Promoting Data Harmonization of COVID-19 Research in Pregnant and Pediatric Populations.

This Viewpoint investigates the use of common data elements to promote data harmonization in COVID-19­related studies of pediatric and pregnant populations.

The Intersection of Disability and Pregnancy: Risks for Maternal Morbidity and Mortality.

It is estimated that 1 in 4 women in the United States live with a disability, and using population-based estimates, 10-12% of women of childbearing age have a disability. There are limited data to suggest that women with disabilities experience higher rates of or risks for adverse outcomes related to pregnancy, delivery, and access to appropriate postpartum care. Research on specific disabling conditions demonstrates variable risk for syndromes that threaten the health of the mother, such as preeclampsia, infection, and coagulation disorders. Much of the literature suggests that normal, healthy pregnancy is possible but points to the need for tailored information for patients and providers about the intersection of their condition with pregnancy and specific care needs. Given the lack of systematic evidence in this area across conditions and functional impairments, more research is needed to clarify the interaction of specific disabilities with pregnancy and provide evidence-based information to the field to decrease the risks to mothers and their infants. This article will provide an overview of conditions that contribute to maternal morbidity and mortality as they relate to pregnancy in women with disabilities and provide resources to the field to further the investigation of this area.

Clinical sensitivity and specificity of meconium fatty acid ethyl ester, ethyl glucuronide, and ethyl sulfate for detecting maternal drinking during pregnancy.

BACKGROUND: We investigated agreement between self-reported prenatal alcohol exposure (PAE) and objective meconium alcohol markers to determine the optimal meconium marker and threshold for identifying PAE. METHODS: Meconium fatty acid ethyl esters (FAEE), ethyl glucuronide (EtG), and ethyl sulfate (EtS) were quantified by LC-MS/MS in 0.1 g meconium from infants of Safe Passage Study participants. Detailed PAE information was collected from women with a validated timeline follow-back interview. Because meconium formation begins during weeks 12-20, maternal self-reported drinking at or beyond 19 weeks was our exposure variable. RESULTS: Of 107 women, 33 reported no alcohol consumption in pregnancy, 16 stopped drinking by week 19, and 58 drank beyond 19 weeks (including 45 third-trimester drinkers). There was moderate to substantial agreement between self-reported PAE at ≥19 weeks and meconium EtG ≥30 ng/g (κ = 0.57, 95% CI 0.41-0.73). This biomarker and associated cutoff was superior to a 7 FAEE sum ≥2 nmol/g and all other individual and combination marker cutoffs. With meconium EtG ≥30 ng/g as the gold standard condition and maternal self-report at ≥19 weeks' gestation as the test condition, 82% clinical sensitivity (95% CI 71.6-92.0) and 75% specificity (95% CI 63.2-86.8) were observed. A significant dose-concentration relationship between self-reported drinks per drinking day and meconium EtG ≥30 ng/g also was observed (all P < 0.01). CONCLUSIONS: Maternal alcohol consumption at ≥19 weeks was better represented by meconium EtG ≥30 ng/g than currently used FAEE cutoffs.

The safe passage study: design, methods, recruitment, and follow-up approach.

BACKGROUND: The Safe Passage Study is a large, prospective, multidisciplinary study designed to (1) investigate the association between prenatal alcohol exposure, sudden infant death syndrome (SIDS), and stillbirth, and (2) determine the biological basis of the spectrum of phenotypic outcomes from exposure, as modified by environmental and genetic factors that increase the risk of stillbirth, SIDS, and in surviving children, fetal alcohol spectrum disorders. METHODS: The results provided are based on an interim assessment of 6004 women enrolled, out of the 12,000 projected, from the Northern Plains, US, and Cape Town, South Africa, areas known to be of high risk for maternal drinking during pregnancy. Research objectives, study design, and descriptive statistics, including consent, recruitment, and retention information, are provided. RESULTS: Overall visit compliance is 87%, and includes prenatal, delivery/newborn, and postnatal contacts through 1 year post-delivery. Pregnancy outcome ascertainment is 98% prior to medical chart review; less than 2% of women withdraw. Consent for the use of DNA and placental tissue exceed 94%, and consent to participate in the autopsy portion of the study is 71%. CONCLUSIONS: The Safe Passage Study is the first multi-site study of SIDS and stillbirth to integrate prospectively collected exposure information with multidisciplinary biological information in the same maternal and fetal/infant dyad using a common protocol. Essential components of the study design and its success are close ties to the community and rigorous systems and processes to ensure compliance with the study protocol and procedures.

Influence of bedsharing activity on breastfeeding duration among US mothers.

IMPORTANCE: Some professional associations advocate bedsharing to facilitate breastfeeding, while others recommend against it to reduce the risk of sudden infant death syndrome and suffocation deaths. A better understanding of the quantitative influence of bedsharing on breastfeeding duration is needed to guide policy. OBJECTIVE: To quantify the influence of bedsharing on breastfeeding duration. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal data were from the Infant Feeding Practices Study II, which enrolled mothers while pregnant and followed them through the first year of infant life. Questionnaires were sent at infant ages 1 to 7, 9, 10, and 12 months, and 1846 mothers answered at least 1 question regarding bedsharing and were breastfeeding at infant age 2 weeks. EXPOSURES: Bedsharing, defined as the mother lying down and sleeping with her infant on the same bed or other sleeping surfaces for nighttime sleep or during the major sleep period. MAIN OUTCOMES AND MEASURES: Survival analysis to investigate the effect of bedsharing on duration of any and exclusive breastfeeding. RESULTS: Longer duration of bedsharing, indicated by a larger cumulative bedsharing score, was associated with a longer duration of any breastfeeding but not exclusive breastfeeding, after adjusting for covariates. Breastfeeding duration was longer among women who were better educated, were white, had previously breastfed, had planned to breastfeed, and had not returned to work in the first year postpartum. CONCLUSIONS AND RELEVANCE: Multiple factors were associated with breastfeeding, including bedsharing. Given the risk of sudden infant death syndrome related to bedsharing, multipronged strategies to promote breastfeeding should be developed and tested.

Integrative transcriptome analysis reveals dysregulation of canonical cancer molecular pathways in placenta leading to preeclampsia.

We previously suggested links between specific XPD mutations in the fetal genome and the risk of placental maldevelopment and preeclampsia, possibly due to impairment of Transcription Factor (TF)IIH-mediated functions in placenta. To identify the underlying mechanisms, we conducted the current integrative analysis of several relevant transcriptome data sources. Our meta-analysis revealed downregulation of TFIIH subunits in preeclamptic placentas. Our overall integrative analysis suggested that, in the presence of hypoxia and oxidative stress, EGFR signaling deficiency, which can be caused by TFIIH impairment as well as by other mechanisms, results in ATF3 upregulation, inducing mediators of clinical symptoms of preeclampsia such as FLT1 and ENG. EGFR- and ATF3-dependent pathways play prominent roles in cancer development. We propose that dysregulation of these canonical cancer molecular pathways occurs in preeclampsia and delineate the relevance of TFIIH, providing etiologic clues which could eventually translate into a therapeutic approach.

VBAC: what does the evidence show?

Declining rates of vaginal birth after cesarean (VBAC) are contributing to rising total cesarean delivery rates. The reasons behind the decreased utilization of VBAC are complex, but concerns about the safety of a trial of labor after cesarean are often cited. This manuscript will present a summary of existing evidence on maternal and fetal/neonatal outcomes associated with trial of labor after cesarean/VBAC, and highlight findings from recent contributions to this literature.

Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects.

BACKGROUND: Neural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk. METHODS: A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case-control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects. RESULTS: Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003-0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing. CONCLUSIONS: To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive correction. We have produced a ranked list of variants with the strongest association signals. Variants in the highest rank of associations are likely to include true associations and should be high priority candidates for further study of NTD risk.

Phenotype-specific adverse effects of XPD mutations on human prenatal development implicate impairment of TFIIH-mediated functions in placenta.

Mutations in XPD (ERCC2), XPB (ERCC3), and TTD-A (GTF2H5), genes involved in nucleotide excision repair and transcription, can cause several disorders including trichothiodystrophy (TTD) and xeroderma pigmentosum (XP). In this study, we tested the hypothesis that mutations in the XPD gene affect placental development in a phenotype-specific manner. To test our hypothesis and decipher potential biologic mechanisms, we compared all XPD-associated TTD (n=43) and XP (n=37) cases reported in the literature with respect to frequencies of gestational complications. Our genetic epidemiologic investigations of TTD and XP revealed that the exact genetic abnormality was relevant to the mechanism leading to gestational complications such as preeclampsia. Through structural mapping, we localized the preeclampsia-associated mutations to a C-terminal motif and the helicase surfaces of XPD, most likely affecting XPD's binding to cdk-activating kinase (CAK) and p44 subunits of transcription factor (TF) IIH. Our results suggested a link between TTD- but not XP-associated XPD mutations, placental maldevelopment and risk of pregnancy complications, possibly due to impairment of TFIIH-mediated functions in placenta. Our findings highlight the importance of the fetal genotype in development of gestational complications, such as preeclampsia. Therefore, future studies of genetic associations of preeclampsia and other placental vascular complications may benefit from focusing on genetic variants within the fetal DNA.

U.S. primary care physicians' diet-, physical activity-, and weight-related care of adult patients.

BACKGROUND: Overweight and obesity are substantial problems in the U.S., but few national studies exist on primary care physicians' (PCPs') clinical practices regarding overweight and obesity. PURPOSE: To profile diet, physical activity, and weight control practice patterns of PCPs who treat adults. METHODS: A nationally representative survey of 1211 PCPs sampled from the American Medical Association's Masterfile was conducted in 2008 and analyzed in 2010. Outcomes included PCPs' assessment, counseling, referral, and follow-up of diet, physical activity, and weight control in adult patients with and without chronic disease and PCPs' use of pharmacologic treatments and surgical referrals for overweight and obesity. RESULTS: The survey response rate was 64.5%. Half of PCPs (49%) reported recording BMI regularly. Fewer than 50% reported always providing specific guidance on diet, physical activity, or weight control. Regardless of patients' chronic disease status, <10% of PCPs always referred patients for further evaluation/management and <22% reported always systematically tracking patients over time concerning weight or weight-related behaviors. Overall, PCPs were more likely to counsel on physical activity than on diet or weight control (p's<0.05). More than 70% of PCPs reported ever using pharmacologic treatments to treat overweight and 86% had referred for obesity-related surgery. CONCLUSIONS: PCPs' assessment and behavioral management of overweight and obesity in adults is at a low level relative to the magnitude of the problem in the U.S. Further research is needed to understand barriers to providing care and to improve physician engagement in tracking and managing healthy lifestyles in U.S. adults.

Pregnancy in women with physical disabilities.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development sponsored a 2-day workshop to assess the body of evidence on pregnancy in women with physical disabilities, identify gaps in knowledge, and formulate recommendations for further research. A multidisciplinary group of experts discussed available data on pregnancy outcomes among women with varying physically disabling conditions, medical and psychosocial risks for mothers and children, and barriers to prenatal care and parenting for women with physical disabilities. Existing evidence is limited by a preponderance of retrospective single-site studies of small sample sizes. For most women, pregnancy outcomes are favorable. However, increased rates of certain adverse outcomes, such as low birth weight (related to preterm birth or growth restriction) and cesarean delivery, have been reported in women with spinal cord injuries, rheumatoid arthritis, multiple sclerosis, or other conditions. Common morbidities across conditions may include urinary tract infections, decreased mobility and independence, skin ulceration, respiratory compromise, interpersonal abuse, stress, and mood disorders. Socioeconomic, physical, and attitudinal barriers to antenatal care and independent parenting can be problematic. Current evidence, although limited, indicates that most women with physical disabilities will have good pregnancy outcomes; however, some data suggest that rates of a range of complications may be more common among women with physical disabilities, depending on the nature and severity of the underlying condition. Many questions remain unanswered. Establishment of a systematic and comprehensive registry of pregnancy course and outcomes among women with physical disabilities is of high priority for addressing persistent gaps in knowledge.

Delivery after previous cesarean: long-term outcomes in the child.

In subsequent pregnancies after a cesarean delivery, women must choose between attempting to deliver vaginally or undergoing another cesarean delivery. Information relevant to this choice includes the long-term benefits and harms to the baby. In this article we discuss the relationship of mode of delivery (planned trial of labor, either with or without vaginal delivery, or elective repeat cesarean delivery) and long-term outcomes, including brachial plexus palsy, neurodevelopmental impairment, and asthma. No randomized trials are available that relate directly to the choice of delivery method after previous cesarean. Observational studies suggest that cesarean delivery might be associated with a greater risk of asthma, caused perhaps by altered gut colonization, increased risk of neonatal respiratory disease, decreased gestational age at birth or decreased likelihood of breastfeeding. By contrast, vaginal delivery after a previous cesarean delivery is associated with greater risks of neurodevelopmental impairment and upper-extremity motor impairment, caused, respectively, by greater risks of perinatal hypoxic-ischemic encephalopathy and brachial plexus injury. Available information does not provide a precise estimate of the relative risks for infants delivered after a trial of labor versus elective cesarean delivery.

Antenatal testing-a reevaluation: executive summary of a Eunice Kennedy Shriver National Institute of Child Health and Human Development workshop.

In August 2007, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health Office of Rare Diseases, the American College of Obstetricians and Gynecologists, and the American Academy of Pediatrics cosponsored a 2-day workshop to reassess the body of evidence supporting antepartum assessment of fetal well-being, identify key gaps in the evidence, and formulate recommendations for further research. Participants included experts in obstetrics and fetal physiology and representatives from relevant stakeholder groups and organizations. This article is a summary of the discussions at the workshop, including synopses of oral presentations on the epidemiology of stillbirth and fetal neurological injury, fetal physiology, techniques for antenatal monitoring, and maternal and fetal indications for monitoring. Finally, a synthesis of recommendations for further research compiled from three breakout workgroups is presented.