Effects of Cooking with Liquefied Petroleum Gas or Biomass on Stunting in Infants.

BACKGROUND: Household air pollution is associated with stunted growth in infants. Whether the replacement of biomass fuel (e.g., wood, dung, or agricultural crop waste) with liquefied petroleum gas (LPG) for cooking can reduce the risk of stunting is unknown. METHODS: We conducted a randomized trial involving 3200 pregnant women 18 to 34 years of age in four low- and middle-income countries. Women at 9 to less than 20 weeks' gestation were randomly assigned to use a free LPG cookstove with continuous free fuel delivery for 18 months (intervention group) or to continue using a biomass cookstove (control group). The length of each infant was measured at 12 months of age, and personal exposures to fine particulate matter (particles with an aerodynamic diameter of ≤2.5 µm) were monitored starting at pregnancy and continuing until the infants were 1 year of age. The primary outcome for which data are presented in the current report - stunting (defined as a length-for-age z score that was more than two standard deviations below the median of a growth standard) at 12 months of age - was one of four primary outcomes of the trial. Intention-to-treat analyses were performed to estimate the relative risk of stunting. RESULTS: Adherence to the intervention was high, and the intervention resulted in lower prenatal and postnatal 24-hour personal exposures to fine particulate matter than the control (mean prenatal exposure, 35.0 µg per cubic meter vs. 103.3 µg per cubic meter; mean postnatal exposure, 37.9 µg per cubic meter vs. 109.2 µg per cubic meter). Among 3061 live births, 1171 (76.2%) of the 1536 infants born to women in the intervention group and 1186 (77.8%) of the 1525 infants born to women in the control group had a valid length measurement at 12 months of age. Stunting occurred in 321 of the 1171 infants included in the analysis (27.4%) of the infants born to women in the intervention group and in 299 of the 1186 infants included in the analysis (25.2%) of those born to women in the control group (relative risk, 1.10; 98.75% confidence interval, 0.94 to 1.29; P = 0.12). CONCLUSIONS: An intervention strategy starting in pregnancy and aimed at mitigating household air pollution by replacing biomass fuel with LPG for cooking did not reduce the risk of stunting in infants. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; HAPIN ClinicalTrials.gov number, NCT02944682.).

Effects of a liquefied petroleum gas stove intervention on stillbirth, congenital anomalies and neonatal mortality: A multi-country household air pollution intervention network trial.

Household air pollution (HAP) from cooking with solid fuels used during pregnancy has been associated with adverse pregnancy outcomes. The Household Air Pollution Intervention Network (HAPIN) trial was a randomized controlled trial that assessed the impact of a liquefied petroleum gas (LPG) stove and fuel intervention on health in Guatemala, India, Peru, and Rwanda. Here we investigated the effects of the LPG stove and fuel intervention on stillbirth, congenital anomalies and neonatal mortality and characterized exposure-response relationships between personal exposures to fine particulate matter (PM2.5), black carbon (BC) and carbon monoxide (CO) and these outcomes. Pregnant women (18 to <35 years of age; gestation confirmed by ultrasound at 9 to <20 weeks) were randomly assigned to intervention or control arms. We monitored these fetal and neonatal outcomes and personal exposure to PM2.5, BC and CO three times during pregnancy, we conducted intention-to-treat (ITT) and exposure-response (E-R) analyses to determine if the HAPIN intervention and corresponding HAP exposure was associated with the risk of fetal/neonatal outcomes. A total of 3200 women (mean age 25.4 ± 4.4 years, mean gestational age at randomization 15.4 ± 3.1 weeks) were included in this analysis. Relative risks for stillbirth, congenital anomaly and neonatal mortality were 0.99 (0.60, 1.66), 0.92 (95 % CI 0.52, 1.61), and 0.99 (0.54, 1.85), respectively, among women in the intervention arm compared to controls in an ITT analysis. Higher mean personal exposures to PM2.5, CO and BC during pregnancy were associated with a higher, but statistically non-significant, incidence of adverse outcomes. The LPG stove and fuel intervention did not reduce the risk of these outcomes nor did we find evidence supporting an association between personal exposures to HAP and stillbirth, congenital anomalies and neonatal mortality.

Liquefied Petroleum Gas or Biomass Cooking and Severe Infant Pneumonia.

BACKGROUND: Exposure to household air pollution is a risk factor for severe pneumonia. The effect of replacing biomass cookstoves with liquefied petroleum gas (LPG) cookstoves on the incidence of severe infant pneumonia is uncertain. METHODS: We conducted a randomized, controlled trial involving pregnant women 18 to 34 years of age and between 9 to less than 20 weeks' gestation in India, Guatemala, Peru, and Rwanda from May 2018 through September 2021. The women were assigned to cook with unvented LPG stoves and fuel (intervention group) or to continue cooking with biomass fuel (control group). In each trial group, we monitored adherence to the use of the assigned cookstove and measured 24-hour personal exposure to fine particulate matter (particles with an aerodynamic diameter of ≤2.5 µm [PM2.5]) in the women and their offspring. The trial had four primary outcomes; the primary outcome for which data are presented in the current report was severe pneumonia in the first year of life, as identified through facility surveillance or on verbal autopsy. RESULTS: Among 3200 pregnant women who had undergone randomization, 3195 remained eligible and gave birth to 3061 infants (1536 in the intervention group and 1525 in the control group). High uptake of the intervention led to a reduction in personal exposure to PM2.5 among the children, with a median exposure of 24.2 µg per cubic meter (interquartile range, 17.8 to 36.4) in the intervention group and 66.0 µg per cubic meter (interquartile range, 35.2 to 132.0) in the control group. A total of 175 episodes of severe pneumonia were identified during the first year of life, with an incidence of 5.67 cases per 100 child-years (95% confidence interval [CI], 4.55 to 7.07) in the intervention group and 6.06 cases per 100 child-years (95% CI, 4.81 to 7.62) in the control group (incidence rate ratio, 0.96; 98.75% CI, 0.64 to 1.44; P = 0.81). No severe adverse events were reported to be associated with the intervention, as determined by the trial investigators. CONCLUSIONS: The incidence of severe pneumonia among infants did not differ significantly between those whose mothers were assigned to cook with LPG stoves and fuel and those whose mothers were assigned to continue cooking with biomass stoves. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; HAPIN ClinicalTrials.gov number, NCT02944682.).

Effects of a LPG stove and fuel intervention on adverse maternal outcomes: A multi-country randomized controlled trial conducted by the Household Air Pollution Intervention Network (HAPIN).

Household air pollution from solid cooking fuel use during gestation has been associated with adverse pregnancy and birth outcomes. The Household Air Pollution Intervention Network (HAPIN) trial was a randomized controlled trial of free liquefied petroleum gas (LPG) stoves and fuel in Guatemala, Peru, India, and Rwanda. A primary outcome of the main trial was to report the effects of the intervention on infant birth weight. Here we evaluate the effects of a LPG stove and fuel intervention during pregnancy on spontaneous abortion, postpartum hemorrhage, hypertensive disorders of pregnancy, and maternal mortality compared to women who continued to use solid cooking fuels. Pregnant women (18-34 years of age; gestation confirmed by ultrasound at 9-19 weeks) were randomly assigned to an intervention (n = 1593) or control (n = 1607) arm. Intention-to-treat analyses compared outcomes between the two arms using log-binomial models. Among the 3195 pregnant women in the study, there were 10 spontaneous abortions (7 intervention, 3 control), 93 hypertensive disorders of pregnancy (47 intervention, 46 control), 11 post postpartum hemorrhage (5 intervention, 6 control) and 4 maternal deaths (3 intervention, 1 control). Compared to the control arm, the relative risk of spontaneous abortion among women randomized to the intervention was 2.32 (95% confidence interval (CI): 0.60, 8.96), hypertensive disorders of pregnancy 1.02 (95% CI: 0.68, 1.52), postpartum hemorrhage 0.83 (95% CI: 0.25, 2.71) and 2.98 (95% CI: 0.31, 28.66) for maternal mortality. In this study, we found that adverse maternal outcomes did not differ based on randomized stove type across four country research sites.

Does antenatal cholecalciferol supplementation affect the mode or timing of delivery? Post hoc analyses of the MAVIDOS randomized controlled trial.

BACKGROUND: Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH). METHODS: MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks' gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records. RESULTS: A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P = 0.054) overall], but similar when stratified by delivery mode. CONCLUSIONS: Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD.

Pregnancy Vitamin D Supplementation and Childhood Bone Mass at Age 4 Years: Findings From the Maternal Vitamin D Osteoporosis Study (MAVIDOS) Randomized Controlled Trial.

In the Maternal Vitamin D Osteoporosis Study (MAVIDOS) randomized trial, vitamin D supplementation in pregnancy did not lead to greater neonatal bone mass across the trial as a whole, but, in a prespecified secondary analysis by season of birth, led to greater neonatal bone mass among winter-born babies. Demonstrating persistence of this effect into childhood would increase confidence in a long-term benefit of this intervention. We investigated whether antenatal vitamin D supplementation increases offspring bone mineralization in early childhood in a prespecified, single-center follow-up of a double-blinded, multicenter, randomized controlled clinical trial based in the UK (MAVIDOS). A total of 1123 women in early pregnancy with a baseline 25-hydroxyvitamin D level 25-100 nmol/L from three research centers (2008-2014) were randomized to 1000 IU/d cholecalciferol or matched placebo from 14 weeks of gestation to delivery. Offspring born at the Southampton, UK research center were assessed at age 4 years (2013-2018). Anthropometry and dual-energy X-ray absorptiometry (DXA) were performed (yielding whole body less head [WBLH] bone mineral content [BMC], areal bone mineral density [aBMD], bone area [BA], and body composition). Of 723 children, 564 (78.0%) children attended the 4-year visit, 452 of whom had a useable DXA. Maternal vitamin D supplementation led to greater WBLH aBMD in the children compared with placebo (mean [95% confidence interval {CI}]: supplemented group: 0.477 (95% CI, 0.472-0.481) g/cm2; placebo group: 0.470 (95% CI, 0.466-0.475) g/cm2, p = 0.048). Associations were consistent for BMC and lean mass, and in age- and sex-adjusted models. Effects were observed across the whole cohort irrespective of season of birth. Maternal-child interactions were observed, with a greater effect size among children with low milk intake and low levels of physical activity. Child weight, height, and body mass index (BMI) were similar by maternal randomization group. These findings suggest a sustained beneficial effect of maternal vitamin D supplementation in pregnancy on offspring aBMD at age 4 years, but will require replication in other trials. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Complex Perinatal Syndromes Affecting Early Human Growth and Development: Issues to Consider to Understand Their Aetiology and Postnatal Effects.

Complex perinatal syndromes (CPS) affecting pregnancy and childhood, such as preterm birth, and intra- and extra-uterine growth restriction, have multiple, diverse contexts of complexity and interaction that determine the short- and long-term growth, health and development of all human beings. Early in life, genetically-guided somatic and cerebral development occurs alongside a psychism "in statu nascendi," with the neural structures subjected to the effects of the intra- and extra-uterine environments in preparation for optimal postnatal functioning. Different trajectories of fetal cranial and abdominal growth have been identified before 25 weeks' gestation, tracking differential growth and neurodevelopment at 2 years of age. Similarly, critical time-windows exist in the first 5-8 months of postnatal life because of interactions between the newborn and their environment, mother/care-givers and feeding practices. Understanding these complex relational processes requires abandoning classical, linear and mechanistic interpretations that are placed in rigid, artificial biological silos. Instead, we need to conduct longitudinal, interdisciplinary research and integrate the resulting new knowledge into clinical practice. An ecological-systemic approach is required to understand early human growth and development, based on a dynamic multidimensional process from the molecular or genomic level to the socio-economic-environmental context. For this, we need theoretical and methodological tools that permit a global understanding of CPS, delineating temporal trajectories and their conditioning factors, updated by the incorporation of new scientific discoveries. The potential to optimize human growth and development across chronological age and geographical locations - by implementing interventions or "treatments" during periods of greatest instability or vulnerability - should be recognized. Hence, it is imperative to take a holistic view of reproductive and perinatal issues, acknowledging at all levels the complexity and interactions of CPS and their sensitive periods, laying the foundations for further improvements in growth and development of populations, to maximize global human potential. We discuss here conceptual issues that should be considered for the development and implementation of such a strategy aimed at addressing the perinatal health problems of the new millenium.

Bone turnover in pregnancy, measured by urinary CTX, is influenced by vitamin D supplementation and is associated with maternal bone health: findings from the Maternal Vitamin D Osteoporosis Study (MAVIDOS) trial.

BACKGROUND: The pattern of change in maternal bone turnover throughout pregnancy is poorly characterized. OBJECTIVES: We investigated changes across pregnancy in a marker of maternal bone resorption, urinary C-terminal telopeptide of type I collagen (CTX), the influence of gestational vitamin D supplementation, and associations between CTX and maternal postnatal bone indices. METHODS: MAVIDOS (the Maternal Vitamin D Osteoporosis Study) is a randomized, double-blind, placebo-controlled trial of 1000 IU cholecalciferol/d compared with placebo from 14 weeks of gestation to birth. Maternal second-void urinary α- and ß-CTX were measured (ELISA) at 14 and 34 weeks of gestation; DXA was performed within 2 wk postpartum. The Mann-Whitney Rank Sum test, Spearman's rank correlation, and linear regression were used to compare median CTX values within and between groups from early to late pregnancy, and associations with maternal bone outcomes. RESULTS: In total, 372 women had CTX and 25-hydroxyvitamin D [25(OH)D] measured in early and late pregnancy. CTX at 14 and 34 weeks of gestation were correlated in both placebo (r = 0.31) and cholecalciferol (r = 0.45) groups (P < 0.0001). Median CTX increased from 14 to 34 weeks of gestation in both groups (n = 372 total) [placebo (n = 188): from 223.6 to 449.7 µg/mmol creatinine; cholecalciferol (n = 184): from 222.3 to 419.3 µg/mmol creatinine; P = 0.03 for placebo compared with cholecalciferol difference in CTX at 34 weeks of gestation]. The conditional mean ± SD increase in CTX [z-score (SD)] from early to late pregnancy was greater in the placebo group (n = 188) than in the cholecalciferol group (n = 184) (placebo: 0.16 ± 0.92; cholecalciferol: -0.16 ± 1.06; P-difference < 0.01). Higher CTX at 34 weeks of gestation was associated, similarly in both groups, with lower maternal total hip and lumbar spine bone mineral content and bone mineral density (BMD) (e.g., lumbar spine BMD: ß = -0.02 g · cm-2 · SD-1 increase in CTX; 95% CI: -0.027, -0.002 g · cm-2 · SD-1; P = 0.02, n = 283). CONCLUSIONS: Maternal urinary CTX, a bone resorption marker, rises through pregnancy, although to a lesser degree with gestational cholecalciferol supplementation, and is inversely associated with maternal bone mass postpartum.This trial was registered at www.isrctn.com as ISRCTN 82927713 and eudract.ema.europa.eu as EudraCT 2007-001716-23.

Fetal cranial growth trajectories are associated with growth and neurodevelopment at 2 years of age: INTERBIO-21st Fetal Study.

Many observational studies and some randomized trials demonstrate how fetal growth can be influenced by environmental insults (for example, maternal infections)1 and preventive interventions (for example, multiple-micronutrient supplementation)2 that can have a long-lasting effect on health, growth, neurodevelopment and even educational attainment and income in adulthood3. In a cohort of pregnant women (n = 3,598), followed-up between 2012 and 2019 at six sites worldwide4, we studied the associations between ultrasound-derived fetal cranial growth trajectories, measured longitudinally from <14 weeks' gestation, against international standards5,6, and growth and neurodevelopment up to 2 years of age7,8. We identified five trajectories associated with specific neurodevelopmental, behavioral, visual and growth outcomes, independent of fetal abdominal growth, postnatal morbidity and anthropometric measures at birth and age 2. The trajectories, which changed within a 20-25-week gestational age window, were associated with brain development at 2 years of age according to a mirror (positive/negative) pattern, mostly focused on maturation of cognitive, language and visual skills. Further research should explore the potential for preventive interventions in pregnancy to improve infant neurodevelopmental outcomes before the critical window of opportunity that precedes the divergence of growth at 20-25 weeks' gestation.

Gestational Vitamin D Supplementation Leads to Reduced Perinatal RXRA DNA Methylation: Results From the MAVIDOS Trial.

We have previously demonstrated inverse associations between maternal 25(OH)-vitamin D status and perinatal DNA methylation at the retinoid-X-receptor-alpha (RXRA) locus and between RXRA methylation and offspring bone mass. In this study, we used an existing randomized trial to test the hypothesis that maternal gestational vitamin D supplementation would lead to reduced perinatal RXRA locus DNA methylation. The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicenter, double-blind, randomized, placebo-controlled trial of 1000 IU/day cholecalciferol or matched placebo from 14 weeks' gestation until delivery. Umbilical cord (fetal) tissue was collected at birth and frozen at -80°C (n = 453). Pyrosequencing was used to undertake DNA methylation analysis at 10 CpG sites within the RXRA locus (identified previously). T tests were used to assess differences between treatment groups in methylation at the three most representative CpG sites. Overall, methylation levels were significantly lower in the umbilical cord from offspring of cholecalciferol-supplemented mothers, reaching statistical significance at four CpG sites, represented by CpG5: mean difference in % methylation between the supplemented and placebo groups was -1.98% (95% CI, -3.65 to -0.32, p = 0.02). ENCODE (Encyclopedia of DNA Elements) evidence supports the functionality of this locus with strong DNase hypersensitivity and enhancer chromatin within biologically relevant cell types including osteoblasts. Enrichment of the enhancer-related H3K4me1 histone mark is also seen in this region, as are binding sites for a range of transcription factors with roles in cell proliferation, response to stress, and growth factors. Our findings are consistent with previous observational results and provide new evidence that maternal gestational supplementation with cholecalciferol leads to altered perinatal epigenetic marking, informing mechanistic understanding of early life mechanisms related to maternal vitamin D status, epigenetic marks, and bone development. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Response to Antenatal Cholecalciferol Supplementation Is Associated With Common Vitamin D-Related Genetic Variants.

Context: Single-nucleotide polymorphisms (SNPs) in genes related to vitamin D metabolism have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentration, but these relationships have not been examined following antenatal cholecalciferol supplementation. Objective: To determine whether SNPs in DHCR7, CYP2R1, CYP24A1, and GC are associated with the response to gestational cholecalciferol supplementation. Design: Within-randomization group analysis of the Maternal Vitamin D Osteoporosis Study trial of antenatal cholecalciferol supplementation. Setting: Hospital antenatal clinics. Participants: In total, 682 women of white ethnicity (351 placebo, 331 cholecalciferol) were included. SNPs at rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1), and rs2282679 (GC) were genotyped. Interventions: 1000 IU/d cholecalciferol from 14 weeks of gestation until delivery. Main Outcome Measure: 25(OH)D at randomization and 34 weeks of gestation were measured in a single batch (Liaison; Diasorin, Dartford, UK). Associations between 25(OH)D and the SNPs were assessed by linear regression using an additive model [ß represents the change in 25(OH)D per additional common allele]. Results: Only rs12785878 (DHCR7) was associated with baseline 25(OH)D [ß = 3.1 nmol/L; 95% confidence interval (CI), 1.0 to 5.2 nmol/L; P < 0.004]. In contrast, rs10741657 (CYP2R1) (ß = -5.2 nmol/L; 95% CI, -8.2 to -2.2 nmol/L; P = 0.001) and rs2282679 (GC) (ß = 4.2 nmol/L; 95% CI, 0.9 to 7.5 nmol/L; P = 0.01) were associated with achieved 25(OH)D status following supplementation, whereas rs12785878 and rs6013897 (CYP24A1) were not. Conclusions: Genetic variation in DHCR7, which encodes 7-dehyrocholesterol reductase in the epidermal vitamin D biosynthesis pathway, appears to modify baseline 25(OH)D. In contrast, the response to antenatal cholecalciferol supplementation was associated with SNPs in CYP2R1, which may alter 25-hydroxylase activity, and GC, which may affect vitamin D binding protein synthesis or metabolite affinity.

Determinants of the Maternal 25-Hydroxyvitamin D Response to Vitamin D Supplementation During Pregnancy.

CONTEXT: Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D (25(OH)D) response. OBJECTIVE: We assessed which maternal and environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol. DESIGN: Within-randomization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy. SETTING: Hospital antenatal clinics. PARTICIPANTS: A total of 829 pregnant women (422 placebo, 407 cholecalciferol). At 14 and 34 weeks of gestation, maternal anthropometry, health, and lifestyle were assessed and 25(OH)D measured. Compliance was determined using pill counts at 19 and 34 weeks. INTERVENTIONS: 1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery. MAIN OUTCOME MEASURE: 25(OH)D at 34 weeks, measured in a single batch (Diasorin Liaison). RESULTS: 25(OH)D at 34 weeks of gestation was higher in the women randomized to vitamin D (mean [SD], 67.7 [21.3] nmol/L) compared with placebo (43.1 [22.5] nmol/L; P < .001). In women randomized to cholecalciferol, higher pregnancy weight gain from 14 to 34 weeks of gestation (kg) (ß = -0.81 [95% confidence interval -1.39, -0.22]), lower compliance with study medication (%) (ß = -0.28 [-0.072, -0.48]), lower early pregnancy 25(OH)D (nmol/L) (ß = 0.28 [0.16, 0.40]), and delivery in the winter vs the summer (ß = -10.5 [-6.4, -14.6]) were independently associated with lower 25(OH)D at 34 weeks of gestation. CONCLUSIONS: Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol. Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy.

Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial.

BACKGROUND: Maternal vitamin D status has been associated with bone mass of offspring in many, but not all, observational studies. However, maternal vitamin D repletion during pregnancy has not yet been proven to improve offspring bone mass in a randomised controlled trial. We aimed to assess whether neonates born to mothers supplemented with vitamin D during pregnancy have greater whole-body bone mineral content (BMC) at birth than those of mothers who had not received supplementation. METHODS: The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicentre, double-blind, randomised, placebo-controlled trial that recruited pregnant women from three study sites in the UK (Southampton, Oxford, and Sheffield). Eligible participants were older than 18 years, with a singleton pregnancy, gestation of less than 17 weeks, and a serum 25-hydroxyvitamin D (25[OH]D) concentration of 25-100 nmol/L at 10-17 weeks' gestation. P'articipants were randomly assigned (1:1), in randomly permuted blocks of ten, to either cholecalciferol 1000 IU/day or matched placebo, taken orally, from 14 weeks' gestation (or as soon as possible before 17 weeks' gestation if recruited later) until delivery. Participants and the research team were masked to treatment allocation. The primary outcome was neonatal whole-body BMC, assessed within 2 weeks of birth by dual-energy x-ray absorptiometry (DXA), analysed in all randomly assigned neonates who had a usable DXA scan. Safety outcomes were assessed in all randomly assigned participants. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN 82927713, and the European Clinical Trials Database, EudraCT 2007-001716-23. FINDINGS: Between Oct 10, 2008, and Feb 11, 2014, we randomly assigned 569 pregnant women to placebo and 565 to cholecalciferol 1000 IU/day. 370 (65%) neonates in the placebo group and 367 (65%) neonates in the cholecalciferol group had a usable DXA scan and were analysed for the primary endpoint. Neonatal whole-body BMC of infants born to mothers assigned to cholecalciferol 1000 IU/day did not significantly differ from that of infants born to mothers assigned to placebo (61·6 g [95% CI 60·3-62·8] vs 60·5 g [59·3-61·7], respectively; p=0·21). We noted no significant differences in safety outcomes, apart from a greater proportion of women in the placebo group with severe post-partum haemorrhage than those in the cholecalciferol group (96 [17%] of 569 mothers in the placebo group vs 65 [12%] of 565 mothers in the cholecalciferol group; p=0·01). No adverse events were deemed to be treatment related. INTERPRETATION: Supplementation of women with cholecalciferol 1000 IU/day during pregnancy did not lead to increased offspring whole-body BMC compared with placebo, but did show that 1000 IU of cholecalciferol daily is sufficient to ensure that most pregnant women are vitamin D replete, and it is safe. These findings support current approaches to vitamin D supplementation in pregnancy. Results of the ongoing MAVIDOS childhood follow-up study are awaited. FUNDING: Arthritis Research UK, Medical Research Council, Bupa Foundation, and National Institute for Health Research.

MAVIDOS Maternal Vitamin D Osteoporosis Study: study protocol for a randomized controlled trial. The MAVIDOS Study Group.

UNLABELLED: MAVIDOS is a randomised, double-blind, placebo-controlled trial (ISRCTN82927713, registered 2008 Apr 11), funded by Arthritis Research UK, MRC, Bupa Foundation and NIHR. BACKGROUND: Osteoporosis is a major public health problem as a result of associated fragility fractures. Skeletal strength increases from birth to a peak in early adulthood. This peak predicts osteoporosis risk in later life. Vitamin D insufficiency in pregnancy is common (31% in a recent Southampton cohort) and predicts reduced bone mass in the offspring. In this study we aim to test whether offspring of mothers supplemented with vitamin D in pregnancy have higher bone mass at birth than those whose mothers were not supplemented. METHODS/DESIGN: Women have their vitamin D status assessed after ultrasound scanning in the twelfth week of pregnancy at 3 trial centres (Southampton, Sheffield, Oxford). Women with circulating 25(OH)-vitamin D levels 25-100 nmol/l are randomised in a double-blind design to either oral vitamin D supplement (1000 IU cholecalciferol/day, n = 477) or placebo at 14 weeks (n = 477). Questionnaire data include parity, sunlight exposure, dietary information, and cigarette and alcohol consumption. At 19 and 34 weeks maternal anthropometry is assessed and blood samples taken to measure 25(OH)-vitamin D, PTH and biochemistry. At delivery venous umbilical cord blood is collected, together with umbilical cord and placental tissue. The babies undergo DXA assessment of bone mass within the first 14 days after birth, with the primary outcome being whole body bone mineral content adjusted for gestational age and age. Children are then followed up with yearly assessment of health, diet, physical activity and anthropometric measures, with repeat assessment of bone mass by DXA at age 4 years. DISCUSSION: As far as we are aware, this randomised trial is one of the first ever tests of the early life origins hypothesis in human participants and has the potential to inform public health policy regarding vitamin D supplementation in pregnancy. It will also provide a valuable resource in which to study the influence of maternal vitamin D status on other childhood outcomes such as glucose tolerance, blood pressure, cardiovascular function, IQ and immunology.