Vitamin B
deficiency is a major public health problem worldwide, with the highest burden in elderly people, pregnant women, and young children. Due to its role in DNA synthesis and methylation, ...folate metabolism, and erythropoiesis, vitamin B
supplementation during pregnancy may confer longer-term benefits to maternal and child health outcomes.
To evaluate the benefits and harms of oral vitamin B
supplementation during pregnancy on maternal and child health outcomes.
We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP) on 2 June 2023, and reference lists of retrieved studies.
Randomised controlled trials (RCTs), quasi-RCTs, or cluster-RCTs evaluating the effects of oral vitamin B
supplementation compared to placebo or no vitamin B
supplementation during pregnancy.
We used standard Cochrane methods. Four review authors independently assessed trial eligibility. Two review authors independently extracted data from included studies and conducted checks for accuracy. Three review authors independently assessed the risk of bias of the included studies using the Cochrane RoB 1 tool. We used GRADE to evaluate the certainty of evidence for primary outcomes.
The review included five trials with 984 pregnant women. All trials were conducted in low- and middle-income countries, including India, Bangladesh, South Africa, and Croatia. At enrolment, 26% to 51% of pregnant women had vitamin B
deficiency (less than 150 pmol/L), and the prevalence of anaemia (haemoglobin less than 11.0 g/dL) ranged from 30% to 46%. The dosage of vitamin B
supplementation varied from 5 μg/day to 250 μg/day, with administration beginning at 8 to 28 weeks' gestation through to delivery or three months' postpartum, and the duration of supplementation ranged from 8 to 16 weeks to 32 to 38 weeks. Three trials, involving 609 pregnant women, contributed data for meta-analyses of the effects of vitamin B
supplementation compared to placebo or no vitamin B
supplementation. Maternal anaemia: there may be little to no difference for maternal anaemia by intervention group, but the evidence is very uncertain (70.9% versus 65.0%; risk ratio (RR) 1.08, 95% confidence interval (CI) 0.93 to 1.26; 2 trials, 284 women; very low-certainty evidence). Maternal vitamin B
status: vitamin B
supplementation during pregnancy may reduce the risk of maternal vitamin B
deficiency compared to placebo or no vitamin B
supplementation, but the evidence is very uncertain (25.9% versus 67.9%; RR 0.38, 95% CI 0.28 to 0.51; 2 trials, 272 women; very low-certainty evidence). Women who received vitamin B
supplements during pregnancy may have higher total vitamin B
concentrations compared to placebo or no vitamin B
supplementation (mean difference (MD) 60.89 pmol/L, 95% CI 40.86 to 80.92; 3 trials, 412 women). However, there was substantial heterogeneity (I
= 85%). Adverse pregnancy outcomes: the evidence is uncertain about the effect on adverse pregnancy outcomes, including preterm birth (RR 0.97, 95% CI 0.55 to 1.74; 2 trials, 340 women; low-certainty evidence), and low birthweight (RR 1.50, 95% CI 0.93 to 2.43; 2 trials, 344 women; low-certainty evidence). Two trials reported data on spontaneous abortion (or miscarriage); however, the trials did not report quantitative data for meta-analysis and there was no clear definition of spontaneous abortion in the study reports. No trials evaluated the effects of vitamin B
supplementation during pregnancy on neural tube defects. Infant vitamin B
status: children born to women who received vitamin B
supplementation had higher total vitamin B
concentrations compared to placebo or no vitamin B
supplementation (MD 71.89 pmol/L, 95% CI 20.23 to 123.54; 2 trials, 144 children). Child cognitive outcomes: three ancillary analyses of one trial reported child cognitive outcomes; however, data were not reported in a format that could be included in quantitative meta-analyses. In one study, maternal vitamin B
supplementation did not improve neurodevelopment status (e.g. cognitive, language (receptive and expressive), motor (fine and gross), social-emotional, or adaptive (conceptual, social, practical) domains) in children compared to placebo (9 months, Bayley Scales of Infant and Toddler Development Third Edition (BSID-III); 1 trial; low-certainty evidence) or neurophysiological outcomes (72 months, event-related potential measures; 1 trial; low-certainty evidence), though children born to women who received vitamin B
supplementation had improved expressive language domain compared to placebo (30 months, BSID-III; 1 trial; low-certainty evidence).
Oral vitamin B
supplementation during pregnancy may reduce the risk of maternal vitamin B
deficiency and may improve maternal vitamin B
concentrations during pregnancy or postpartum compared to placebo or no vitamin B
supplementation, but the evidence is very uncertain. The effects of vitamin B
supplementation on other primary outcomes assessed in this review were not reported, or were not reported in a format for inclusion in quantitative analyses. Vitamin B
supplementation during pregnancy may improve maternal and infant vitamin B
status, but the potential impact on longer-term clinical and functional maternal and child health outcomes has not yet been established.
Neonatal morbidity attributable to prematurity predominantly occurs among early preterm births (<32 weeks) rather than late preterm births (32 to <37 weeks). Methods to distinguish early and late ...preterm births are lacking given the heterogeneity in pathophysiology and risk factors, including maternal obesity. Although preterm births are often characterized by clinical presentation (spontaneous or clinically indicated), classifying deliveries by placental features detected on histopathology reports may help identify subgroups of preterm births with similar etiology and risk factors. Latent class analysis is an empirical approach to characterize preterm births on the basis of observed combinations of placental features.
To identify histopathologic markers that can distinguish early (<32 weeks) and late preterm births (32 to <37 weeks) that are also associated with maternal obesity and neonatal outcomes.
Women with a singleton preterm birth at University of Pittsburgh Medical Center Magee-Womens Hospital (Pittsburgh, PA) from 2008 to 2012 and a placental evaluation (89% of preterm births) were stratified into early (n=900, 61% spontaneous) and late preterm births (n=3362, 57% spontaneous). Prepregnancy body mass index was self-reported at first prenatal visit and 16 abstracted placental features were analyzed. Placental subgroups (ie, latent classes) of early and late preterm births were determined separately by latent class analysis of placental features. The optimal number of latent classes was selected by comparing fit statistics. The probability of latent class membership across prepregnancy body mass indexes was estimated in early preterm births and in late preterm births by an extension of multinomial regression called pseudo-class regression, adjusting for race, smoking, education, and parity. The frequencies of severe neonatal morbidity (composite outcome: respiratory distress, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, periventricular leukomalacia, patent ductus arteriosus, and retinopathy of prematurity), small-for-gestational-age, and length of neonatal intensive care unit stay were compared across latent classes by chi-square and Kruskal-Wallis tests.
Early preterm births were grouped into 4 latent classes based on placental histopathologic features: acute inflammation (38% of cases), maternal vascular malperfusion with inflammation (29%), maternal vascular malperfusion (25%), and fetal vascular thrombosis with hemorrhage (8%). As body mass index increased from 20 to 50kg/m2, the probability of maternal vascular malperfusion and fetal vascular thrombosis with hemorrhage increased, whereas the probability of maternal vascular malperfusion with inflammation decreased. There was minimal change in the probability of acute inflammation with increasing body mass index. Late preterm births also had 4 latent classes: maternal vascular malperfusion (22%), acute inflammation (12%), fetal vascular thrombosis with hemorrhage (9%), and low-risk pathology (58%). Body mass index was not associated with major changes in likelihood of the latent classes in late preterm births. Associations between body mass index and likelihood of the latent classes were not modified by type of delivery (spontaneous or indicated) in early or late preterm births. Maternal malperfusion and fetal vascular thrombosis with hemorrhage were associated with greater neonatal morbidity than the other latent classes in early and late preterm births.
Obesity may predispose women to early but not late preterm birth through placental vascular impairment. Latent class analysis of placental histopathologic data provides an evidence-based approach to group preterm births with shared underlying etiology and risk factors.
Placental histopathology is a resource for investigating obesity-associated pregnancy conditions. However, studies oversample adverse pregnancies, biasing findings. We examine the association between ...prepregnancy obesity (risk factor for inflammation) and histologic placental inflammation (correlated with impaired infant neurodevelopment) and how selection bias may influence the association.
Singleton term deliveries between 2008 and 2012 from the Magee Obstetric Maternal and Infant database were analyzed. Prepregnancy body mass index (BMI) was categorized as underweight, lean (referent), overweight, and obese. Outcomes were diagnoses of acute (acute chorioamnionitis and fetal inflammation) and chronic placental inflammation (chronic villitis). Risk ratios for associations between BMI and placental inflammation were estimated using selection bias approaches: complete case, exclusion of pregnancy complications, multiple imputation, and inverse probability weighting. E-values approximated how susceptible estimates were to residual selection bias.
Across methods, obesity was associated with an 8–15% lower risk of acute chorioamnionitis, a 7%–14% lower risk of acute fetal inflammation, and a 12%–30% higher risk of chronic villitis relative to lean women. E-values indicated modest residual selection bias could explain away associations, though few measured indications of placental evaluations met this threshold.
Obesity may contribute to placental inflammation, and we highlight robust methods to analyze clinical data susceptible to selection bias.
Human chorionic gonadotropin (hCG) is a placental hormone measured in pregnancy to predict individual level risk of fetal aneuploidy and other complications; yet may be useful in understanding ...placental origins of child development more generally. hCG was associated with maternal body mass index (BMI) and with birthweight. The primary aim here was to evaluate hCG as a mediator of maternal BMI effects on birthweight by causal mediation analysis. Subjects were 356 women from 3 U.S. sites (2010-2013). The 4-way decomposition method using med4way (STATA) was applied to screen for 5 types of effects of first trimester maternal BMI on birthweight: the total effect, the direct effect, mediation by hCG, additive interaction of BMI and hCG, and mediation in the presence of an additive interaction. Effect modification by fetal sex was evaluated, and a sensitivity analysis was performed to evaluate the assumption of unmeasured confounding. Additional placental-fetal biomarkers pregnancy associated plasma protein A (PAPPA), second trimester hCG, inhibin-A, estriol, alpha fetoprotein were analyzed for comparison. For first trimester hCG, there was a 0.20 standard deviation increase in birthweight at the 75th vs. 25th percentile of maternal BMI (95% CI 0.04, 0.36). Once stratified, the direct effect association was null in women carrying females. In women carrying males, hCG did not mediate the relationship. In women carrying females, there was a mediated effect of maternal BMI on birthweight by hCG in the reverse direction (-0.06, 95% CI: -0.12, 0.01), and a mediated interaction in the positive direction (0.06, 95% CI 0.00, 0.13). In women carrying males, the maternal BMI effect on birthweight was reverse mediated by PAPPA (-0.09, 95% CI: -0.17, 0.00). Sex-specific mediation was mostly present in the first trimester. Second trimester AFP was a positive mediator of maternal BMI effects in male infants only (0.06, 95% CI: -0.01, 0.13). Effect estimates were robust to potential bias due to unmeasured confounders. These findings motivate research to consider first trimester placental biomarkers and sex-specific mechanisms when quantifying the effects of maternal adiposity on fetal growth.
Purpose of Review
In this review, we provide essential background knowledge and an analytical framework for the application of placental-fetal molecular biomarkers in fetal origins chronic disease ...epidemiology. The widely available and highly quantitative placental hormone human chorionic gonadotropin (hCG) is used as an example. hCG is currently used for diagnosing fetal genetic disorders; yet, it can and should be expanded to understanding the fetal origins of chronic diseases. We provide justification and methods to do this.
Recent Findings
Ten papers published in the last 5 years were identified with supportive findings relevant to the application of biomarkers of hCG in epidemiologic studies on the developmental origins of health and disease (DOHaD).
Summary
There is increasing and consistent evidence that placental-fetal biomarkers may be highly informative in observational studies, as exemplified by hCG, with the correct approaches for measurement and data analysis.
The function of the gestational sac (GS) and the placenta in the closely related processes of embryogenesis and teratogenicity in the first trimester has been minimally described. The prevailing ...assumption is that direct teratogenic effects are mediated by the critical extraembryonic organ, the placenta, which either blocks or transfers exposures to the foetus. Placental transfer is a dominant mechanism, but there are other paradigms by which the placenta can mediate teratogenic effects. Knowledge of these paradigms and first trimester human developmental biology can be useful to the epidemiologist in the conduct of biomarker-based studies of both maternal and child health.
Our aim is to provide a causal framework for modelling the teratogenic effects of first trimester exposures on child health outcomes mediated by the GS and placenta using biomarker data collected in the first trimester. We initially present first trimester human developmental biology for the sake of informing and strengthening epidemiologic approaches. We then propose analytic approaches of modelling placental mechanisms by way of causal diagrams using classical non-embryolethal teratogens (diethylstilboestrol DES, folic acid deficiency and cytomegalovirus CMV) as illustrative examples. We extend this framework to two chronic exposures of particular current interest, phthalates and maternal adiposity.
Information on teratogens was identified by a non-systematic, narrative review. For each teratogen, we included papers that answered the five following questions: (i) why were these exposures declared teratogens? (ii) is there a consensus on biologic mechanism? (iii) is there reported evidence of a placental mechanism? (iv) can we construct a theoretical model of a placental mechanism? and (v) can this knowledge inform future work on measurement and modelling of placental-foetal teratogenesis? We prioritized literature specific to human development, the organogenesis window in the first trimester and non-embryolethal mechanisms.
As a result of our review of the literature on five exposures considered harmful in the first trimester, we developed four analytic strategies to address first trimester placental mechanisms in birth cohort studies: placental transfer and direct effects on the foetus (DES and maternal adiposity), indirect effects through targeted placental molecular pathways (DES and phthalates), pre-placental effects through disruptions in embryonic and extraembryonic tissue layer differentiation (folic acid deficiency), and multi-step mechanisms that involve maternal, placental and foetal immune function and inflammation (DES and CMV).
The significance of this review is to offer a causal approach to classify the large number of potentially harmful exposures in pregnancy when the exposure occurs in the first trimester. Our review will facilitate future research by advancing knowledge of the first trimester mechanisms necessary for researchers to effectively associate environmental exposures with child health outcomes.
Acute pancreatitis (AP), resulting from inflammation of the pancreas, accounts for more than 300,000 US hospital discharges per year. Although glucose intolerance has been known as a complication of ...severe AP, this effect was thought to be transient. Recently, cohort studies and meta-analysis of 24 published studies of 1100 patients who survived one or more episodes of AP revealed that 30% to 40% of patients developed diabetes or impaired glucose tolerance within 3 to 4 years of even a single episode of AP. The National Institute of Diabetes and Digestive and Kidney Diseases funded the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC) to undertake a prospective observational study of the occurrence of diabetes during an AP episode or subsequently, with emphasis on type 1 diabetes. Key factors for funding T1DAPC are the increasing incidence and prevalence of AP, its association with the development of type 1 diabetes and other forms of diabetes after AP, its complications, and associated health care cost. The T1DAPC structure, governance, and research objectives are described in this article. The DREAM (Diabetes RElated to Acute pancreatitis and its Mechanisms) studies to be undertaken by the T1DAPC are described in other articles in this journal's issue.
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