Recent Advances in Genomic Studies of Gestational Duration and Preterm Birth.

Preterm birth (PTB) is the leading cause of infant mortality and morbidity. For several decades, extensive epidemiologic and genetic studies have highlighted the significant contribution of maternal and offspring genetic factors to PTB. This review discusses the challenges inherent in conventional genomic analyses of PTB and underscores the importance of adopting nonconventional approaches, such as analyzing the mother-child pair as a single analytical unit, to disentangle the intertwined maternal and fetal genetic influences. We elaborate on studies investigating PTB phenotypes through 3 levels of genetic analyses: single-variant, multi-variant, and genome-wide variants.

A common allele increases endometrial Wnt4 expression, with antagonistic implications for pregnancy, reproductive cancers, and endometriosis.

The common human SNP rs3820282 is associated with multiple phenotypes including gestational length and likelihood of endometriosis and cancer, presenting a paradigmatic pleiotropic variant. Deleterious pleiotropic mutations cause the co-occurrence of disorders either within individuals, or across population. When adverse and advantageous effects are combined, pleiotropy can maintain high population frequencies of deleterious alleles. To reveal the causal molecular mechanisms of this pleiotropic SNP, we introduced this substitution into the mouse genome by CRISPR/Cas 9. Previous work showed that rs3820282 introduces a high-affinity estrogen receptor alpha-binding site at the Wnt4 locus. Here, we show that this mutation upregulates Wnt4 transcription in endometrial stroma, following the preovulatory estrogen peak. Effects on uterine transcription include downregulation of epithelial proliferation and induction of progesterone-regulated pro-implantation genes. We propose that these changes increase uterine permissiveness to embryo invasion, whereas they decrease resistance to invasion by cancer and endometriotic foci in other estrogen-responsive tissues.

Association of maternal prenatal copper concentration with gestational duration and preterm birth: a multicountry meta-analysis.

BACKGROUND: Copper (Cu), an essential trace mineral regulating multiple actions of inflammation and oxidative stress, has been implicated in risk for preterm birth (PTB). OBJECTIVES: This study aimed to determine the association of maternal Cu concentration during pregnancy with PTB risk and gestational duration in a large multicohort study including diverse populations. METHODS: Maternal plasma or serum samples of 10,449 singleton live births were obtained from 18 geographically diverse study cohorts. Maternal Cu concentrations were determined using inductively coupled plasma mass spectrometry. The associations of maternal Cu with PTB and gestational duration were analyzed using logistic and linear regressions for each cohort. The estimates were then combined using meta-analysis. Associations between maternal Cu and acute-phase reactants (APRs) and infection status were analyzed in 1239 samples from the Malawi cohort. RESULTS: The maternal prenatal Cu concentration in our study samples followed normal distribution with mean of 1.92 µg/mL and standard deviation of 0.43 µg/mL, and Cu concentrations increased with gestational age up to 20 wk. The random-effect meta-analysis across 18 cohorts revealed that 1 µg/mL increase in maternal Cu concentration was associated with higher risk of PTB with odds ratio of 1.30 (95% confidence interval [CI]: 1.08, 1.57) and shorter gestational duration of 1.64 d (95% CI: 0.56, 2.73). In the Malawi cohort, higher maternal Cu concentration, concentrations of multiple APRs, and infections (malaria and HIV) were correlated and associated with greater risk of PTB and shorter gestational duration. CONCLUSIONS: Our study supports robust negative association between maternal Cu and gestational duration and positive association with risk for PTB. Cu concentration was strongly correlated with APRs and infection status suggesting its potential role in inflammation, a pathway implicated in the mechanisms of PTB. Therefore, maternal Cu could be used as potential marker of integrated inflammatory pathways during pregnancy and risk for PTB.

Addressing Health-Related Social Needs and Mental Health Needs in the Neonatal Intensive Care Unit: Exploring Challenges and the Potential of Technology.

Unaddressed health-related social needs (HRSNs) and parental mental health needs in an infant's environment can negatively affect their health outcomes. This study examines the challenges and potential technological solutions for addressing these needs in the neonatal intensive care unit (NICU) setting and beyond. In all, 22 semistructured interviews were conducted with members of the NICU care team and other relevant stakeholders, based on an interpretive description approach. The participants were selected from three safety net hospitals in the U.S. with level IV NICUs. The challenges identified include navigating the multitude of burdens families in the NICU experience, resource constraints within and beyond the health system, a lack of streamlined or consistent processes, no closed-loop referrals to track status and outcomes, and gaps in support postdischarge. Opportunities for leveraging technology to facilitate screening and referral include automating screening, initiating risk-based referrals, using remote check-ins, facilitating resource navigation, tracking referrals, and providing language support. However, technological implementations should avoid perpetuating disparities and consider potential privacy or data-sharing concerns. Although advances in technological health tools alone cannot address all the challenges, they have the potential to offer dynamic tools to support the healthcare setting in identifying and addressing the unique needs and circumstances of each family in the NICU.

Examining the Role of Women, Infant, and Children in Black Women Breastfeeding Duration and Exclusivity: A Systematic Review.

Background: African American women continue to experience low rates of breastfeeding initiation as well as low rates of exclusive breastfeeding for 6 months. Research has indicated that there are several social determinants that impact breastfeeding rates, but there is a dearth of literature that allows African American women to give voice to their experiences. In addition, research has shown women, infant, and children (WIC) participants to have lower breastfeeding rates than non-WIC eligible women. Research Aim/Question: The aim of this systematic review was to examine the relationship between WIC program participation and breastfeeding initiation and duration among non-Hispanic African American/Black women. Methods: The approach for this review used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Four online databases, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, MEDLINE, and SCOPUS, were used to search for peer-reviewed articles and grey literature. Results: Two hundred eighteen articles were retrieved through the database search and underwent initial screening, yielding 59 potential eligible articles. Full-text articles were further reviewed and 11 met the inclusion criteria and were included in this systematic review. Conclusions: Included studies show mixed results regarding the association between WIC participation and breastfeeding initiation, but there is a general negative association between WIC participation and breastfeeding duration, especially among Black women.

Genetics, epigenetics, and transcriptomics of preterm birth.

Preterm birth contributes significantly to neonatal mortality and morbidity. Despite its global significance, there has only been limited progress in preventing preterm birth. Spontaneous preterm birth (sPTB) results from a wide variety of pathological processes. Although many non-genetic risk factors influence the timing of gestation and labor, compelling evidence supports the role of substantial genetic and epigenetic influences and their interactions with the environment contributing to sPTB. To investigate a common and complex disease such as sPTB, various approaches such as genome-wide association studies, whole-exome sequencing, transcriptomics, and integrative approaches combining these with other 'omics studies have been used. However, many of these studies were typically small or focused on a single ethnicity or geographic region with limited data, particularly in populations at high risk for sPTB, or lacked a robust replication. These studies found many genes involved in the inflammation and immunity-related pathways that may affect sPTB. Recent studies also suggest the role of epigenetic modifications of gene expression by the environmental signals as a potential contributor to the risk of sPTB. Future genetic studies of sPTB should continue to consider the contributions of both maternal and fetal genomes as well as their interaction with the environment.

Provision of Small-Quantity Lipid-Based Nutrient Supplements Increases Plasma Selenium Concentration in Pregnant Women in Malawi: A Secondary Outcome of a Randomized Controlled Trial.

Background: Pregnant women in Malawi are at risk of selenium deficiency, which can have adverse effects on pregnancy outcomes. Interventions for improving selenium status are needed. Objectives: To assess the effect of provision of small-quantity lipid-based nutrient supplements (SQ-LNSs) to Malawian women during pregnancy on their plasma selenium concentrations at 36 wk of gestation. Methods: Pregnant women (≤20 wk of gestation) were randomly assigned to receive daily either: 1) iron and folic acid (IFA); 2) multiple micronutrients (MMN; 130 µg selenium per capsule); or 3) SQ-LNS (130 µg selenium/20 g). Plasma selenium concentrations were measured by inductively coupled plasma mass spectrometry at baseline and after ≥16 wk of intervention (at 36 wk of gestation) and compared by intervention group. Results: At 36 wk of gestation, median (quartile 1, quartile 3) plasma selenium concentrations (micromoles per liter) were 0.96 (0.73, 1.23), 0.94 (0.78, 1.18), and 1.01 (0.85, 1.28) in the IFA, MMN, and SQ-LNS groups, respectively. Geometric mean (GM) plasma selenium concentration was 5.4% (95% CI: 1.8%, 9.0%) higher in the SQ-LNS group than in the MMN group and tended to be higher than in the IFA group (+4.2%; 95% CI: 1.0%, 7.8%). The prevalence of adjusted plasma selenium concentrations <1 µmol/L was 55.1%, 57.8%, and 47.3% in the IFA, MMN, and SQ-LNS groups, respectively; it was lower in the SQ-LNS group than in the MMN group, OR = 0.44 (95% CI: 0.24, 0.83), and tended to be lower than in the IFA group, OR = 0.54 (95% CI: 0.29, 1.03). There was a significant interaction between baseline plasma selenium concentration and intervention group (P = 0.003). In the lowest tertile of baseline selenium concentrations, GM plasma selenium concentration was higher, and the prevalence of low values was lower in the SQ-LNS group compared with the MMN and IFA groups at 36 wk of gestation (P ≤ 0.007). Conclusions: Provision of SQ-LNS containing selenium to pregnant women can be an effective strategy for improving their selenium status.This trial was registered at clinicaltrials.gov (identifier: NCT01239693).

Association of maternal prenatal selenium concentration and preterm birth: a multicountry meta-analysis.

BACKGROUND: Selenium (Se), an essential trace mineral, has been implicated in preterm birth (PTB). We aimed to determine the association of maternal Se concentrations during pregnancy with PTB risk and gestational duration in a large number of samples collected from diverse populations. METHODS: Gestational duration data and maternal plasma or serum samples of 9946 singleton live births were obtained from 17 geographically diverse study cohorts. Maternal Se concentrations were determined by inductively coupled plasma mass spectrometry analysis. The associations between maternal Se with PTB and gestational duration were analysed using logistic and linear regressions. The results were then combined using fixed-effect and random-effect meta-analysis. FINDINGS: In all study samples, the Se concentrations followed a normal distribution with a mean of 93.8 ng/mL (SD: 28.5 ng/mL) but varied substantially across different sites. The fixed-effect meta-analysis across the 17 cohorts showed that Se was significantly associated with PTB and gestational duration with effect size estimates of an OR=0.95 (95% CI: 0.9 to 1.00) for PTB and 0.66 days (95% CI: 0.38 to 0.94) longer gestation per 15 ng/mL increase in Se concentration. However, there was a substantial heterogeneity among study cohorts and the random-effect meta-analysis did not achieve statistical significance. The largest effect sizes were observed in UK (Liverpool) cohort, and most significant associations were observed in samples from Malawi. INTERPRETATION: While our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalise across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations for Se supplementation are considered.

Maternal selenium levels and whole genome screen in recurrent spontaneous preterm birth population: A nested case control study.

OBJECTIVE: To establish if low maternal selenium (Se) was associated with sPTB in women with recurrent sPTB and identify genetic link with maternal Se levels. DESIGN: Nested case-control study. SETTING: Tertiary Maternity Hospital. POPULATION: Plasma and whole blood from pregnant women with history of early sPTB/PPROM < 34+0 and European ancestry were obtained at 20 weeks (range 15-24 weeks). 'Cases' were recurrent PTB/PPROM < 34+0 weeks and term (≥37+0) deliveries were classified as 'high-risk controls.' Women with previous term births and index birth ≥ 39 weeks were 'low-risk controls'. METHODS: Maternal plasma Se measured by ICP-MS was used as a continuous phenotype in a GWAS analysis. Se was added to a logistic regression model using PTB predictor variables. MAIN OUTCOME MEASURES: Maternal Se concentration, recurrent early sPTB/PPROM. RESULTS: 53/177 high-risk women had a recurrent sPTB/PPROM < 34+0weeks and were 2.7 times more likely to have a Se level < 83.3 ppm at 20weeks of pregnancy compared with low-risk term controls (n = 179), (RR 2.7, 95%CI 1.5-4.8; p = .001). One SNP from a non-coding region (FOXN3 intron variant, rs55793422) reached genome-wide significance level (p = 3.73E-08). Targeted analysis of Se gene variant did not show difference between preterm and term births. (χ2 test, OR = 0.95; 95%CI = 0.59-1.56; p = 0.82). When Se levels were added to a clinical prediction model, only an additional 5% of cases (n = 3) and 0.6% (n = 1) of controls were correctly identified. CONCLUSIONS: Low plasma Se is associated with sPTB risk but is not sufficiently predictive at individual patient level. We did not find a genetic association between maternal Se levels and Se-related genes.

The genetics of preterm birth: Progress and promise.

Preterm birth is the single leading cause of mortality for neonates and children less than 5 years of age. Compared to other childhood diseases, such as infections, less progress in prevention of prematurity has been made. In large part, the continued high burden of prematurity results from the limited understanding of the mechanisms controlling normal birth timing in humans, and how individual genetic variation and environmental exposures disrupt these mechanisms to cause preterm birth. In this review, we summarize the outcomes and limitations from studies in model organisms for birth timing in humans, the evidence that genetic factors contribute to birth timing and risk for preterm birth, and recent genetic and genomic studies in women and infants that implicate specific genes and pathways. We conclude with discussing areas of potential high impact in understanding human parturition and preterm birth in the future.

Vitamin D status of early preterm infants and the effects of vitamin D intake during hospital stay.

OBJECTIVES: To evaluate vitamin D (vitD) status in early preterm infants (EPTIs) at birth and during birth hospitalisation on current vitD intake. DESIGN/METHODS: Serum 25-hydroxyvitamin-D [25(OH)D] concentrations, vitD intake and risk factors for low vitD status were assessed in 120 infants born at ≤32 weeks gestation. RESULTS: Mean (SD) serum 25(OH)D at birth was 46.2 (14.0) nmol/L with lower concentrations in infants born <28 weeks than at 28-32 weeks gestation, p=0.02. Serum 25(OH)D was <50 nmol/L in 63% of mothers, 64% of infants at birth and 35% of infants at discharge. Mean daily vitD intake was 289±96 IU at 4 weeks of age and 60% achieved 400 IU/day intake at discharge. CONCLUSIONS: Serum 25(OH)D <50 nmol/L was widespread in parturient women and in EPTIs at birth and at discharge. Optimising maternal vitD status during pregnancy and improving postnatal vitD intake may enhance infant vitD status during hospitalisation.