Poor Fetal Growth Research Articles

Neighborhood Walkability as a Risk Factor for Preterm Birth Phenotypes in Two Philadelphia Hospitals from 2013-2016.

A total of one in ten infants is born preterm in the U.S. with large racial disparities. Recent data suggest that neighborhood exposures may play a role. Walkability-how easily individuals can walk to amenities-may encourage physical activity. We hypothesized that walkability would be associated with a decreased risk of preterm birth (PTB) and that associations would vary by PTB phenotype. PTB can be spontaneous (sPTB) from conditions such as preterm labor and preterm premature rupture of membranes, or medically indicated (mPTB) from conditions such as poor fetal growth and preeclampsia. We analyzed associations of neighborhood walkability (quantified by their Walk Score® ranking) with sPTB and mPTB in a Philadelphia birth cohort (n = 19,203). Given racial residential segregation, we also examined associations in race-stratified models. Walkability (per 10 points of Walk Score ranking) was associated with decreased odds of mPTB (aOR 0.90, 95% CI: 0.83, 0.98), but not sPTB (aOR 1.04, 95% CI: 0.97, 1.12). Walkability was not protective for mPTB for all patients; there was a non-significant protective effect for White (aOR 0.87, 95% CI: 0.75, 1.01), but not Black patients (aOR 1.05, 95% CI: 0.92, 1.21) (interaction p = 0.03). Measuring health effects of neighborhood characteristics across populations is key for urban planning efforts focused on health equity.

Cord blood fatty acid binding protein 4 and lipids in infants born small- or large-for-gestational-age.

Adverse (poor or excessive) fetal growth "programs" an elevated risk of type 2 diabetes. Fatty acid binding protein 4 (FABP4) has been implicated in regulating insulin sensitivity and lipid metabolism relevant to fetal growth. We sought to determine whether FABP4 is associated with poor or excessive fetal growth and fetal lipids. In a nested case-control study in the Shanghai Birth Cohort including 60 trios of small-for-gestational-age (SGA, an indicator of poor fetal growth), large-for-gestational-age (LGA, an indicator of excessive fetal growth) and optimal-for-gestational-age (OGA, control) infants, we measured cord blood concentrations of FABP4 and lipids [high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterols, triglycerides (TG)]. Adjusting for maternal and neonatal characteristics, higher cord blood FABP4 concentrations were associated with a lower odds of SGA [OR = 0.29 (0.11-0.77) per log unit increment in FABP4, P = 0.01], but were not associated with LGA (P = 0.46). Cord blood FABP4 was positively correlated with both LDL (r = 0.29, P = 0.025) and HDL (r = 0.33, P = 0.01) in LGA infants only. FABP4 was inversely associated with the risk of SGA. The study is the first to demonstrate LGA-specific positive correlations of cord blood FABP4 with HDL and LDL cholesterols, suggesting a role of FABP4 in fetal lipid metabolism in subjects with excessive fetal growth.

Periconceptional maternal diet quality influences blood heavy metal concentrations and their effect on low birth weight: the Japan Environment and Children’s Study

BackgroundBoth poor maternal nutrition and toxic heavy metal exposure influence foetal growth and development. However, whether consumption of a variety of healthy foods modifies the association between prenatal heavy metal exposure and foetal growth is unknown. ObjectiveWe examined whether long-term maternal diet quality in periconception modifies the associations between maternal circulating concentrations of heavy metals and foetal growth. DesignData of 72,317 Japanese women who delivered singleton infants was extracted from the Japan Environment and Children’s Study. Maternal diet over a 1-year before the first trimester of pregnancy was assessed using a validated food frequency questionnaire, and overall diet quality was determined using the balanced diet score based on the Japanese Food Guide Spinning Top. Maternal whole-blood concentrations of mercury (Hg), lead (Pb) and cadmium (Cd) were measured during the second/third trimester of pregnancy. Bayesian inference of multiple linear regression analysis was performed to evaluate the relationships between maternal diet quality and the blood concentrations of heavy metals; Bayesian logistic regression was used to analyse the risk of low birth weight (LBW; <2,500 g). ResultsAfter controlling for confounders, a high maternal balanced diet score was associated with low concentrations of blood Pb and Cd and high Hg. While all heavy metals assessed were positively associated with LBW risk, a higher maternal balanced diet score was negatively associated with LBW risk. A high-quality maternal diet attenuated the effect of Pb on LBW, an effect that was more marked at high blood Pb concentrations. ConclusionA high-quality, ‘well-balanced’ diet prior to conception may reduce exposure to some heavy metals and mitigate the elevated risk of LBW associated with prenatal Pb exposure in Japanese mother–child pairs.

Maternal nutritional status modifies heat-associated growth restriction in women with chronic malnutrition.

Rapid changes in the global climate are deepening existing health disparities from resource scarcity and malnutrition. Rising ambient temperatures represent an imminent risk to pregnant women and infants. Both maternal malnutrition and heat stress during pregnancy contribute to poor fetal growth, the leading cause of diminished child development in low-resource settings. However, studies explicitly examining interactions between these two important environmental factors are lacking. We leveraged maternal and neonatal anthropometry data from a randomized controlled trial focused on improving preconception maternal nutrition (Women First Preconception Nutrition trial) conducted in Thatta, Pakistan, where both nutritional deficits and heat stress are prevalent. Multiple linear regression of ambient temperature and neonatal anthropometry at birth (n=459) showed a negative association between daily maximal temperatures in the first trimester and Z-scores of birth length and head circumference. Placental mRNA-sequencing and protein analysis showed transcriptomic changes in protein translation, ribosomal proteins, and mTORC1 signaling components in term placenta exposed to excessive heat in the first trimester. Targeted metabolomic analysis indicated ambient temperature associated alterations in maternal circulation with decreases in choline concentrations. Notably, negative impacts of heat on birth length were in part mitigated in women randomized to comprehensive maternal nutritional supplementation before pregnancy suggesting potential interactions between heat stress and nutritional status of the mother. Collectively, the findings bridge critical gaps in our current understanding of how maternal nutrition may provide resilience against adverse effects of heat stress in pregnancy.

Клинико-анамнестические факторы риска антенатальной смерти доношенного плода

Introduction. Current clinical and laboratory methods for assessing the intrauterine growth of a fetus are indirect and often have a low prognostic significance. Meanwhile, the determination of risk factors of antenatal death of a full-term fetus with the assessment of their prognostic significance and the possible preventability of adverse perinatal outcome will identify ways to reduce the stillbirth rate. Aim. Determine the clinical and anamnestic risk factors for antenatal death of a full-term fetus in the Chelyabinsk region. Materials and methods. A retrospective analysis of the medical records of all cases with antenatal fetal death at 37 weeks 0 days – 41 weeks 6 days of pregnancy, registered in the territory of the Chelyabinsk region from 2019 to 2021, was carried out. Two groups were assigned: group 1 – women with antenatal death of the full-term fetus (158 patients), group 2 – women with live full-term births (50 patients). Results. Women with antenatal death of the full-term fetus statistically significantly more often lived in the city of Chelyabinsk and big cities of the Chelyabinsk region, had secondary vocational education and used to smoke tobacco; they had first or second pregnancy and first delivery. Among these women, female pelvic inflammatory diseases, hypertension, endocrine system diseases and specific infectious diseases (HIV infection, hepatitis C and tuberculosis) were statistically more common. These women had statistically more pregnancy-related complications such as hypertension without significant proteinuria; diabetes mellitus arising in pregnancy; gestational edema; false labour up to 37 full weeks of pregnancy; placental disorders; maternal care for poor fetal growth; acute respiratory infections. The following factors have a direct impact on antenatal death at full-term pregnancy: a history of hypertension, moderate pre-eclampsia, placental disorders, and fetal growth retardation. Conclusion. In the presence of risk factors directly affecting the occurrence of antenatal death of a full-term fetus, we consider it appropriate to deliver at 37 weeks 0 days – 38 weeks 0 days of pregnancy in order to reduce the risk of an adverse outcome of pregnancy.

Performance of a risk factor-based approach in the detection of small for gestational age neonates: A cohort study.

Antenatal detection of fetal growth restriction allows the opportunity to increase surveillance and initiate intervention to prevent adverse outcomes. Detection of small for gestational age (SGA) fetuses with risk factor screening and selective ultrasonography is the standard of care in Australia, but evidence regarding performance is lacking. To evaluate the diagnostic performance of a risk factor-based screening approach in detection of SGA neonates. Retrospective cohort study conducted in a metropolitan maternity service, including all consecutive singleton deliveries over 20 weeks gestation from July 2016 to December 2017, and excluding terminations of pregnancy. An SGA neonate was defined by birthweight below the tenth percentile according to Australian reference ranges. Antenatally detected SGA cases were defined by estimated fetal weight or abdominal circumference below the tenth percentile for gestational age, or abnormal symphysio-fundal height. The diagnostic accuracy of the screening protocol was calculated using detection rates and false-positive rates. There were 13 384 singleton pregnancies included. There were 1330 infants (10.0%) who were SGA at birth. Antenatal detection rate of SGA neonates was 39.6% (95% confidence interval (CI) 37.0-42.3%), with a false-positive rate of 10.2% (95% CI 9.6-10.7%). There were 10 266 pregnancies (77.0%) which had at least one risk factor for an SGA infant. Of these, 6650 (64.8%) underwent at least one fetal growth ultrasound after 24 weeks gestation. Antenatal recognition of poor fetal growth is suboptimal using our current screening protocol. Three-quarters of pregnancies demonstrated risk factors for delivering an SGA infant, but growth ultrasonography may be underutilised.

Clinical Assessment of Fetal Well-Being and Fetal Safety Indicators.

Delivering safe clinical trials of novel therapeutics is central to enable pregnant women and their babies to access medicines for better outcomes. This review describes clinical monitoring of fetal well‐being and safety. Current pregnancy surveillance includes regular antenatal checks of blood pressure and urine for signs of gestational hypertension. Fetal and placental development is assessed routinely using the first‐trimester “dating” and mid‐trimester “anomaly” ultrasound scans, but the detection of fetal anomalies can continue throughout pregnancy using targeted sonography or magnetic resonance imaging (MRI). Serial sonography can be used to assess fetal size, well‐being, and placental function. Carefully defined reproducible imaging parameters, such as the head circumference (HC), abdominal circumference (AC), and femur length (FL), are combined to calculate an estimate of the fetal weight. Doppler analysis of maternal uterine blood flow predicts placental insufficiency, which is associated with poor fetal growth. Fetal doppler analysis can indicate circulatory decompensation and fetal hypoxia, requiring delivery to be expedited. Novel ways to assess fetal well‐being and placental function using MRI, computerized cardiotocography (CTG), serum circulating fetoplacental proteins, and mRNA may improve the assessment of the safety and efficacy of maternal and fetal interventions. Progress has been made in how to define and grade clinical trial safety in pregnant women, the fetus, and neonate. A new system for improved safety monitoring for clinical trials in pregnancy, Maternal and Fetal Adverse Event Terminology (MFAET), describes 12 maternal and 18 fetal adverse event (AE) definitions and severity grading criteria developed through an international modified Delphi consensus process. This fills a vital gap in maternal and fetal translational medicine research.

Association of distinct features of villitis of unknown etiology histopathology and fetal growth restriction diagnosis in a retrospective cohort from Eastern Ontario

IntroductionVillitis of unknown etiology (VUE) is associated with fetal growth restriction (FGR) and adverse short-term neonatal outcomes. No investigation to date has found which VUE features are driving the association with FGR diagnosis. MethodsA retrospective cohort study of placenta pathology specimens (2013–2017) was conducted. Independent variables of interest were: VUE distribution (focal vs diffuse), location (basal vs non-basal), and grade (high vs low). The primary outcome was FGR, and secondary outcomes were neonatal intensive care unit (NICU) admission, NICU length of stay, Apgar scores <7 at 1, 5, and 10-min, and recurrence rate of villitis in subsequent pregnancies. Association between VUE characteristics and our primary outcome were investigated using logistic regression. Secondary outcomes were explored with regression analyses and recurrence rate of VUE for members of the cohort with a recorded subsequent pregnancy was calculated. ResultsOne hundred and twenty seven placentas were included. Adjusted models showed no difference in the odds of FGR between high-grade versus low-grade VUE [aOR 1.25 95% CI (0.50, 3.26), p = 0.6], focal/multi-focal vs diffuse cases [aOR 1.03 95% CI (0.28, 4.34), p = >0.9], and basal vs non-basal VUE [aOR 0.06 95% CI (0.00, 1.10), p = 0.058]. After adjusting for prematurity <37 weeks, there were lower odds of NICU admission in basal vs non-basal cases [aOR 0.25, 95% CI (0.06, 0.90), p = 0.048). There was no difference in the odds of neonates presenting with Apgar <7 for the distinct VUE histopathology features. Three cases had recurrent VUE, resulting in a 6.8% [95% CI (3.02%, 10.61%)] recurrence rate. All recurrent cases were high-grade and identified with basal localization. DiscussionThere are no statistical associations between distinct VUE features and FGR diagnosis, however location of villitis may be associated with worse neonatal outcomes. Villitis of any type (severity, degree, location) could potentially drive insufficient placental function and poor fetal growth.

Sex-dependent differential transcript expression in the placenta of growth restricted infants

IntroductionThe pathological decrease of fetal growth during gestation can lead to subsequent poor health outcomes for the fetus. This process is commonly controlled by the placenta, the interface between mother and baby during gestation. Sex-specific gene expression has been implicated in placental function, therefore, there is a need to determine if it is important during reduced fetal growth. We therefore aimed to characterise placental gene expression at term to evaluate sex-specific genetic changes that occur in small for gestational age (SGA) infants. MethodsRNA-sequencing of twelve human placental tissue samples collected from pregnancies yielding either term appropriate for gestational age (AGA) or SGA infants identified at delivery. Candidate genes associated with fetal size and fetal sex were identified using differential gene expression and weighted gene co-expression network analyses. Single-cell sequencing data was used for candidate validation and to estimate candidate transcript expression in specific placental cell populations. ResultsDifferential gene expression and weighted gene co-expression network analyses identified 403 candidate transcripts associated with SGA infants. One hundred and three of these transcripts showed sex-specific expression. . Published placental sequencing datasets were used to validate the key expression results from the twelve placental samples initially studied; the sex-independent transcript expression for genes involved in cell cycle processes in males (7 transcripts) and endoplasmic reticulum stress in females (17 transcripts). DiscussionThis study identified the activation of multiple molecular mechanisms involved in the placental response to an adverse environmental stressor. Mechanisms such as disrupted protein synthesis were shared between infant biological sex when comparing AGA to SGA, whilst other pathways such as cell cycle and endoplasmic reticulum stress appear as independent/specific to either males or females when investigating reduced fetal growth. This data suggests that sexual dimorphism is an important consideration when examining placental dysfunction and poor fetal growth.

Newborn body composition and child cardiovascular risk markers: a prospective multi-ethnic Asian cohort study.

Early epidemiological studies have associated low birthweight with increased cardiovascular risk. We aimed to examine whether the fat and fat-free components of birthweight have differing relationships with childhood cardiovascular risk markers. In the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort, air displacement plethysmography was conducted within 24 h after delivery in 290 naturally conceived singletons. We investigated associations of newborn cohort-specific standardized z-score of fat mass, fat-free mass, body fat percentage and birthweight on child (at 6 years of age) carotid intima-media thickness, pulse wave velocity, blood pressure, prehypertension/hypertension (>110/70 mmHg) and standardized systolic and diastolic blood pressure (SBP and DBP) trajectories (at 3-6 years of age), taking account of maternal education, height, tobacco exposure, parity, ethnicity, child's sex, gestational age, age at follow-up, and other maternal factors. Clear inverse associations were seen for blood pressure with z-score of fat mass [SBP, β (95% CI): -1.31 mmHg (-2.57, -0.06); DBP: -0.79 mmHg (-1.74, 0.15)] and body fat percentage [SBP: -1.46 mmHg (-2.73, -0.19); DBP: -0.80 mmHg (-1.75, 0.16)], but not with fat-free mass [SBP: 0.27 mmHg (-1.29, 1.83)]; DBP: -0.14 mmHg (-1.30, 1.03)]. Being in the lowest tertile of fat mass or body fat percentage was associated with higher blood pressure trajectories and prehypertension/hypertension risk [OR (95% CI), fat mass: 4.23 (1.41, 12.68); body fat percentage: 3.22 (1.09, 9.53)] without concomitantly higher overweight/obesity risk. At birth, low adiposity was associated with increased childhood blood pressure. Low newborn adiposity might serve as a marker of poor fetal growth or suboptimal intrauterine conditions associated with hypertension risk later in life.

Effect of Epilepsy on Sleep Quality During Pregnancy and Postpartum.

This study seeks to understand how sleep is affected in pregnant women with epilepsy (WWE) relative to healthy pregnant women during pregnancy and postpartum and to nonpregnant WWE during comparative periods. Sleep affects maternal health and mood during pregnancy. Maternal sleep disturbances are related to poor fetal growth and increased fetal deaths. Epilepsy is the most common neurologic condition in pregnancy. Sleep disruption can worsen epileptic seizures. The interplay between epilepsy, pregnancy, and sleep is poorly understood. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter study, enrolling women from December 2012 through January 2016. Sleep quality was assessed using the average Pittsburgh Sleep Quality Index collected during pregnancy, postpartum, or analogous periods. Sleep scores range from 0 to 21 with higher scores indicating worse sleep quality; scores >5 are associated with poor sleep quality. Of 351 pregnant WWE, 105 healthy pregnant women, and 109 nonpregnant WWE enrolled in the MONEAD study, data from 241 pregnant WWE, 74 healthy pregnant women, and 84 nonpregnant WWE were analyzed. Pregnant WWE had worse sleep (a higher mean sleep score) during pregnancy compared with healthy pregnant women in unadjusted analysis (p = 0.006), but no longer significant in adjusted analysis (p = 0.062); pregnant WWE (least square mean sleep score [95% CI] = 5.8 [5.5-6.1]) vs healthy pregnant women (5.1 [4.6-5.7]). During postpartum period, WWE (5.6 [5.4-5.9]) had similarly impaired sleep compared with healthy women (5.7 [5.2-6.2]; adjusted p = 0.838). Sleep was significantly worse in pregnant WWE vs nonpregnant WWE (for comparable period) in pregnancy and postpartum in unadjusted and adjusted analyses; adjusted scores for pregnant WWE in pregnancy (5.7 [5.4-6.0]) and those in postpartum (5.7 [5.4-6.0]) compared with those for nonpregnant WWE (4.7 [4.2-5.3]; p = 0.002) and (4.1 [3.6-4.7]; p < 0.001), respectively. Sleep quality between pregnancy and postpartum varied only in healthy pregnant women (change in mean score = 0.8 [0.2-1.3]; p = 0.01), whose sleep was worse in postpartum. Pregnant WWE had worse sleep during pregnancy and postpartum period than nonpregnant WWE during comparable periods in the adjusted analysis. The study is registered at ClinicalTrials.gov as NCT01730170.

Microstructural alterations in association tracts and language abilities in schoolchildren born very preterm and with poor fetal growth

BackgroundPrematurity and perinatal risk factors may influence white matter microstructure. In turn, these maturational changes may influence language development in this high-risk population of children.ObjectiveTo evaluate differences in the microstructure of association tracts between preterm and term children and between preterm children with appropriate growth and those with fetal growth restriction and to study whether the diffusion tensor metrics of these tracts correlate with language abilities in schoolchildren with no severe neurological impairment.Materials and methodsThis study prospectively followed 56 very preterm children (mean gestational age: 28.7 weeks) and 21 age- and gender-matched term children who underwent diffusion tensor imaging at a mean age of 9 years. We used automated probabilistic tractography and measured fractional anisotropy in seven bilateral association tracts known to belong to the white matter language network. Both groups participated in language assessment using five standardised tests at the same age.ResultsPreterm children had lower fractional anisotropy in the right superior longitudinal fasciculus 1 compared to term children (P < 0.05). Preterm children with fetal growth restriction had lower fractional anisotropy in the left inferior longitudinal fasciculus compared to preterm children with appropriate fetal growth (P < 0.05). Fractional anisotropy in three dorsal tracts and in two dorsal and one ventral tract had a positive correlation with language assessments among preterm children and preterm children with fetal growth restriction, respectively (P < 0.05).ConclusionThere were some microstructural differences in language-related tracts between preterm and term children and between preterm children with appropriate and those with restricted fetal growth. Children with better language abilities had a higher fractional anisotropy in distinct white matter tracts.

P-769 Endometrial thickness is not associated with birthweight as well as serum levels of pregnancy-associated plasma protein-A: a retrospective analysis of 560 newborns following frozen cycles

Abstract Study question Does endometrial thickness (EMT) affect birthweight and maternal serum evels of pregnancy-associated plasma protein-A (PAPP-A) in singleton pregnancies following frozen-thawed blastocyst transfer (FET)? Summary answer EMT does not significantly affect birthweight and maternal serum evels of PAPP-A in singleton pregnancies following FET. What is known already Several studies have shown an association between EMT and low birth weight in pregnancies resulting from fresh embryo transfers. Supraphyiological levels of steroid hormone during ovarian stimulation may be responsible for poor fetal growth. Few studies have investigated the relationship between EMT and fetal growth potential in frozen-thawed embryo transfers. Study design, size, duration This retrospective study included women who underwent first-trimester combined screening for aneuploidy after frozen-thawed blastocyst transfer and subsequently delivered a singleton live birth after 24 weeks of gestations between January 2016 and July 2020 in a private IVF center. Participants/materials, setting, methods A total of 560 women met the inclusion criteria and were stratified into three groups based on the EMT percentiles: &amp;lt;7.7 mm (&amp;lt;10th percentile), 7.7–12 mm (10-90th percentile), and &amp;gt;12 mm (&amp;gt;90th percentile). The primary outcome measures were mean birth weight and mean PAPP-A level. A multivariable linear regression analysis was carried out to identify the association between birth weight and EMT after adjusting for variables found at &amp;lt; 0.1 level in the univariate analysis. Main results and the role of chance The mean birth weight was 3127 ± 783 g in those with EMT &amp;lt;7.7 mm 3225 ± 644 g in those with EMT 7.7-12 mm, and 3256 ± 599 g in those with EMT &amp;gt;12 mm (p = 0.577). The mean PAPP-A levels and PAPP-A&amp;lt;0.5 rates were similar in the groups, as well. In multivariate analysis, the number of previous ART attempts and maternal serum levvels of PAPP-A were found to be significant predictors of birth weight (p = 0.001 and p = 0.013, respectively). EMT was not a predictor of birth weight in both univariate and multivariate analyses. The multivariate logistic regression analysis indicated that the number of previous ART attempts was an independent factor for low birth weight (OR:1.39, 95%CI:1.09-1.76, p = 0.006). Limitations, reasons for caution The study has inheret limitations due to its retrospective nature. Further studies are needed to investigate the relationship between EMT and birth weight along with maternal serum levels of PAPP-A. Wider implications of the findings Our study provided a new angle of view for evaluating the association between EMT and neonatal birth weight by analyzing this association along with maternal serum levels of PAPP-A as a marker for placental function, suggesting that EMT is not an independent factor for neonatal birth weight. Trial registration number NA

Safety of tetanus, diphtheria, acellular pertussis (Tdap) vaccination during pregnancy

The objective of this study was to evaluate the safety of prenatal tetanus, diphtheria, acellular pertussis (Tdap) vaccination. This cohort study was conducted among pregnant members at Kaiser Permanente Southern California (KPSC). The exposed cohort consisted of women who received Tdap vaccine on or after the 27th week of pregnancy between January 2018 and January 2019. The unexposed cohort consisted of matched women who were pregnant between January 2012 and December 2014 and were not vaccinated with any Tdap vaccine throughout their pregnancy. Maternal and infant characteristics and pre-specified endpoints were collected through automated data and review of the electronic health records. Unadjusted and adjusted relative risks (aRRs) with confidence intervals (CIs) were estimated by Poisson regression. Non-inferiority testing (i.e., to rule out a two-fold increase) was conducted for primary endpoints with adjustment for multiplicity. Superiority testing was conducted without multiplicity adjustment for secondary endpoints. The analysis consisted of 16,606 pairs of Tdap recipients and unexposed pregnant women. For the primary endpoints, the aRR for preeclampsia/eclampsia was 1.38 (98.75% CI:1.21–1.58) and the aRR for intrauterine infection was 1.28 (98.75% CI:1.12–1.47). These increases were consistent with the background increasing trend of these diagnoses among all pregnant women at KPSC since 2011, and the upper limit of the 98.75% CI of both aRRs did not exceed the pre-specified threshold of 2. No increased risks of small for gestational age (aRR = 1.04, 98.75% CI:0.94–1.16) or preterm delivery (aRR = 0.71, 98.75% CI:0.64–0.78) were observed. No evidence of increased risks for secondary endpoints, including poor fetal growth, preterm pre-labor rupture of membranes, stillbirth/fetal death, placental abruption, transfusion during delivery hospitalization, and neonatal death, was observed. Prenatal Tdap vaccination after the 27th week of pregnancy was not associated with increased risks of pre-specified maternal and infant outcomes, supporting the safety of Tdap vaccination during pregnancy.

Maternal Low Volume Circulation Relates to Normotensive and Preeclamptic Fetal Growth Restriction.

This narrative review summarizes current evidence on the association between maternal low volume circulation and poor fetal growth. Though much work has been devoted to the study of cardiac output and peripheral vascular resistance, a low intravascular volume may explain why high vascular resistance causes hypertension in women with preeclampsia (PE) that is associated with fetal growth restriction (FGR) and, at the same time, presents with normotension in FGR itself. Normotensive women with small for gestational age babies show normal gestational blood volume expansion superimposed upon a constitutionally low intravascular volume. Early onset preeclampsia (EPE; occurring before 32 weeks) is commonly associated with FGR, and poor plasma volume expandability may already be present before conception, thus preceding gestational volume expansion. Experimentally induced low plasma volume in rodents predisposes to poor fetal growth and interventions that enhance plasma volume expansion in FGR have shown beneficial effects on intrauterine fetal condition, prolongation of gestation and birth weight. This review makes the case for elevating the maternal intravascular volume with physical exercise with or without Nitric Oxide Donors in FGR and EPE, and evaluating its role as a potential target for prevention and/or management of these conditions.

Biomarkers of Environmental Enteric Dysfunction in Pregnancy and Adverse Birth Outcomes: An Observational Study Among Women Living With HIV in Tanzania

ObjectivesEnvironmental enteric dysfunction (EED), a subclinical state of intestinal inflammation, may contribute to poor fetal growth in low-resource settings. Pregnant women living with HIV may be particularly susceptible to effects of EED, given their increased risk of infections and adverse birth outcomes. We sought to explore the associations of biomarkers of EED, inflammation and growth hormones with birth outcomes in pregnant women living with HIV in Dar es Salaam, Tanzania.MethodsWe performed a sub-study of 706 HIV-infected pregnant women participating in a randomized, double-blind, placebo-controlled trial assessing the effect of vitamin D3 supplementation. Maternal serum samples collected at 32 weeks gestation were analyzed for anti-flagellin and anti-LPS IgA and IgG via ELISA as well as using an 11-plex Micronutrient and EED Assessment Tool, which includes markers of EED [intestinal fatty acid-binding protein (I-FABP) and soluble CD14], systemic inflammation [C-reactive protein and α1-acid glycoprotein (AGP)], insulin-like growth factor 1 (IGF-1) and fibroblast growth factor 21 (FGF21). Biomarkers were categorized as quartiles. Associations with birth outcomes were assessed using linear regression analyses.ResultsPregnant women in the highest quartile of I-FABP had more than twice the risk of stillbirth compared to those in the lowest quartile (RR 2.43, 95% CI 0.98–6.03, ptrend = 0.02). Compared to women in the lowest quartile of AGP, those in the highest quartile gave birth to infants weighing 176g less (95% CI -280 to -71g, ptrend = 0.005). Maternal AGP was associated with increased risk of small-for-gestational age births; those in the highest quartile had a 70% greater risk compared to the lowest (RR 1.70, 95% CI 1.08–2.69, ptrend = 0.03). IGF1 was positively associated with birthweight and birthweight-for-age z-score; FGF21 was negatively associated with gestation duration and risk of preterm birth.ConclusionsMaternal biomarkers of EED, systemic inflammation, and the growth hormone axis were associated with birth outcomes. Further studies are needed to confirm these results and study the biologic mechanisms involved.Funding SourcesNational Institutes of Health (NICHD, NIDDK).

Preterm birth, poor foetal growth and anxiety disorders in a Finnish nationwide register sample.

AimWe examined the associations between preterm birth, poor foetal growth and anxiety disorders among children and adolescents. Additionally, we examined the impact of common comorbidities and specific anxiety disorders separately.MethodsThree Finnish registers provided data on a nationwide birth cohort of 22,181 cases with anxiety disorders and 74,726 controls. Conditional logistic regression was used to examine the associations.ResultsExtremely very preterm birth and moderate‐late preterm birth were associated with increased adjusted odds ratios (aOR) for anxiety disorders (aOR 1.39, 95% CI 1.11–1.75 and aOR 1.13, 95% CI 1.03–1.23, respectively). Weight for gestational age of less than −2SD (aOR 1.29, 95% CI 1.17–1.42) and −2SD to −1SD (aOR 1.08, 95% CI 1.03–1.14) were associated with increased odds ratios for anxiety disorders. When comorbidities were considered, the associations became statistically insignificant for pure anxiety disorders, but remained significant in the groups with comorbid depressive or neurodevelopmental disorders.ConclusionPreterm birth and poor foetal growth increased the odds for anxiety disorders. However, the associations seem to be explained by the conditions of comorbid depressive and neurodevelopmental disorders. Comorbidities should be considered when examining and treating child and adolescent anxiety disorders.

Brain volumes and white matter microstructure in 8- to 10-year-old children born with fetal growth restriction

BackgroundFetal growth restriction caused by placental insufficiency is associated with increased risk of poor neurodevelopment, even in the absence of specific perinatal brain injury. Placental insufficiency leads to chronic hypoxaemia that may alter cerebral tissue organisation and maturation.ObjectiveThe aim of this study was to assess the effects fetal growth restriction and fetal haemodynamic abnormalities have on brain volumes and white matter microstructure at early school age.Materials and methodsThis study examined 32 children born with fetal growth restriction at 24 to 40 gestational weeks, and 27 gestational age-matched children, who were appropriate for gestational age. All children underwent magnetic resonance imaging (MRI) at the age of 8–10 years. Cerebral volumes were analysed, and tract-based spatial statistics and atlas-based analysis of white matter were performed on 17 children born with fetal growth restriction and 14 children with birth weight appropriate for gestational age.ResultsChildren born with fetal growth restriction demonstrated smaller total intracranial volumes compared to children with normal fetal growth, whereas no significant differences in grey or white matter volumes were detected. On atlas-based analysis of white matter, children born with fetal growth restriction demonstrated higher mean and radial diffusivity values in large white matter tracts when compared to children with normal fetal growth.ConclusionChildren ages 8–10 years old born with fetal growth restriction demonstrated significant changes in white matter microstructure compared to children who were appropriate for gestational age, even though no differences in grey and white matter volumes were detected. Poor fetal growth may impact white matter maturation and lead to neurodevelopmental impairment later in life.

Are there sex differences in fetal growth strategies and in the long-term effects of pregnancy complications on cognitive functioning?

Males and females have been proposed to have different prenatal growth strategies, whereby males invest more in fetal growth and less in placental development, leaving them more susceptible to early-life adversity. We tested predictions of this hypothesis using data from the National Collaborative Perinatal Project. Male newborns were heavier than females, but there was no difference in placental weight, adjusting for birthweight. Among infants born prior to 33 weeks, the difference in birthweight between males and females was greater among those who did not survive than among those who did, potentially reflecting a strategy whereby males maintained growth in the face of prenatal insults, while females adjusted growth. However, there was no significant difference in mortality between the sexes. Being born small-for-gestational age or very preterm (prior to 33 weeks) was associated with significantly reduced performance for most of the cognitive traits examined at 7 years, although maternal preeclampsia was associated with reduced performance in fewer traits. Generally, these effects of early-life adversity (poor fetal growth, prematurity, and preeclampsia) did not differ between the sexes. However, analyzing the sexes separately (rather than testing the interaction between sex and adversity) resulted in numerous spurious sex-specific effects, whereby the effect of early-life adversity appeared to be significant in one sex but not the other. Overall, we found little support for the hypothesis that males prioritize growth more than females, and that this makes them more susceptible to early-life adversity. Furthermore, our results show that analyzing the sexes separately, rather than testing the adversity by sex interaction, can be highly misleading.

Vitamin D3 supplementation during pregnancy and lactation for women living with HIV in Tanzania: A randomized controlled trial.

BackgroundObservational studies suggest that vitamin D deficiency among people living with HIV is associated with a greater risk of disease progression and death. Low levels of vitamin D in pregnancy are also associated with poor fetal and infant growth. Therefore, vitamin D supplementation may improve clinical outcomes for pregnant women living with HIV and improve fetal and postnatal growth for their infants.Methods and findingsWe conducted a randomized, triple-blind, placebo-controlled trial of vitamin D3 supplementation among pregnant and lactating women living with HIV in Dar es Salaam, Tanzania (ClinicalTrials.gov NCT02305927). Participants were randomized with 1:1 allocation stratified by study clinic to receive either daily 3,000 IU vitamin D3 supplements or matching placebo supplements from the second trimester of pregnancy (12–27 weeks) until 1 year postpartum. The primary outcomes were (i) maternal HIV progression or death, (ii) small-for-gestational-age (SGA) live births (<10th percentile), and (iii) infant stunting at 1 year of age (length-for-age z-score < −2). We also examined the effect of vitamin D3 supplementation on secondary maternal and infant health outcomes, maternal and infant serum 25-hydroxyvitamin D (25[OH]D) concentrations, and maternal hypercalcemia. An intent-to-treat analysis was used as the primary analytic approach. We enrolled 2,300 pregnant women between June 15, 2015, and April 17, 2018, and follow-up of mothers and infants was completed on October 20, 2019. There were 1,148 pregnant women randomly assigned to the vitamin D3 group, and 1,152 to the placebo group. The proportion of mothers lost to follow-up at 1 year postpartum was 6.6% in the vitamin D3 group (83 of 1,148) and 6.6% in the placebo group (76 of 1,152). The proportion of children lost to follow-up at 1 year of age was 5.5% in the vitamin D3 group (59 of 1,074 live births) and 5.2% in the placebo group (57 of 1,093 live births). There was no difference in the risk of maternal HIV progression or death, with 166 events during 1,461 person-years of follow-up in the vitamin D3 group and 141 events during 1,469 person-years of follow-up in the placebo group (hazard ratio 1.21, 95% CI 0.97 to 1.52, p = 0.09). There was no difference in the risk of SGA birth between the vitamin D3 (229 SGA births among 1,070 live births) and placebo groups (236 SGA births among 1,091 live births) (relative risk 1.03, 95% CI 0.87 to 1.22, p = 0.70). There was also no difference in the risk of infant stunting at 1 year of age between the vitamin D3 (407 events among 867 infants) and placebo groups (413 events among 873 infants) (relative risk 1.00, 95% CI 0.92 to 1.10, p = 0.95). In terms of adverse events, no cases of maternal hypercalcemia were identified. One hypersensitivity reaction to the trial supplements occurred for a pregnant woman in the placebo group. A limitation of our study is that our findings may not be generalizable to HIV-negative pregnant women or contexts where severe vitamin D deficiency is prevalent.ConclusionsThe trial findings do not support routine vitamin D supplementation for pregnant and lactating women living with HIV in Tanzania.Trial registrationClinicalTrials.gov Identifier: NCT02305927.