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Background Plasma volume expansion is an important physiologic change across gestation. High or low expansion has been related to adverse pregnancy outcomes, yet there is a limited understanding of normal/healthy plasma volume expansion. We aimed to evaluate the pattern of plasma volume expansion across healthy pregnancies from longitudinal studies. Methods We conducted a systematic review and meta-analysis to identify original studies that measured plasma volume in singleton pregnancies of healthy women. Specifically, we included studies that measured plasma volume at least two times across gestation and one time before or after pregnancy in the same women. PubMed, Web of Science, Cochrane, CINAHL, and clinicaltrials.gov databases were searched from the beginning of each database to February 2019. We combined data across studies using a random effects model. Results Ten observational studies with a total of 347 pregnancies were eligible. Plasma volume increased by 6% (95% CI 3–9) in the first trimester compared to the nonpregnant state. In the second trimester, plasma volume was increased by 18% (95% CI 12–24) in gestational weeks 14–20 and 29% (95% CI 21–36) in weeks 21–27 above the nonpregnant state. In the third trimester, plasma volume was increased by 42% (95% CI 38–46) in weeks 28–34 and 48% (95% CI 44–51) in weeks 35–38. The highest rate of increase occurred in the first half of the second trimester. Included studies were rated from moderate to high quality; 7 out of 10 studies were conducted over 30 years ago. Conclusions In healthy pregnancies, plasma volume begins to expand in the first trimester, has the steepest rate of increase in the second trimester, and peaks late in the third trimester. The patterns observed from these studies may not reflect the current population, partly due to the changes in BMI over the last several decades. Additional longitudinal studies are needed to better characterize the range of normal plasma volume expansion across maternal characteristics.

Events in fetal life impact long-term health outcomes. The placenta is the first organ to form and is the site of juxtaposition between the maternal and fetal circulations. Most diseases of pregnancy are caused by, impact, or are reflected in the placenta. The purpose of this review is to describe the main inflammatory processes in the placenta, discuss their immunology, and relate their short- and long-term disease associations. Acute placental inflammation (API), including maternal and fetal inflammatory responses corresponds to the clinical diagnosis of chorioamnionitis and is associated with respiratory and neurodevelopmental diseases. The chronic placental inflammatory pathologies (CPI), include chronic villitis of unknown etiology, chronic deciduitis, chronic chorionitis, eosinophilic T-cell vasculitis, and chronic histiocytic intervillositis. These diseases are less-well studied, but have complex immunology and show mechanistic impacts on the fetal immune system. Overall, much work remains to be done in describing the long-term impacts of placental inflammation on offspring health.

To explore how placental pathology is currently used by clinicians and what placental information would be most useful in the immediate hours after delivery. We used a qualitative study design to conduct in-depth, semi-structured interviews with obstetric and neonatal clinicians who provide delivery or postpartum care at an academic medical center in the US (n = 19). Interviews were transcribed and analyzed using descriptive content analysis. Clinicians valued placental pathology information yet cited multiple barriers that prevent the consistent use of pathology. Four main themes were identified. First, the placenta is sent to pathology for consistent reasons, however, the pathology report is accessed by clinicians inconsistently due to key barriers: difficult to find in the electronic medical record, understand, and get quickly. Second, clinicians value placental pathology for explanatory capability as well as for contributions to current and future care, particularly when there is fetal growth restriction, stillbirth, or antibiotic use. Third, a rapid placental exam (specifically including placental weight, infection, infarction, and overall assessment) would be helpful in providing clinical care. Fourth, placental pathology reports that connect clinically relevant findings (similar to radiology) and that are written with plain, standardized language and that non-pathologists can more readily understand are preferred. Placental pathology is important to clinicians that care for mothers and newborns (particularly those that are critically ill) after birth, yet many problems stand in the way of its usefulness. Hospital administrators, perinatal pathologists, and clinicians should work together to improve access to and contents of reports. Support for new methods to provide quick placenta information is warranted.

Background Angiogenesis is essential for placental growth and development. Improper placental vascular development can reduce blood flow to the fetus and increase the risk of adverse pregnancy and birth outcomes. The objectives of this study were to examine the effect of prenatal vitamin D supplementation on placental angiogenic factors and terminal villi, and associations between angiogenic factors, terminal villi and birth outcomes. Methods This is a secondary analysis using data and specimens from the Maternal Vitamin D for Infant Growth trial in Dhaka, Bangladesh ( n  = 1298). Participants were enrolled at 17–24 weeks gestation and randomized to receive (IU/week): placebo, 4200, 16,800 or 28,000 vitamin D 3 supplement until birth. Newborns and placentas were measured at birth. We examined a subset of randomly selected placentas ( n  = 80). Tissue sections were evaluated for vascular endothelial growth factor (VEGF-A) and placental growth factor (PlGF) using immunofluorescence. We measured intensity and percent area of expression for angiogenic factors, and total number and surface area of terminal villi. Vitamin D treatment effect was estimated using ANOVA. Regression models were used to assess associations of markers of placental angiogenesis with birth outcomes. Interactions by infant sex were examined. Results The overall mean (SD) percent area of expression was 17.0 (4.0) for VEGF-A and 15.0 (1.9) for PlGF. The mean (SD) number of terminal villi was 39 (15) per 12 in 2 , and surface area was 0.096 (0.040) in 2 . Vitamin D treatment groups were similar to placebo for all outcomes. No associations were observed between angiogenic factors or terminal villi placental and birth outcomes. Conclusions Vitamin D supplementation starting from mid-pregnancy until birth did not affect expression of two key angiogenic factors or terminal villi in the placenta. Placental angiogenic factors or terminal villi did not have an association with birth outcomes. These results do not support a role of maternal vitamin D starting mid-pregnancy in impacting placental development.

Background Accurate estimation of vitamin D status is important for health research and can impact prevention and treatment of deficiency in women of reproductive age. We aimed to assess if blood concentrations of 25-hydroxyvitamin D [25(OH)D] or 1,25-dihydroxyvitamin D [1,25(OH) 2 D] change across the menstrual cycle. Methods We conducted a systematic search in PubMed, Web of Science, CAB and BIOSIS of literature published until December 2018 which reported concentrations of vitamin D metabolites at two or more identified points among women with regular menstrual cycles. Results Ten longitudinal studies met the inclusion criteria; nine studies measured 1,25(OH) 2 D and five studies measured 25(OH)D. Study size ranged from 5 to 47 subjects, with an age range of 18–47 years. One study found a decrease in concentration of 25(OH)D in the periovulatory and luteal phase. Four studies found no changes in concentrations of 25(OH)D. Two studies found a rise in 1,25(OH) 2 D within the follicular phase, including a 128% increase from day 1 to 15 and a 56% increase from day 0 to 12. Two studies found rises in 1,25(OH) 2 D concentrations from the follicular to luteal phase of 13 and 26%. Five studies did not find any changes in concentrations of 1,25(OH) 2 D. Conclusions No conclusion can be drawn on the pattern of 1,25(OH) 2 D concentrations across the normal menstrual cycle due to inconsistencies in study findings. Evidence is currently insufficient to assess 25(OH)D concentrations across the cycle. Future studies should aim to measure 1,25(OH) 2 D and 25(OH)D longitudinally, to understand relationships with other hormones and the potential impact on estimates of vitamin D deficiency.

Vitamin B12, or cobalamin, is an essential nutrient required for diverse physiological functions secondary to its role as a critical cofactor for two mammalian enzymes, methionine synthase and methylmalonyl‐CoA mutase. While essential throughout all life stages, several pathways that require vitamin B12, including hematopoiesis, myelination, and DNA/histone methylation, are particularly critical during pregnancy and fetal development. This narrative review aims to describe vitamin B12 in pregnancy, with emphasis on the placenta’s role in ensuring adequate nutrition of the fetus and impacts of vitamin B12 deficiency on placental development and function. Our literature search included preclinical model systems and human cohorts and interventions. Our review identified evidence of B12 deficiency resulting in impaired placental development, greater placental inflammation, and modulation of placental docosahexaenoic acid concentration, collectively suggestive of vitamin B12 deficiency as a determinant of both maternal and fetal health outcomes. Heterogeneity in study design complicated generalization of findings. Future studies should consider selecting a B12 marker that is relatively stable across pregnancy, such as holotranscobalamin, while accounting for important confounders such as maternal folate.

Key Points Micronutrient deficiencies during pregnancy are a global public health concern, yet the full extent of their burden and health consequences are unclear due to infrequent and inadequate assessment Micronutrient deficiencies have been linked to compromised conception, length of gestation, and fetal development and growth, which can lead to pregnancy loss, preterm delivery, small birth size, birth defects and long-term metabolic disturbances Antenatal supplementation with multiple micronutrients can improve birth outcomes and merits policy and program consideration in low-income settings Preconception and periconception intervention research is needed to further assess the full public health effect of micronutrient adequacy on pregnancy outcomes Vitamin and mineral deficiencies during pregnancy can have a major effect on neonatal development. In this Review, Gernand and colleagues discuss the evidence supporting the need for micronutrient supplementation and how it can benefit pregnancy, especially in low-income settings. Micronutrients, vitamins and minerals accessible from the diet, are essential for biologic activity. Micronutrient status varies widely throughout pregnancy and across populations. Women in low-income countries often enter pregnancy malnourished, and the demands of gestation can exacerbate micronutrient deficiencies with health consequences for the fetus. Examples of efficacious single micronutrient interventions include folic acid to prevent neural tube defects, iodine to prevent cretinism, zinc to reduce risk of preterm birth, and iron to reduce the risk of low birth weight. Folic acid and vitamin D might also increase birth weight. While extensive mechanistic and association research links multiple antenatal micronutrients with plausible materno–fetal health advantages, hypothesized benefits have often been absent, minimal or unexpected in trials. These findings suggest a role for population context in determining health responses and filling extensive gaps in knowledge. Multiple micronutrient supplements reduce the risks of being born with low birth weight, small for gestational age or stillborn in undernourished settings, and justify micronutrient interventions with antenatal care. Measurable health effects of gestational micronutrient exposure might persist into childhood but few data exists on potential long-term benefits. In this Review, we discuss micronutrient intake recommendations, risks and consequences of deficiencies, and the effects of interventions with a particular emphasis on offspring.

Increases in reproductive hormones like estrogen, play an important role in the remarkable increases in plasma volume observed in pregnancy. Accurate estimates of plasma volume expansion during pregnancy depend on correctly timing and measuring plasma volume in nonpregnant women. However, to date, there is no consensus on the pattern of plasma volume across the menstrual cycle. We prospectively measured plasma volume in 45 women across a single menstrual cycle. A urine‐based fertility monitor was used to time three clinic visits to distinct points in the menstrual cycle: the early follicular phase (~day 2), periovulation (~day 12), and the mid‐point of the luteal phase (~day 21)—based on a 28‐day cycle length. Healthy women aged 18–41 years with regular menstrual cycles and a healthy body weight were enrolled in the study. At each visit, blood samples were collected before and after injection of 0.25 mg/kg body weight of indocyanine green dye (ICG). Pre‐ and post‐ICG injection plasma samples were used to measure plasma volume. Preinjection samples were used to measure ovarian hormones and plasma osmolality. Mean plasma volume was highest during the early follicular phase (2,276 ± 478 ml); it declined to 2,232 ± 509 ml by the late follicular phase and to 2,228 ± 502 ml by the midluteal phase. This study found that overall variations in plasma volume are small across the menstrual cycle. Therefore, in clinical practice and research, the menstrual cycle phase may not be an important consideration when evaluating plasma volume among women of reproductive age. In this study, we timed plasma volume measurements based on the pattern of change in estrogen and progesterone concentrations, across the menstrual cycle. We showed that plasma volume remained stable across the menstrual cycle irrespective of the concentration of estrogen and progesterone. Our data established that plasma volume measurements can occur at any timepoint across the menstrual cycle, and that estimates are not impacted by physiological fluctuations observed in estrogen and progesterone concentrations in women of reproductive age.

Prenatal multiple micronutrient (MM) supplementation improves birth weight through increased fetal growth and gestational age, but whether maternal or fetal growth factors are involved is unclear. Our objective was to examine the effect of prenatal MM supplementation on intrauterine growth factors and the associations between growth factors and birth outcomes in a rural setting in Bangladesh. In a double-blind, cluster-randomized, controlled trial of MM vs. iron and folic acid (IFA) supplementation, we measured placental growth hormone (PGH) at 10 weeks and PGH and human placental lactogen (hPL) at 32 weeks gestation in maternal plasma (n = 396) and insulin, insulin-like growth factor-1 (IGF-1), and IGF binding protein-1 (IGFBP-1) in cord plasma (n = 325). Birth size and gestational age were also assessed. Early pregnancy mean (SD) BMI was 19.5 (2.4) kg/m2 and birth weight was 2.68 (0.41) kg. There was no effect of MM on concentrations of maternal hPL or PGH, or cord insulin, IGF-1, or IGFBP-1. However, among pregnancies of female offspring, hPL concentration was higher by 1.1 mg/L in the third trimester (95% CI: 0.2, 2.0 mg/L; p = 0.09 for interaction); and among women with height <145 cm, insulin was higher by 59% (95% CI: 3, 115%; p = 0.05 for interaction) in the MM vs. IFA group. Maternal hPL and cord blood insulin and IGF-1 were positively, and IGFBP-1 was negatively, associated with birth weight z score and other measures of birth size (all p<0.05). IGF-1 was inversely associated with gestational age (p<0.05), but other growth factors were not associated with gestational age or preterm birth. Prenatal MM supplementation had no overall impact on intrauterine growth factors. MM supplementation altered some growth factors differentially by maternal early pregnancy nutritional status and sex of the offspring, but this should be examined in other studies. ClinicalTrials.gov NCT00860470.

It is unclear whether maternal vitamin D supplementation during pregnancy and lactation improves fetal and infant growth in regions where vitamin D deficiency is common. We conducted a randomized, double-blind, placebo-controlled trial in Bangladesh to assess the effects of weekly prenatal vitamin D supplementation (from 17 to 24 weeks of gestation until birth) and postpartum vitamin D supplementation on the primary outcome of infants' length-for-age z scores at 1 year according to World Health Organization (WHO) child growth standards. One group received neither prenatal nor postpartum vitamin D (placebo group). Three groups received prenatal supplementation only, in doses of 4200 IU (prenatal 4200 group), 16,800 IU (prenatal 16,800 group), and 28,000 IU (prenatal 28,000 group). The fifth group received prenatal supplementation as well as 26 weeks of postpartum supplementation in the amount of 28,000 IU (prenatal and postpartum 28,000 group). Among 1164 infants assessed at 1 year of age (89.5% of 1300 pregnancies), there were no significant differences across groups in the mean (±SD) length-for-age z scores. Scores were as follows: placebo, -0.93±1.05; prenatal 4200, -1.11±1.12; prenatal 16,800, -0.97±0.97; prenatal 28,000, -1.06±1.07; and prenatal and postpartum 28,000, -0.94±1.00 (P=0.23 for a global test of differences across groups). Other anthropometric measures, birth outcomes, and morbidity did not differ significantly across groups. Vitamin D supplementation had expected effects on maternal and infant serum 25-hydroxyvitamin D and calcium concentrations, maternal urinary calcium excretion, and maternal parathyroid hormone concentrations. There were no significant differences in the frequencies of adverse events across groups, with the exception of a higher rate of possible hypercalciuria among the women receiving the highest dose. In a population with widespread prenatal vitamin D deficiency and fetal and infant growth restriction, maternal vitamin D supplementation from midpregnancy until birth or until 6 months post partum did not improve fetal or infant growth. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT01924013 .).