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Birth outcomes across the spectrum of maternal age: dissecting aging effect versus confounding by social and medical determinants.
Olapeju, B, Hong, X, Wang, G, Summers, A, Burd, I, Cheng, TL, Wang, X
BMC pregnancy and childbirth. 2021;(1):594
Abstract
BACKGROUND Given the trend of increasing maternal age and associated adverse reproductive outcomes in the US, this study aimed to assess whether this association is due to an independent aging or confounded by sociodemographic, biomedical, or behavioral determinants in a predominantly Black US population. METHODS Data was from 8509 women enrolled in the Boston Birth Cohort. Adverse reproductive outcomes included spontaneous preterm delivery, cesarean delivery, and low birth weight. Covariates included sociodemographic (parity, race/ethnicity, education, marital status, income, receipt of public assistance, nativity); biomedical (obesity, hypertensive disorders, diabetes mellitus); and behavioral (consistent intake of multivitamin supplements, support from father of baby, support from family, major stress in pregnancy, cigarette smoking, alcohol intake). Analysis included Lowess and marginal probability plots, crude and adjusted sequential logistic regression models to examine age-outcome associations and to what degree the association can be explained by the above covariables. RESULT Overall, the study sample had high levels of spontaneous preterm birth (18%), cesarean delivery (33%) and low birth weight (26%). Unadjusted models showed no significant difference odds of spontaneous preterm birth by maternal age but higher odds of cesarean section (aOR: 1.77, 95% CI: 1.60, 1.95) and low birth weight (aOR: 1.15, 95% CI: 1.04, 1.28) among women 30 years or older. Adjustment for sociodemographic factors, biomedical conditions and behavioral factors revealed higher odds of spontaneous preterm birth: (aOR: 1.30, 95% CI: 1.14, 1.49), cesarean section deliveries (aOR: 1.68, 95% CI: 1.51, 1.87) and low birth weight (aOR: 1.36, 95% CI: 1.21, 1.53). Across all ages, optimal BMI status and consistent multivitamin supplement intake were protective of spontaneous preterm birth and low birth weight. CONCLUSION In this high-risk minority population, we demonstrated that the association between increasing maternal age and adverse pregnancy outcomes was due to an independent aging effect and the presence of confounding by sociodemographic, biomedical, and behavioral factors. Some modifiable risk factors to counteract aging effect, include optimizing BMI and consistent intake of multivitamin supplement. A fundamental change in how care is provided to women, particularly low income Black women, is needed with emphasis on the protective role of optimal nutritional status. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03228875.
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Higher-Dose DHA Supplementation Modulates Immune Responses in Pregnancy and Is Associated with Decreased Preterm Birth.
Valentine, CJ, Khan, AQ, Brown, AR, Sands, SA, Defranco, EA, Gajewski, BJ, Carlson, SE, Reber, KM, Rogers, LK
Nutrients. 2021;(12)
Abstract
Pregnancy and parturition involve extensive changes in the maternal immune system. In our randomized, multi-site, double-blind superiority trial using a Bayesian adaptive design, we demonstrated that 1000 mg/day of docosahexaenoic acid (DHA) was superior to 200 mg/day in preventing both early preterm birth (less than 34 weeks' gestation) and preterm birth (less than 37 weeks' gestation). The goal of this secondary study is to compare the effects of 1000 mg/day versus 200 mg/day on maternal inflammation, a possible mechanism by which DHA may prevent preterm birth. Maternal blood samples were collected at enrollment (12-20 weeks' gestation) and at delivery. Red blood cell DHA levels were measured by gas chromatography, and plasma concentrations of sRAGE, IL-6, IL-1β, TNFα, and INFγ were measured by ELISA. Data were analyzed for associations with the DHA dose, gestational age at birth, and preterm birth (<37 weeks). Higher baseline and lower delivery levels of maternal sRAGE were associated with a greater probability of longer gestation and delivery at term gestation. Higher-dose DHA supplementation increased the probability of a smaller decrease in delivery sRAGE levels. Higher IL-6 concentrations at delivery were associated with the probability of delivering after 37 weeks, and higher-dose DHA supplementation increased the probability of greater increases in IL-6 concentrations between enrollment and delivery. These data provide a proposed mechanistic explanation of how a higher dose of DHA during pregnancy provides immunomodulatory regulation in the initiation of parturition by influencing sRAGE and IL-6 levels, which may explain its ability to reduce the risk of preterm birth.
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Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials.
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Lancet (London, England). 2021;(10280):1183-1194
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BACKGROUND Preterm birth is a global health priority. Using a progestogen during high-risk pregnancy could reduce preterm birth and adverse neonatal outcomes. METHODS We did a systematic review of randomised trials comparing vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate (17-OHPC), or oral progesterone with control, or with each other, in asymptomatic women at risk of preterm birth. We identified published and unpublished trials that completed primary data collection before July 30, 2016, (12 months before data collection began), by searching MEDLINE, Embase, CINAHL, the Maternity and Infant Care Database, and relevant trial registers between inception and July 30, 2019. Trials of progestogen to prevent early miscarriage or immediately-threatened preterm birth were excluded. Individual participant data were requested from investigators of eligible trials. Outcomes included preterm birth, early preterm birth, and mid-trimester birth. Adverse neonatal sequelae associated with early births were assessed using a composite of serious neonatal complications, and individually. Adverse maternal outcomes were investigated as a composite and individually. Individual participant data were checked and risk of bias assessed independently by two researchers. Primary meta-analyses used one-stage generalised linear mixed models that incorporated random effects to allow for heterogeneity across trials. This meta-analysis is registered with PROSPERO, CRD42017068299. FINDINGS Initial searches identified 47 eligible trials. Individual participant data were available for 30 of these trials. An additional trial was later included in a targeted update. Data were therefore available from a total of 31 trials (11 644 women and 16185 offspring). Trials in singleton pregnancies included mostly women with previous spontaneous preterm birth or short cervix. Preterm birth before 34 weeks was reduced in such women who received vaginal progesterone (nine trials, 3769 women; relative risk [RR] 0·78, 95% CI 0·68-0·90), 17-OHPC (five trials, 3053 women; 0·83, 0·68-1·01), and oral progesterone (two trials, 181 women; 0·60, 0·40-0·90). Results for other birth and neonatal outcomes were consistently favourable, but less certain. A possible increase in maternal complications was suggested, but this was uncertain. We identified no consistent evidence of treatment interaction with any participant characteristics examined, although analyses within subpopulations questioned efficacy in women who did not have a short cervix. Trials in multifetal pregnancies mostly included women without additional risk factors. For twins, vaginal progesterone did not reduce preterm birth before 34 weeks (eight trials, 2046 women: RR 1·01, 95% CI 0·84-1·20) nor did 17-OHPC for twins or triplets (eight trials, 2253 women: 1·04, 0·92-1·18). Preterm premature rupture of membranes was increased with 17-OHPC exposure in multifetal gestations (rupture <34 weeks RR 1·59, 95% CI 1·15-2·22), but we found no consistent evidence of benefit or harm for other outcomes with either vaginal progesterone or 17-OHPC. INTERPRETATION Vaginal progesterone and 17-OHPC both reduced birth before 34 weeks' gestation in high-risk singleton pregnancies. Given increased underlying risk, absolute risk reduction is greater for women with a short cervix, hence treatment might be most useful for these women. Evidence for oral progesterone is insufficient to support its use. Shared decision making with woman with high-risk singleton pregnancies should discuss an individual's risk, potential benefits, harms and practicalities of intervention. Treatment of unselected multifetal pregnancies with a progestogen is not supported by the evidence. FUNDING Patient-Centered Outcomes Research Institute.
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Magnesium levels in relation to rates of preterm birth: a systematic review and meta-analysis of ecological, observational, and interventional studies.
Zhang, Y, Xun, P, Chen, C, Lu, L, Shechter, M, Rosanoff, A, He, K
Nutrition reviews. 2021;(2):188-199
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CONTEXT Experimental studies suggest that magnesium levels in pregnant women may affect the length of gestation, as magnesium affects the activity of smooth muscle in the uterus. Little is known about the association between magnesium levels or supplementation and the rate of preterm birth. OBJECTIVE The aim of this systematic review was to summarize the data on magnesium soil levels and preterm birth rates from ecological, observational, and interventional studies. DATA SOURCES Soil magnesium levels were obtained from US Geological Survey data, and preterm birth rates were acquired from the March of Dimes Foundation. Relevant epidemiological and clinical studies published until April 2019 in peer-reviewed journals were retrieved from PubMed, Google Scholar, and related reference lists. STUDY SELECTION Original studies published in English, conducted in humans, and in which magnesium (dietary/supplemental intake or biomarkers) was an exposure and preterm birth was an outcome were included. DATA EXTRACTION Eleven studies were included in the systematic review. Meta-analysis was performed on 6 studies. Overall relative risk (RR) and corresponding 95%CIs for risk of preterm birth in relation to magnesium supplementation were estimated by a random-effects model. RESULTS The ecological study revealed an inverse correlation between magnesium content in soil and rates of preterm birth across the United States (r = -0.68; P < 0.001). Findings from 11 observational studies generally support an inverse association between serum magnesium levels and rates of preterm birth. Of the 6 eligible randomized controlled trials, which included 3068 pregnant women aged 20 to 35 years and 352 preterm infants, the pooled RR was 0.58 (95%CI, 0.35-0.96) for women in the magnesium supplementation group compared with women in the control group. CONCLUSIONS Accumulated evidence from ecological, observational, and interventional studies consistently indicates that adequate magnesium intake during pregnancy may help reduce the incidence of preterm birth.
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Influence of clinical characteristics on maternal DHA and other polyunsaturated fatty acid status in pregnancy: A systematic review.
Wilson, NA, Mantzioris, E, Middleton, PF, Muhlhausler, BS
Prostaglandins, leukotrienes, and essential fatty acids. 2020;:102063
Abstract
INTRODUCTION Omega-3 DHA is important for the prevention of preterm birth, however there is limited knowledge of the determinants of omega-3 status during pregnancy. The primary objective of this systematic review was to synthesise data from existing studies assessing relationships between clinical factors and maternal DHA status. MATERIALS AND METHODS The Medline, Embase, Amed, and CINAHL databases were searched for studies reporting measures of maternal omega-3 status and one or more clinical characteristics. RESULTS Eighteen studies were included in the final analyses. Factors associated with a higher BMI (overweight, higher gestational weight gain, gestational diabetes), or lower parity were each associated with higher omega-3 status in the majority of studies, with mixed findings for other comparisons. DISCUSSION Inconsistent findings between studies make it difficult to draw clear conclusions about the relationship between clinical factors and maternal omega-3 DHA status. However, maternal overweight and associated metabolic conditions may increase lipid metabolism.
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Early life factors for endometriosis: a systematic review.
Olšarová, K, Mishra, GD
Human reproduction update. 2020;(3):412-422
Abstract
BACKGROUND Despite its high prevalence and health burden, many aspects of endometriosis remain unclear, including risk factors and the underlying biological mechanisms. Exposures during early life, including in utero, are thought to play an important role in the subsequent onset of the condition. To date, however, much of the evidence from studies on early life exposures and diagnosed endometriosis appears mixed and difficult to assess. OBJECTIVE AND RATIONALE This study aims to provide a systematic review of the epidemiologic evidence on early life factors associated with the subsequent diagnosis of endometriosis. In utero and early life exposures have previously been linked to a range of adult health outcomes, including infertility. SEARCH METHODS A systematic review of case-control, cross-sectional and cohort studies was conducted using the search terms 'endometriosis'[MeSH] AND ('risk factors'[MeSH] OR 'protective factors'[MeSH]) AND ('in utero', 'fetal', 'neonatal, 'perinatal', 'developmental origins', 'early life', 'childhood' OR 'life course') in Embase, PubMed and Scopus databases. The review included articles published in English until 10 June 2018 with original data from studies with diagnosed endometriosis. The quality of primary studies was evaluated using the Newcastle-Ottawa Scale by both authors independently. Due to the degree of inconsistency in the measurements and study methods, a qualitative assessment of findings was undertaken rather than meta-analysis. OUTCOMES The search retrieved 70 records without duplicates that contained 20 records on human case-control, cross-sectional or cohort studies, from which 11 papers/studies were selected based on their assessment score. The majority of studies found that women born with low birthweight (<2.5 kg or <5.5 lb) were more likely to be diagnosed with endometriosis. For other early life factors, the evidence is mixed or limited, with further research needed on the association of endometriosis with preterm birth, in utero exposure to diethylstilbestrol and to maternal smoking, passive smoking in early life, and infant formula feeding (compared with breastfeeding). WIDER IMPLICATIONS While the weight of evidence points to low birthweight as a risk factor for diagnosis of endometriosis, future research is warranted on this and other key early life exposures where the findings are mixed to provide more robust evidence and for insights on potential causal pathways. Such research, however, needs to address current methodological issues, such as the use of prospective data from large population-based studies, better diagnostic methods to confirm disease free status, more consistent definitions of variables and consideration of potential biological mechanisms to guide the analyses. The improvements will advance the future synthesis of evidence to support clinically relevant risk assessment for a more timely diagnosis and treatment of endometriosis.
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Antenatal Corticosteroids and Magnesium Sulfate for Improved Preterm Neonatal Outcomes: A Review of Guidelines.
Tsakiridis, I, Mamopoulos, A, Athanasiadis, A, Dagklis, T
Obstetrical & gynecological survey. 2020;(5):298-307
Abstract
IMPORTANCE In cases of anticipated preterm delivery, corticosteroids for fetal lung maturation and magnesium sulfate for fetal neuroprotection may improve neonatal outcomes. OBJECTIVE The aim of this study was to summarize and compare published guidelines from 4 leading medical societies on the administration of antenatal corticosteroids and magnesium sulfate. EVIDENCE ACQUISITION A descriptive review of major national guidelines on corticosteroids and magnesium sulfate was conducted: National Institute for Health and Care Excellence on "Preterm labour and birth," World Health Organization on "WHO recommendations on interventions to improve preterm birth outcomes," American College of Obstetricians and Gynecologists on "Antenatal corticosteroid therapy for fetal maturation" and "Magnesium sulfate use in obstetrics," and Society of Obstetricians and Gynecologists of Canada on "Antenatal corticosteroid therapy for improving neonatal outcomes" and "Magnesium sulphate for fetal neuroprotection." RESULTS A variation in the appropriate timing of administration exists, whereas repeated courses are not routinely recommended for corticosteroids or magnesium sulfate. In addition, the recommendations are the same for singleton and multiple gestations, and no specific recommendation exists according to maternal body mass index. Finally, a variation in guidelines regarding the administration of corticosteroids before cesarean delivery exists. CONCLUSION The adoption of an international consensus on corticosteroids and magnesium sulfate may increase their endorsement by health care professionals, leading to more favorable neonatal outcomes after preterm delivery.
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Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age.
Merid, SK, Novoloaca, A, Sharp, GC, Küpers, LK, Kho, AT, Roy, R, Gao, L, Annesi-Maesano, I, Jain, P, Plusquin, M, et al
Genome medicine. 2020;(1):25
Abstract
BACKGROUND Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. METHODS We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. RESULTS We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10- 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. CONCLUSIONS We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
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BRAzil magnesium (BRAMAG) trial: a double-masked randomized clinical trial of oral magnesium supplementation in pregnancy.
de Araújo, CAL, Ray, JG, Figueiroa, JN, Alves, JG
BMC pregnancy and childbirth. 2020;(1):234
Abstract
BACKGROUND There is conflicting evidence about the role of oral magnesium supplementation in the prevention of preterm birth and related adverse outcomes. The objective of this study was to compare magnesium citrate with placebo in the prevention of adverse perinatal and maternal outcomes among women at higher risk. METHODS This multicenter, double-masked, placebo-controlled randomized superiority clinical trial compared oral magnesium citrate 300 mg to matched placebo, from 12 to 20 weeks' gestation until delivery. This trial was completed in three centers in northeastern Brazil. Eligible women were those with a singleton pregnancy and ≥ 1 risk factor, such as prior preterm birth or preeclampsia, or current chronic hypertension or pre-pregnancy diabetes mellitus, age > 35 years or elevated body mass index. The primary perinatal composite outcome comprised preterm birth < 37 weeks' gestation, stillbirth > 20 weeks, neonatal death or NICU admission < 28 days after birth, or small for gestational age birthweight < 3rd percentile. The co-primary maternal composite outcome comprised preeclampsia or eclampsia < 37 weeks, severe gestational hypertension < 37 weeks, placental abruption, or maternal stroke or death during pregnancy or ≤ 7 days after delivery. RESULTS Analyses comprised 407 women who received magnesium citrate and 422 who received placebo. The perinatal composite outcome occurred among 75 (18.4%) in the magnesium arm and 76 (18.0%) in the placebo group - an adjusted odds ratio (aOR) of 1.10 (95% CI 0.72-1.68). The maternal composite outcome occurred among 49 (12.0%) women in the magnesium arm and 41 women (9.7%) in the placebo group - an aOR of 1.29 (95% CI 0.83-2.00). CONCLUSIONS Oral magnesium citrate supplementation did not appear to reduce adverse perinatal or maternal outcomes in high-risk singleton pregnancies. TRIAL REGISTRATION ClinicalTrials.gov NCT02032186, registered January 9, 2014.
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Fat-soluble nutrients and Omega-3 fatty acids as modifiable factors influencing preterm birth risk.
Thoene, M, Van Ormer, M, Yuil-Valdes, A, Bruett, T, Natarajan, SK, Mukherjee, M, Thompson, M, Nordgren, TM, Van Lippevelde, W, Overby, NC, et al
Placenta. 2020;:38-42
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Preterm birth is a leading cause of child morbidity and mortality, so strategies to reduce early birth must remain a priority. One key approach to enhancing birth outcomes is improving maternal dietary intake. Therefore, the purpose of this review is to discuss mechanisms on perinatal status of fat-soluble nutrients (carotenoids, retinol, tocopherols) and omega-3 fatty acids and how they impact risk for preterm birth. Literature review demonstrates that maternal dietary intake and biological (blood and placental tissue) levels of fat-soluble nutrients during pregnancy may provide antioxidative, anti-inflammatory, and immunomodulatory health benefits. Omega-3 fatty acids also promote increased production of specialized pro-resolving mediators, subsequently mediating inflammation resolution. Combined effects of these nutrients support appropriate placental organogenesis and function. Consequently, fat-soluble nutrients and omega-3 fatty acids serve as strong influencers for preterm birth risk. As dietary intake remains a modifiable factor, future intervention would benefit from a focus on optimizing perinatal status of these specific nutrients.