A longitudinal study of exposure to fine particulate matter during pregnancy, small-for-gestational age births, and birthweight percentile for gestational age in a statewide birth cohort

Background Previous studies observed associations between prenatal exposure to fine particulate matter (≤ 2.5 μm; PM2.5) and small-for-gestational-age (SGA) birth and lower birthweight percentile for gestational age. Few, if any, studies examine prenatal air pollution exposure and these pregnancy outcomes in neonates born to the same women. Here, we assess whether prenatal exposure to ambient fine particulate matter (PM2.5) is associated with small-for-gestational-age (SGA) birth or birthweight percentile for gestational age in a longitudinal setting. Methods Detailed birth record data were used to identify women who had singleton live births at least twice in North Carolina during 2002–2006 (n = 53,414 women, n = 109,929 births). Prenatal PM2.5 exposures were calculated using daily concentration estimates obtained from the US EPA Fused Air Quality Surface using Downscaling data archive. Associations between PM2.5 exposure and birthweight percentile and odds of SGA birth were calculated using linear and generalized mixed models, comparing successive pregnancies to the same woman. Odds ratios and associations were also estimated in models that did not account for siblings born to the same mother. Results Among NHW women, pregnancy-long PM2.5 exposure was associated with SGA (OR: 1.11 [1.06, 1.18]) and lower birthweight percentile (− 0.46 [− 0.74, − 0.17]). Trimester-specific PM2.5 was also associated with SGA and lower birthweight percentile. Among NHB women, statistically significant within-woman associations between PM2.5, SGA, and birthweight percentile were not observed. However, in models that did not account for births to the same mother, statistically significant associations were observed between some PM2.5 exposure windows and higher odds of SGA and lower birthweight percentile among NHB women. Conclusions Findings suggest that a woman is at greater risk of delivering an SGA or low birthweight percentile neonate when she has been exposed to higher PM2.5 levels. The within-woman comparison implemented here better controls for factors that may differ between women and potentially confound the relationship between PM2.5 exposure and pregnancy outcomes. This adds to the evidence that PM2.5 exposure may be causally related to SGA and birthweight percentile, even at concentrations close to or below National Ambient Air Quality Standards.

Plasma Acylcarnitines during Pregnancy and Neonatal Anthropometry: A Longitudinal Study in a Multiracial Cohort

As surrogate readouts reflecting mitochondrial dysfunction, elevated levels of plasma acylcarnitines have been associated with cardiometabolic disorders, such as obesity, gestational diabetes, and type 2 diabetes. This study aimed to examine prospective associations of acylcarnitine profiles across gestation with neonatal anthropometry, including birthweight, birthweight z score, body length, sum of skinfolds, and sum of body circumferences. We quantified 28 acylcarnitines using electrospray ionization tandem mass spectrometry in plasma collected at gestational weeks 10–14, 15–26, 23–31, and 33–39 among 321 pregnant women from the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons. A latent-class trajectory approach was applied to identify trajectories of acylcarnitines across gestation. We examined the associations of individual acylcarnitines and distinct trajectory groups with neonatal anthropometry using weighted generalized linear models adjusting for maternal age, race/ethnicity, education, parity, gestational age at blood collection, and pre-pregnancy body mass index (BMI). We identified three distinct trajectory groups in C2, C3, and C4 and two trajectory groups in C5, C10, C5–DC, C8:1, C10:1, and C12, respectively. Women with nonlinear decreasing C12 levels across gestation (5.7%) had offspring with significantly lower birthweight (−475 g; 95% CI, −942, −6.79), birthweight z score (−0.39, −0.71, −0.06), and birth length (−1.38 cm, −2.49, −0.27) than those with persistently stable C12 levels (94.3%) (all nominal p value < 0.05). Women with consistently higher levels of C10 (6.1%) had offspring with thicker sum of skinfolds (4.91 mm, 0.85, 8.98) than did women with lower levels (93.9%) during pregnancy, whereas women with lower C10:1 levels (12.6%) had offspring with thicker sum of skinfolds (3.23 mm, 0.19, 6.27) than did women with abruptly increasing levels (87.4%) (p < 0.05). In conclusion, this study suggests that distinctive trajectories of C10, C10:1, and C12 acylcarnitine levels throughout pregnancy were significantly associated with neonatal anthropometry.

The rs1421085 variant within FTO promotes thermogenesis and is associated with human migration

One lead risk signal of obesity–rs1421085 T > C within the FTO gene–is reported to be functional in vitro but lack of organismal evidence. Here, we established global and the brown-adipocyte specific locus-knock-in mice to recapitulate this homologous variant in humans and discovered that mice carrying the C-alleles showed increased thermogenic capacity and a resistance to high-fat diet-induced adiposity with enhanced FTO transcription, while FTO knockdown or inhibition effectively eliminated the increased thermogenic ability of brown adipocytes. In humans, the C-allele was associated with lower birthweight, and its allele frequency increases following the environmental temperature decreases. Cumulatively, these findings identified rs1421085 T > C as a functional variant promoting whole-body thermogenesis and was associated with early human migration from hot to cold environments.

Maternal bleeding complications in pregnancies affected by red blood cell alloimmunization

Purpose To investigate whether women with red blood cell (RBC) alloimmunization are more likely to experience bleeding complications during pregnancy or delivery than women without RBC alloimmunization. Methods Retrospective study involving all singleton pregnancies affected by RBC alloimmunization and without pre-existing maternal bleeding disorders or placenta previa, from 1 July 1999 to 30 June 2019 (“cases”). Only bleedings not related to invasive procedures (amnio- or cordocenteses) were included. Cases were compared to controls without RBC alloimmunization, matched for maternal age and body mass index, from the same tertiary referral center in Austria. Results 130 cases were compared to 130 controls. Cases had significantly more previous pregnancies and miscarriages and their newborns had lower birthweight and were more often transferred to the intensive care unit than newborns of controls. 18/130 (13.8%) cases, compared to 8/130 (6.2%) controls experienced any bleeding during pregnancy or delivery (p = 0.061). Bleeding most often happened during the third trimester (cases: 4.6% vs. controls 0.8%, p = 0.12) and during or after delivery (cases: 7.7% vs. controls: 4.6%, p = 0.168). Binary logistic regression for the prediction of any bleeding complication during pregnancy, delivery or postpartum revealed immunization against RBC antigens as the only independent contributor (p = 0.04). Age, smoking, or previous obstetric history had no influence on the likelihood of maternal bleeding complications. Neither RBC antibody specificity nor titers were predictive of maternal bleeding during pregnancy or delivery. Conclusion Pregnancies affected by RBC alloimmunization are at increased risk of maternal bleeding complications during pregnancy and delivery.

1014Maternal educational qualification and child’s birth weight: Findings from Office for National Statistics Longitudinal Study

Background Lower maternal education was found to be associated with lower child’s birthweight which in turn was a possible risk factor for later poor health. Presented research aims to assess the association between maternal education and singleton’s birthweight in large UK data, accounting for characteristics such child’s gender, parity, maternal age, partnership status, ethnicity, and household socioeconomic characteristics. Methods Using England and Wales Office for National Statistics Longitudinal Study (ONS-LS), data from over 240,000 children born since 1981 to ONS-LS sample mothers were used. Maternal education was derived into 3 categories (below secondary, complete secondary education, degree and higher). Results Crude analysis confirmed significant association between the level of education and birthweight in each Census cohort (p &lt; 0.001). In adjusted models, the education gradient was partly explained but remained strongly significant, and substantially increased over the years: for example, the birthweight difference between those with below secondary educated mothers and those with degree increased from 29 to 92 grams (p for change&lt;0.001). Conclusions Our findings support previous evidence using different, usually smaller, population samples. Children of mothers with no or low qualification are more prone to be born with lower birthweight leading potentially into health disadvantages in their later life. Our results suggest that the inequalities in birth weight increased over the last 35 years. Key messages Low levels of maternal education predicts low birthweight in children.

289Birthweight and risks of adult-onset diabetes in women who are and are not overweight

Background Higher adult body mass index (BMI) increases diabetes risk, whereas, paradoxically, lower birthweight is associated with higher risks of adult-onset diabetes. Increased diabetes risks associated with low birthweight might be due to increased risks among those who become overweight or obese as adults but evidence on risks among those of normal BMI is limited. Methods In the Million Women Study, 413,516 women without prior diabetes, at mean age 60(SD5) years, reported their birthweight, and current height and weight. Birthweight and BMI at age 60 years were validated against recorded values at similar ages. Participants were followed for diabetes by electronic linkage to national hospital admissions records. Cox regression yielded multivariable-adjusted relative risks (RRs) for diabetes, overall and subdivided simultaneously by categories of birthweight and adult BMI. Results During 15(SD3) years follow-up, 24,528 women had hospital admissions with diabetes, first recorded at average age 70(SD6) years. Adult-onset diabetes risks increased strongly with increasing adult BMI (RR per 5 kg/m2 increase: 2.03, 95% CI 2.01-2.06). Compared to those with birthweight 3.0-3.4 kg, RRs of diabetes for birthweight &lt;2.5 kg and ≥4.0 kg were 1.35(1.30-1.38) and 0.73(0.70-0.75), respectively. The association between low birthweight and increased diabetes risk was strongly evident among women who were of normal BMI, overweight and obese (p &lt; 0.0001 for each). Conclusions At every level of adult adiposity, there were strong inverse associations between birthweight and adult-onset diabetes risk. Key messages While adult adiposity increases diabetes risk, there is a strong and independent increase in diabetes risk with decreasing birthweight.

sFlt-1/PlGF Ratio in Prediction of Short-Term Neonatal Outcome of Small for Gestational Age Neonates

Background: Small for gestational age is a pregnancy complication associated with a variety of adverse perinatal outcomes. The aim of the study was to investigate if sFlt-1/PlGF ratio is related to adverse short-term neonatal outcome in neonates small for gestational age in normotensive pregnancy. Methods: A prospective observational study was conducted. Serum sFlt-1/PlGF ratio was measured in women in singleton gestation diagnosed with fetus small for gestational age. Short-term neonatal outcome analyzed in the period between birth and discharge home. Results: Eighty-two women were included. Women with sFlt-1/PlGF ratio ≥33 gave birth to neonates with lower birthweight at lower gestational age. Neonates from high ratio group suffered from respiratory disorders and NEC significantly more often. They were hospitalized at NICU more often and were discharged home significantly later. sFlt-1/PlGF ratio predicted combined neonatal outcome with sensitivity of 73% and specificity of 82.2%. Conclusions: sFlt-1/PlGF ratio is a useful toll in prediction of short-term adverse neonatal outcome in SGA pregnancies.

The rs1421085 variant within FTO promotes but not inhibits thermogenesis and is potentially associated with human migration

Disease-associated GWAS loci are predominantly scattered among noncoding regions of the human genome, which impedes causality estimation. One lead risk signal of obesity-rs1421085 T>C within the FTO gene-is reported to functional in vitro but lack of organismal evidence. Here, we established global and the brown-adipocyte specific locus-knock-in mice to recapitulate this homologous variant in humans, and discovered the minor allele (C-allele) as one candidate thermogenic locus. Mice carrying the C-alleles showed increased thermogenic capacity and a resistance to high-fat diet-induced adiposity. In terms of mechanism, the knock-in models showed enhanced FTO expression, while FTO knockdown or inhibition effectively eliminated the increased thermogenic ability of brown adipocytes. In humans, the C-allele was associated with lower birthweight, and its allele frequency increases following the environmental temperature decreases. Cumulatively, these findings demonstrated rs1421085 T>C as a functional variant regulating whole-body thermogenesis, and this variation was possibly related to early human migration from hot to cold environments.

O-184 Maternally inherited differences in mitochondrial DNA genotype between ART and spontaneously conceived individuals associate with low birthweight

Study question Can mitochondrial DNA (mtDNA) variants explain the differences in birthweight between ART and spontaneously conceived (SC) individuals and how do they originate? Summary answer Children born after ART carry more frequently a different mtDNA variant composition, both maternally inherited and de novo, which are predictive of their birthweight percentile. What is known already Children born after ART show an increased risk of lower birthweight and of developing a mild abnormal cardio-metabolic profile later in life. Variation in the mtDNA associates with overall health in the general population, including cardio-metabolic fitness, and can result in changes in mitochondrial function. We hypothesized that mitochondrial DNA variants could explain the differences in birthweight between ART and SC individuals and that these differences may result from maternal transmission and/or from the ovarian stimulation (OS) used in ART. Study design, size, duration We deep-sequenced the mtDNA of 472 individuals of who 283 ART and 189 SC, 182 mother-child pairs and 113 single oocytes from both natural menstrual cycles and OS cycles. The mtDNA was compared between groups and Fisher linear discriminant analysis was used as predictive model for the birthweight percentile. Participants/materials, setting, methods Mitochondrial DNA was enriched by long-range PCR and subsequently sequenced on an Illumina platform. mtDNA server and MuTect were used for variant calling for variants with a load higher than 1.5%, versus the reference NC_012920.1. An orthogonally rotated factor analysis was used to reduce the dimensionality of the studied dependent variables in the complex data of the heteroplasmic variants. Main results and the role of chance ART individuals carried more frequently haplogroup U4 (p = 0.004) and component analysis indicated that they carry a different mtDNA heteroplasmic variant composition than SC individuals (p = 0.01), driven by non-synonymous protein-coding and rRNA-coding variants. These differences were also predictive of the risk of a lower birthweight percentile, especially for the SC children, together with the absence of haplogroup T, the presence of homoplasmic tRNA-variants, pregnancy-induced hypertension and the embryo culture medium used. The differences in heteroplasmic variation observed in the ART children resulted from both maternal transmission (p = 0.03) and de novo mutagenesis (p = 0.02). Mothers of ART children showed a similar mtDNA genotype as their children and differed in the same variant composition when compared to the mothers of SC children (p = 0.03). Furthermore, the comparison of oocytes from the same donors retrieved in natural menstrual cycles and after one OS cycle showed that OS does not increase de novo mutagenesis. Additionally, clinical parameters such as the total dosage of FSH units, the number of oocytes retrieved, and maternal age did not show any correlation with the differences observed in ART individuals. Limitations, reasons for caution This study is observational with no functional tests being performed. Wider implications of the findings We demonstrate an association between a lower birthweight percentile and a mtDNA variant composition which is more frequently carried by ART children. These non-disease associated mtDNA variants could cause a suboptimal mitochondrial function affecting the birthweight. Long-term health consequences of these differences remain to be further elucidated. Trial registration number Not applicable

Use of Vasopressors in Extremely Preterm Infants in First Week of Life

Objective A significant variability exists for diagnosis and treatment of hypotension in extremely preterm infants. Benefits of the use of vasopressors remain unclear. We wanted to identify the risk factors associated with use of vasopressors in the first week of life and their impact on outcomes of extremely preterm infants. Study Design Retrospective review of all newborns ≤28 weeks of gestational age (GA) admitted in neonatal intensive care unit from October 1, 2012 to October 31, 2015 done. Data regarding antenatal and neonatal characteristics and outcomes were recorded. Study infants were divided into two cohorts and compared based on vasopressor use. Chi-square, t-test, and multiple logistic regression were performed as appropriate and significance set at p <0.05. Results Of 213 extremely preterm infants, 90 (42.3%) received vasopressors in first week of life. The mean arterial pressure (MAP) at admission in these infants was significantly lower than that of infants who did not require vasopressors (27 ± 8 vs. 30 ± 6 mmHg, p < 0.05). Vasopressors were initiated within 24 hours in 91% of babies. After controlling for other variables, use of vasopressors was significantly higher in infants with lower birthweight (odds ratio [OR]: 3.2, 95% confidence interval [CI]: 1.6–8.3), 5-minute Apgar's score ≤5 (OR: 1.8, 95% CI: 1.2–3.12), and admission hypothermia (OR: 2.7, 95% CI: 1.3–4.9). The use of vasopressors was significantly associated with severe intraventricular hemorrhage (IVH), even after controlling for other significant variables (OR: 5.9, 95% CI: 1.6–9.3). Conclusion Lower birthweight, low 5-minute Apgar's score, and admission hypothermia are characteristics associated with early use of vasopressors in extremely preterm infants. Infants treated with vasopressors are at a higher risk of developing severe IVH. Key Points