our results provide new insights into the relationship of genotype to epigenotype and phenotype and indicate cross-talk between histone and DNA methylation machineries exposed by inborn errors of the epigenetic apparatus.

Autism Spectrum Disorder (ASD) is phenotypically and etiologically heterogeneous, with evidence for genetic and environmental contributions to disease risk. Research has focused on the prenatal period as a time where environmental exposures are likely to influence risk for ASD. Epidemiological studies have shown significant associations between prenatal exposure to maternal immune activation (MIA), caused by infections and fever, and ASD. However, due to differences in study design and exposure measurements no consistent patterns have emerged revealing specific times or type of MIA exposure that are most important to ASD risk. No prior studies have examined prenatal MIA exposure and ASD risk in an under-represented minority population of African ancestry. To overcome these limitations, we estimated the association between prenatal exposure to fever and maternal infections and ASD in a prospective birth cohort of an understudied minority population in a city in the United States. No association was found between prenatal exposure to genitourinary infections or flu and the risk of ASD in a nested sample of 116 ASD cases and 988 typically developing controls in crude or adjusted analyses. Prenatal exposure to fever was associated with increased ASD risk (aOR = 2.02 [1.04 – 3.92]) after adjustment for educational attainment, marital status, race, child sex, maternal age, birth year, gestational age and maternal smoking. This effect may be specific to fever during the third trimester (aOR 2.70 [1.00 – 7.29]). Our findings provide a focus for future research efforts and ASD prevention strategies across diverse populations. Lay summary We looked at whether activation of the immune system during pregnancy increases the chance a child will develop ASD. We examined 116 children with ASD and 988 children without ASD that came from a predominantly low income, urban, minority population. We found that having the flu or genitourinary tract infections during pregnancy is not related to the child being diagnosed with ASD. However, we did find children were at increased risk for ASD when their mothers had a fever during pregnancy.

Prenatal exposure to maternal immune activation (MIA) has been implicated as a risk factor for the development of autism spectrum disorder (ASD), though the conditions under which this elevated risk occurs are unclear. Animal literature demonstrates that antibiotic use, which affects the composition of the maternal gut microbiota, modifies the effect of MIA on neurodevelopmental outcomes in the offspring. The aim of this study was to assess whether antibiotic use during pregnancy modifies the association between MIA and subsequent risk of ASD, in a prospective birth cohort with 116 ASD cases and 860 typically developing (TD) child controls. There was no evidence of interaction between fever or genitourinary infection and antibiotic use on the odds of ASD in unadjusted or adjusted analyzes. However, we found evidence of an interaction between flu, specifically in second trimester, and antibiotic use at any point during pregnancy on the odds of ASD in the child. Among women who received an antibiotic during pregnancy, flu in trimester two was not associated with ASD (adjusted odds ratio [aOR] = 0.99 [0.43-2.28]). Among women who were not exposed to an antibiotic at any point during pregnancy, flu in second trimester was significantly associated with increased odds of ASD (aOR = 4.05 [1.14-14.38], P = .03), after adjustment for child sex, child birth year, maternal age, gestational age, C-section delivery, and low birthweight. These findings should be treated as hypothesis-generating and suggest that antibiotic use may modify the influence that MIA has on autism risk in the child.

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Children exposed to maternal sickle cell disease (SCD) have many theoretical risks for developmental disorders, but little is known about long-term outcomes for these children. We used the Boston Birth Cohort to compare developmental outcomes between children exposed to maternal SCD and matched, unexposed controls. Children with exposure to maternal SCD had increased risk of attention deficit hyperactivity disorder (OR 5.12, 95% CI 1.36-19.19, p = 0.02) and obesity (OR 2.74, 95% CI 1.10-6.87, p = 0.03). In utero and/or environmental exposures may help explain these findings. Further studies of outcomes of children born to women with SCD are needed.

BACKGROUND: Pregnant women with SCD have an increased risk of both maternal and fetal complications, including preeclampsia, venous thromboembolism, and cardiomyopathy, as well as an increased risk of intrauterine growth restriction, preterm birth, low birth weight, and fetal demise. While in general children with a history of intrauterine growth restriction are at risk for abnormal neurodevelopment as well as later obesity and metabolic syndrome, the long-term developmental outcomes of children without SCD but exposed to maternal SCD are unknown. Better data about the long-term developmental outcome for children of mothers with SCD will provide guidance about the utility of disease modifying therapy during pregnancy. The objective of this study is to explore outcomes for children born to mothers with SCD using data from the Boston Birth Cohort (BBC). METHODS: The BBC is a prospective birth cohort established in 1998 at the Boston Medical Center (BMC) that recruits preterm cases (born at less than 37 weeks gestation) and full term controls. The BBC enrolls predominantly urban, low-income minority mothers and their children 24-72 hours after delivery at the BMC and follows the children from birth up to age 21 years. Data is collected on maternal preconception medical conditions, pregnancy complications, and pregnancy exposures through structured interviews at the time of enrollment and medical record extraction. Data on child development is collected from medical records and structured interviews performed by trained study staff at their scheduled pediatric appointments. Approximately 38% of study participants self-identify as black/African American, 22% as Hispanic, 19% as Haitian, and 8.5% as white. From maternal electronic medical record data capturing 147,827 emergency room and outpatient visits contributed by 5,972 subjects, we identified all women with ICD-9-CM codes for sickle cell disease (282.60-64, 282.68, 282.69, 282.41, 282.42) and probable (two or more 282.62 codes) sickle cell anemia. We then linked maternal and child data on the basis of a unique family-level study ID. Information on child development was obtained from electronic medical record data, based on the presence of relevant ICD-9-CM hospital diagnosis codes from pediatric outpatient, inpatient, and emergency room visits. RESULTS: We identified 93 women who had at least one of the ICD-9 codes for SCD. For this report we have included only those forty-one women who were coded at least twice with a 282.62 diagnosis (Hemoglobin SS disease with crisis). Six (15%) had poor fetal growth during their pregnancy, while eight (20%) were diagnosed with preeclampsia or antepartum hypertension. Among these mothers with available questionnaire and medical record extraction data (n = 38), 7 (18%) delivered their children before 37 weeks gestation, and 6 (16%) had children weighing less than 2500 grams at birth. Twenty mothers had children who received pediatric care at the Boston Medical Center, with ages ranging from 2 to 9 years of age; one was diagnosed with SCA, while 19 are unaffected carriers. Among the 19 children without SCD with available follow-up data, 5 (26%) carried a diagnosis code of overweight/obesity; their mothers were seen for an average of 73 medical visits (SD 50) during their pregnancy. Five children, without any overlap with the children diagnosed with obesity, were diagnosed with failure to thrive; while not statistically significantly different, their mothers had fewer medical encounters (mean 55, SD 37). Five children were diagnosed with delayed milestones, two of whom were late preterm (35 and 33 weeks gestation); two of these children were diagnosed with obesity and two with failure to thrive. DISCUSSION: This exploratory, descriptive study represents the first data on long-term outcomes of children without SCD who were exposed to maternal SCD in utero . While we are limited by small sample size, finding that 26% of children born to mothers with SCD have developmental delay is a significant concern. This compares to the overall cohort where 12% of control children and 39% of preterm cases have been found to have developmental delay. Future studies will include medical record review of mothers to identify additional mothers with confirmed SCD in the cohort and exploration of additional predictors of these concerning outcomes. Figure Figure. Disclosures Lanzkron: Prolong: Research Funding; HRSA: Research Funding; Bayer: Research Funding; Global Blood Therapeutics: Research Funding; Pfizer: Research Funding; PCORI: Research Funding.