Questioning the fetal microbiome illustrates pitfalls of low-biomass microbial studies.

Whether the human fetus and the prenatal intrauterine environment (amniotic fluid and placenta) are stably colonized by microbial communities in a healthy pregnancy remains a subject of debate. Here we evaluate recent studies that characterized microbial populations in human fetuses from the perspectives of reproductive biology, microbial ecology, bioinformatics, immunology, clinical microbiology and gnotobiology, and assess possible mechanisms by which the fetus might interact with microorganisms. Our analysis indicates that the detected microbial signals are likely the result of contamination during the clinical procedures to obtain fetal samples or during DNA extraction and DNA sequencing. Furthermore, the existence of live and replicating microbial populations in healthy fetal tissues is not compatible with fundamental concepts of immunology, clinical microbiology and the derivation of germ-free mammals. These conclusions are important to our understanding of human immune development and illustrate common pitfalls in the microbial analyses of many other low-biomass environments. The pursuit of a fetal microbiome serves as a cautionary example of the challenges of sequence-based microbiome studies when biomass is low or absent, and emphasizes the need for a trans-disciplinary approach that goes beyond contamination controls by also incorporating biological, ecological and mechanistic concepts.

Inherent mosaicism and extensive mutation of human placentas.

Placentas can exhibit chromosomal aberrations that are absent from the fetus1. The basis of this genetic segregation, which is known as confined placental mosaicism, remains unknown. Here we investigated the phylogeny of human placental cells as reconstructed from somatic mutations, using whole-genome sequencing of 86 bulk placental samples (with a median weight of 28 mg) and of 106 microdissections of placental tissue. We found that every bulk placental sample represents a clonal expansion that is genetically distinct, and exhibits a genomic landscape akin to that of childhood cancer in terms of mutation burden and mutational imprints. To our knowledge, unlike any other healthy human tissue studied so far, the placental genomes often contained changes in copy number. We reconstructed phylogenetic relationships between tissues from the same pregnancy, which revealed that developmental bottlenecks genetically isolate placental tissues by separating trophectodermal lineages from lineages derived from the inner cell mass. Notably, there were some cases with full segregation-within a few cell divisions of the zygote-of placental lineages and lineages derived from the inner cell mass. Such early embryonic bottlenecks may enable the normalization of zygotic aneuploidy. We observed direct evidence for this in a case of mosaic trisomic rescue. Our findings reveal extensive mutagenesis in placental tissues and suggest that mosaicism is a typical feature of placental development.

Author Correction: Human placenta has no microbiome but can contain potential pathogens.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Human placenta has no microbiome but can contain potential pathogens.

We sought to determine whether pre-eclampsia, spontaneous preterm birth or the delivery of infants who are small for gestational age were associated with the presence of bacterial DNA in the human placenta. Here we show that there was no evidence for the presence of bacteria in the large majority of placental samples, from both complicated and uncomplicated pregnancies. Almost all signals were related either to the acquisition of bacteria during labour and delivery, or to contamination of laboratory reagents with bacterial DNA. The exception was Streptococcus agalactiae (group B Streptococcus), for which non-contaminant signals were detected in approximately 5% of samples collected before the onset of labour. We conclude that bacterial infection of the placenta is not a common cause of adverse pregnancy outcome and that the human placenta does not have a microbiome, but it does represent a potential site of perinatal acquisition of S. agalactiae, a major cause of neonatal sepsis.

Association between adverse pregnancy outcome and placental biomarkers in the first trimester: A prospective cohort study.

OBJECTIVE: To determine the inter-relationships between five first-trimester biomarkers (pregnancy associated plasma protein A [PAPP-A], alpha-fetoprotein [AFP], beta human chorionic gonadotrophin [beta-hCG], placenta growth factor [PlGF] and soluble fms-like tyrosine kinase receptor-1 [sFlt-1]) and a range of adverse pregnancy outcomes (APOs). DESIGN: Prospective cohort study of nulliparous singleton pregnancy. SETTING: Cambridge, UK. POPULATION OR SAMPLE: 4056 pregnancy outcome prediction study participants. METHODS: The biomarker concentrations were measured in maternal serum at ~12 weeks of gestation. Univariable analysis of APOs was performed using logistic regression. Multivariable analysis used best subsets logistic regression with cross-validation. MAIN OUTCOME MEASURES: Pre-eclampsia (PE), small for gestational age (SGA), including severe SGA (birthweight <3rd), fetal growth restriction (FGR), preterm birth (PTB, both induced and spontaneous [iPTB and sPTB, respectively]), pre-viable loss and stillbirth, plus combinations of outcomes. RESULTS: Lower values of PAPP-A, PlGF and sFlt-1 and higher values of AFP were associated with FGR (OR for 1 SD higher value 0.59 [95% CI 0.48-0.74], OR 0.56 [95% CI 0.44-0.70], OR 0.68 [95% CI 0.54-0.87] and OR 1.53 [95% CI 1.25-1.88]), severe SGA (OR 0.59 [95% CI 0.49-0.72], OR 0.71 [95% CI 0.57-0.87], OR 0.74 [95% CI 0.60-0.91] and OR 1.41 [95% CI 1.17-1.71]), sPTB (OR 0.61 [95% CI 0.50-0.73], OR 0.79 [95% CI 0.66-0.96], OR 0.57 [95% CI 0.47-0.70] and OR 1.41 [95% CI 1.18-1.67]) and iPTB (OR 0.72 [95% CI 0.57-0.91], OR 0.62 [95% CI 0.49-0.78], OR 0.71 [95% CI 0.56-0.90] and OR 1.44 [95% CI 1.16-1.78]), respectively. When combinations of biomarkers were assessed, PAPP-A and AFP were independently associated with severe SGA; PAPP-A alone with PE + PTB; PlGF alone with severe PE; PlGF, beta-hCG, AFP and PAPP-A with the combination of PE and SGA; AFP and sFlt-1 with sPTB; and AFP and PlGF with iPTB. CONCLUSIONS: Combinations of first-trimester placental biomarkers are associated with APOs. However, the patterns vary for different types of APO, indicating heterogeneity in the underlying pathophysiological pathways.

Physiologically relevant culture medium Plasmax improves human placental trophoblast stem cell function.

Human trophoblast cultures provide powerful tools to model key processes of placental development. In vitro trophoblast studies to date have relied on commercial media that contains nonphysiological levels of nutrients, and the impact of these conditions on trophoblast metabolism and function is unknown. Here, we show that the physiological medium (Plasmax) with nutrient and metabolite concentrations recapitulating human plasma improves human trophoblast stem cell (hTSC) proliferation and differentiation compared with standard medium (DMEM-F12). hTSCs cultured in Plasmax-based medium also show altered glycolytic and mitochondrial metabolism, as well as reduced S-adenosylmethionine/S-adenosyl-homocysteine ratio compared with DMEM-F12-based medium. These findings demonstrate the importance of the nutritional environment for phenotyping cultured human trophoblasts.

Group B Streptococcus and the risk of perinatal morbidity and mortality following term labor.

Streptococcus agalactiae (group B Streptococcus) colonizes the genital tract of approximately 20% of pregnant women. In the absence of intervention, approximately 1% of infants born to colonized mothers exhibit a clinical infection. This has led to implementation of screening and intervention in the form of intrapartum antibiotic prophylaxis in many countries, including the United States. However, screening has not been introduced in a substantial minority of other countries because of the absence of supportive level 1 evidence, the very large number needed to treat to prevent 1 case, and concerns about antimicrobial resistance. Optimal screening would involve rapid turnaround (to facilitate intrapartum testing) and report antibiotic sensitivity, but no such method exists. There is significant scope for a personalized medicine approach, targeting intrapartum antibiotic prophylaxis to cases at greatest risk, but the pathogen and host factors determining the risk of invasive disease are incompletely understood. Epidemiologic data have indicated the potential of prelabor invasion of the uterus by group B Streptococcus, and metagenomic analysis revealed the presence of group B Streptococcus in the placenta in approximately 5% of pregnant women at term before onset of labor and membrane rupture. However, the determinants and consequences of prelabor invasion of the uterus by group B Streptococcus remain to be established. The vast majority (98%) of invasive neonatal disease is caused by 6 serotypes, and hexavalent vaccines against these serotypes have completed phase 2 trials. However, an obstacle to phase 3 studies is conducting an adequately powered trial to demonstrate clinical effectiveness given that early-onset disease affects approximately 1 in 1000 births in the absence of vaccination.

Maternal serum levels of soluble fms-like tyrosine kinase-1 and placental growth factor at 20 and 28 weeks of gestational age and the risk of spontaneous preterm birth.

BACKGROUND: Spontaneous preterm birth is the endpoint of multiple different pathophysiological pathways. Fetal growth restriction, assessed by serial ultrasonic fetal biometry, has been shown to predict both preterm and early-term spontaneous labor. The soluble fms-like tyrosine kinase-1 to placental growth factor ratio is predictive of early-term spontaneous labor, but its association with spontaneous preterm birth is unclear. OBJECTIVE: This study aimed to determine whether maternal serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and the soluble fms-like tyrosine kinase-1: placental growth factor ratio at 20 and 28 weeks' gestation, and the rate of change in these biomarkers between 20 and 28 weeks were predictive of risk of spontaneous preterm birth. STUDY DESIGN: The biomarkers were measured in maternal serum at 20- and 28-weeks' gestation in women recruited to a prospective cohort of unselected nulliparous women as part of the Pregnancy Outcome Prediction study in Cambridge, United Kingdom. The risk of spontaneous preterm birth was assessed using Cox regression and competing-risks regression. Associations from Cox regression were quantified by the adjusted hazard ratio for a 1 standard deviation higher level of a given biomarker or a 1 standard deviation increase in the marker between 20 and 28 weeks' gestation. A previously identified risk factor, slow femur length growth, was used as an additional predictor of spontaneous preterm birth for the purpose of risk stratification. RESULTS: Of the 3763 participants in the analysis, 95 (2.5%) had spontaneous preterm birth and 54 (1.4%) had medically indicated preterm birth. At 20 weeks' gestation, higher levels of soluble fms-like tyrosine kinase-1 and the soluble fms-like tyrosine kinase-1:placental growth factor ratio were associated with reduced risk of spontaneous preterm birth (adjusted hazard ratio [95% confidence interval], 0.75 [0.61-0.92]; P=.006 and 0.71 [0.59-0.87]; P=.0009, respectively). At 28 weeks' gestation, there was no association between either soluble fms-like tyrosine kinase-1 or placental growth factor and the risk of spontaneous preterm birth, but there was a U-shaped relation with the soluble fms-like tyrosine kinase-1:placental growth factor ratio. However, when the biomarkers were quantified as the rate of increase between 20 and 28 weeks' gestation, there were strong positive associations between spontaneous preterm birth and rate of increase in soluble fms-like tyrosine kinase-1 (1.36 [1.13-1.63]; P=.001) and the soluble fms-like tyrosine kinase-1:placental growth factor ratio (1.50 [1.30-1.73]; P<.0001), and a strong negative association with the rate of increase in placental growth factor (0.71 [0.61-0.82]; P<.0001). Women who were in the highest decile of increase in the soluble fms-like tyrosine kinase-1:placental growth factor ratio and the lowest decile of femur length growth between 20 and 28 weeks' gestation had approximately 9-fold risk of spontaneous preterm birth (9.27 [4.21-20.37]; P<.0001). Competing-risks regression yielded similar results. CONCLUSION: Changing levels of soluble fms-like tyrosine kinase-1 and placental growth factor are indicative of placental dysfunction and are strongly associated with the risk of spontaneous preterm birth, especially when combined with slower fetal femur length growth.

Maternal high body mass index, but not gestational diabetes, is associated with poorer educational attainment in mid-childhood.

BACKGROUND: Previous studies suggest that gestational diabetes mellitus is associated with poorer cognitive outcomes in children. However, confounding factors, especially maternal body mass index, have been poorly accounted for. OBJECTIVE: This study aimed to examine the independent associations between maternal body mass index, gestational diabetes mellitus status, and educational outcomes. STUDY DESIGN: Antenatal data from a prospective birth cohort (Pregnancy Outcome Prediction Study, 2008-2012, Cambridge, United Kingdom) were linked to mid-childhood educational outcomes (Department for Education, United Kingdom). A total of 3249 children born at term were stratified by maternal gestational diabetes mellitus status and body mass index at booking (<25 vs ≥25 kg/m2). Regression models adjusted for relevant maternal, child, and socioeconomic factors were used to determine associations with academic outcomes at ages of 5 to 7 years. RESULTS: No differences in educational attainment were found between children exposed to gestational diabetes mellitus and nonexposed children. Neither maternal glucose levels measured at 11 to 14 or 24 to 28 weeks, nor acceleration of the fetal abdominal circumference growth velocity were related to educational attainment at ages of 5 to 7 years. Children of mothers with booking body mass index ≥25 kg/m2 (vs <25 kg/m2) were ∼50% more likely to not meet expected educational standards regardless of gestational diabetes mellitus status (age 5: adjusted odds ratio, 1.44; 95% confidence interval, 1.19-1.74; P<.001; age 6: adjusted odds ratio, 1.61; 95% confidence interval, 1.28-2.02; P<.001). The association between maternal body mass index and offspring educational attainment is dose-dependent and robust to stratification by gestational diabetes mellitus status and adjustment for socioeconomic factors. CONCLUSION: Mid-childhood educational attainment is not associated with maternal glucose status. This may provide important reassurance for pregnant women and clinicians. However, maternal body mass index is associated with lower childhood educational attainment and may be modifiable with intervention before or during pregnancy.

Prediction of spontaneous preterm birth using supervised machine learning on metabolomic data: A case-cohort study.

OBJECTIVES: To identify and internally validate metabolites predictive of spontaneous preterm birth (sPTB) using multiple machine learning methods and sequential maternal serum samples, and to predict spontaneous early term birth (sETB) using these metabolites. DESIGN: Case-cohort design within a prospective cohort study. SETTING: Cambridge, UK. POPULATION OR SAMPLE: A total of 399 Pregnancy Outcome Prediction study participants, including 98 cases of sPTB. METHODS: An untargeted metabolomic analysis of maternal serum samples at 12, 20, 28 and 36 weeks of gestation was performed. We applied six supervised machine learning methods and a weighted Cox model to measurements at 28 weeks of gestation and sPTB, followed by feature selection. We used logistic regression with elastic net penalty, followed by best subset selection, to reduce the number of predictive metabolites further. We applied coefficients from the chosen models to measurements from different gestational ages to predict sPTB and sETB. MAIN OUTCOME MEASURES: sPTB and sETB. RESULTS: We identified 47 metabolites, mostly lipids, as important predictors of sPTB by two or more methods and 22 were identified by three or more methods. The best 4-predictor model had an optimism-corrected area under the receiver operating characteristics curve (AUC) of 0.703 at 28 weeks of gestation. The model also predicted sPTB in 12-week samples (0.606, 95% CI 0.544-0.667) and 20-week samples (0.657, 95% CI 0.597-0.717) and it predicted sETB in 36-week samples (0.727, 95% CI 0.606-0.849). A lysolipid, 1-palmitoleoyl-GPE (16:1)*, was the strongest predictor of sPTB at 12 weeks of gestation (0.609, 95% CI 0.548-0.670), 20 weeks (0.630, 95% CI 0.569-0.690) and 28 weeks (0.660, 95% CI 0.599-0.722), and of sETB at 36 weeks (0.739, 95% CI 0.618-0.860). CONCLUSIONS: We identified and internally validated maternal serum metabolites predictive of sPTB. A lysolipid, 1-palmitoleoyl-GPE (16:1)*, is a novel predictor of sPTB and sETB. Further validation in external populations is required.

Evolutionary History of Endogenous Human Herpesvirus 6 Reflects Human Migration out of Africa.

Human herpesvirus 6A and 6B (HHV-6) can integrate into the germline, and as a result, ∼70 million people harbor the genome of one of these viruses in every cell of their body. Until now, it has been largely unknown if 1) these integrations are ancient, 2) if they still occur, and 3) whether circulating virus strains differ from integrated ones. Here, we used next-generation sequencing and mining of public human genome data sets to generate the largest and most diverse collection of circulating and integrated HHV-6 genomes studied to date. In genomes of geographically dispersed, only distantly related people, we identified clades of integrated viruses that originated from a single ancestral event, confirming this with fluorescent in situ hybridization to directly observe the integration locus. In contrast to HHV-6B, circulating and integrated HHV-6A sequences form distinct clades, arguing against ongoing integration of circulating HHV-6A or "reactivation" of integrated HHV-6A. Taken together, our study provides the first comprehensive picture of the evolution of HHV-6, and reveals that integration of heritable HHV-6 has occurred since the time of, if not before, human migrations out of Africa.

Association of birthweight centiles and early childhood development of singleton infants born from 37 weeks of gestation in Scotland: A population-based cohort study.

BACKGROUND: Birthweight centiles beyond the traditional thresholds for small or large babies are associated with adverse perinatal outcomes but there is a paucity of data about the relationship between birthweight centiles and childhood development among children born from 37 weeks of gestation. This study aims to establish the association between birthweight centiles across the whole distribution and early childhood development among children born from 37 weeks of gestation. METHODS AND FINDINGS: This is a population-based cohort study of 686,284 singleton infants born from 37 weeks of gestation. The cohort was generated by linking pregnancy and delivery data from the Scottish Morbidity Records (2003 to 2015) and the child developmental assessment at age 2 to 3.5 years. The main outcomes were child's fine motor, gross motor, communication, and social developmental concerns measured with the Ages and Stages Questionnaires-3 (ASQ-3) and Ages and Stages Questionnaire: Social & Emotional-2 (ASQ:SE-2), and for a subset of children with additional specialist tools such as the Modified Checklist for Autism in Toddlers (M-CHAT) if the ASQ3/SE indicate these are necessary. The ASQ score for each domain was categorised as "concern" and "no concern." We used multivariate cubic regression splines to model the associations between birthweight centiles and early childhood developmental concerns. We used multivariate Poisson regression models, with cluster robust errors, to estimate the relative risks (RRs) of developmental concerns below and above the established thresholds. We adjusted for maternal age, early pregnancy body mass index (BMI), parity, year of delivery, gestational age at delivery, smoking history, substance misuse in pregnancy, alcohol intake, ethnicity, residential area deprivation index, maternal clinical conditions in pregnancy (such as diabetes and pre-eclampsia), induction of labour, and child's sex. Babies born from 37 weeks of gestation with birthweight below the 25th centile, compared to those between the 25th and 74th centile, were at higher risk of developmental concerns. Those born between the 10th and 24th centile had an RR of 1.07 (95% CI: 1.03 to 1.12, p < 0.001), between the 3rd and 9th centile had an RR: 1.18 (95% CI: 1.12 to 1.25, p < 0.001), and <3rd centile had an RR of 1.37 (95% CI: 1.24 to 1.50, p < 0.001). There was no substantial increase in the risk of early childhood developmental concerns for larger birthweight categories of 75th to 89th (RR: 1.01; 95% CI: 0.97 to 1.05; p = 0.56), 90th to 96th (RR: 0.99; 95% CI: 0.94 to 1.05; p = 0.86), and ≥97th centiles (RR: 1.04; 95% CI: 0.97 to 1.12; p = 0.27), referent to birthweight between 25th and 74th centile. The percentage of developmental concerns attributable to birthweight between the 10th and 24th centile was more than that of birthweight <3rd centile (p = 0.023) because this group includes more of the population. Approximately 2.50% (95% CI: 1.26 to 3.61) of social skills concerns and 3.00% (95% CI: 1.33 to 4.67) of fine motor developmental concerns were attributable to birthweight between the 10th and 24th centile compared to 0.90% (95% CI: 0.48 to 1.26) and 2.30% (95% CI: 1.73 to 2.67) respectively for birthweight <3rd centile. We acknowledge the limitation of ASQ as a screening tool, the subjective nature of developmental assessments (particularly for speech) among young children, and inability to control for early childhood illness and upbringing factors may have an impact on our findings. CONCLUSIONS: We observed that from 37 weeks of gestation birthweight below the 25th centile was associated with child developmental concerns, with an association apparent at higher centiles above the conventional threshold defining small for gestational age (SGA, 3rd or 10th centile). Mild to moderate SGA is an unrecognised potentially important contributor to the prevalence of developmental concerns. Closer surveillance, appropriate parental counselling, and increased support during childhood may reduce the risks associated with lower birthweight centiles.

Association between hypertensive disorders of pregnancy and later risk of cardiovascular outcomes.

BACKGROUND: Hypertensive disorders of pregnancy are common pregnancy complications that are associated with greater cardiovascular disease risk for mothers. However, risk of cardiovascular disease subtypes associated with gestational hypertension or pre-eclampsia is unclear. The present study aims to compare the risk of cardiovascular disease outcomes for women with and without a history of gestational hypertension and pre-eclampsia using national hospital admissions data. METHODS: This was a retrospective cohort study of national medical records from all National Health Service hospitals in England. Women who had one or more singleton live births in England between 1997 and 2015 were included in the analysis. Risk of total cardiovascular disease and 19 pre-specified cardiovascular disease subtypes, including stroke, coronary heart disease, cardiomyopathy and peripheral arterial disease, was calculated separately for women with a history of gestational hypertension and pre-eclampsia compared to normotensive pregnancies. RESULTS: Amongst 2,359,386 first live births, there were 85,277 and 74,542 hospital admissions with a diagnosis of gestational hypertension and pre-eclampsia, respectively. During 18 years (16,309,386 person-years) of follow-up, the number and incidence of total CVD for normotensive women, women with prior gestational hypertension and women with prior pre-eclampsia were n = 8668, 57.1 (95% CI: 55.9-58.3) per 100,000 person-years; n = 521, 85.8 (78.6-93.5) per 100,000 person-years; and n = 518, 99.3 (90.9-108.2) per 100,000 person-years, respectively. Adjusted HRs (aHR) for total CVD were aHR (95% CI) = 1.45 (1.33-1.59) for women with prior gestational hypertension and aHR = 1.62 (1.48-1.78) for women with prior pre-eclampsia. Gestational hypertension was strongly associated with dilated cardiomyopathy, aHR = 2.85 (1.67-4.86), and unstable angina, aHR = 1.92 (1.33-2.77). Pre-eclampsia was strongly associated with hypertrophic cardiomyopathy, aHR = 3.27 (1.49-7.19), and acute myocardial infarction, aHR = 2.46 (1.72-3.53). Associations were broadly homogenous across cardiovascular disease subtypes and increased with a greater number of affected pregnancies. CONCLUSIONS: Women with either previous gestational hypertension or pre-eclampsia are at greater risk of a range of cardiovascular outcomes. These women may benefit from clinical risk assessment or early interventions to mitigate their greater risk of various cardiovascular outcomes.

Placental energy metabolism in health and disease-significance of development and implications for preeclampsia.

The placenta is a highly metabolically active organ fulfilling the bioenergetic and biosynthetic needs to support its own rapid growth and that of the fetus. Placental metabolic dysfunction is a common occurrence in preeclampsia although its causal relationship to the pathophysiology is unclear. At the outset, this may simply be seen as an "engine out of fuel." However, placental metabolism plays a vital role beyond energy production and is linked to physiological and developmental processes. In this review, we discuss the metabolic basis for placental dysfunction and propose that the alterations in energy metabolism may explain many of the placental phenotypes of preeclampsia such as reduced placental and fetal growth, redox imbalance, oxidative stress, altered epigenetic and gene expression profiles, and the functional consequences of these aberrations. We propose that placental metabolic reprogramming reflects the dynamic physiological state allowing the tissue to adapt to developmental changes and respond to preeclampsia stress, whereas the inability to reprogram placental metabolism may result in severe preeclampsia phenotypes. Finally, we discuss common tested and novel therapeutic strategies for treating placental dysfunction in preeclampsia and their impact on placental energy metabolism as possible explanations into their potential benefits or harm.

Comparison of estimated fetal weight percentiles near term for predicting extremes of birthweight percentile.

BACKGROUND: The INTERGROWTH-21st estimated fetal weight percentiles are recommended for predicting extremes of birthweight percentile, although evidence for their superiority over the widely employed Hadlock method is lacking. OBJECTIVE: This study aimed to compare the ability of estimated fetal weight percentiles calculated using the Hadlock method and the INTERGROWTH-21st method to predict extremes of birthweight percentile. STUDY DESIGN: A prospective cohort study of blinded serial ultrasonography in nulliparous women with a singleton pregnancy, The Pregnancy Outcome Prediction study was conducted in Cambridge, United Kingdom. The study participants who had a research estimated fetal weight performed at 36 weeks' gestation were eligible for the analysis. Estimated fetal weight percentiles for gestational age calculated using (1) the Hadlock method or (2) the INTERGROWTH-21st method were used as exposures. Birthweight percentiles of <10th (small for gestational age) and >90th (large for gestational age) for gestational age and fetal sex using the United Kingdom 1990 reference or the INTERGROWTH-21st birthweight reference were analyzed as outcomes using receiver operating characteristic curve analysis. Screening statistics from 2×2 tables were calculated for dichotomized exposures and each outcome. RESULTS: The Hadlock estimated fetal weight percentile performed better than the INTERGROWTH-21st estimated fetal weight percentile at discriminating both small for gestational age birthweight (areas under the receiver operating characteristic curves, 0.87 vs 0.85; 95% confidence intervals, 0.85-0.89 vs 0.83-0.87, respectively; P<.0001) and large for gestational age birthweight (areas under the receiver operating characteristic curves, 0.87 vs 0.86; 95% confidence intervals, 0.85-0.90 vs 0.83-0.89, respectively; P=.005). When the estimated fetal weight percentiles were dichotomized and screen positive was defined at 90% specificity, the sensitivity for the Hadlock vs the INTERGROWTH-21st method was 58.6% vs 52.3%, respectively, for small for gestational age, and 71.0% vs 60.9%, respectively, for birthweight at less than the third percentile (United Kingdom 1990 reference). The results were similar when the birthweight percentile was defined using the INTERGROWTH-21st birthweight reference, when the estimated fetal weight was calculated without the inclusion of head measurements, or when the women who had clinically indicated scans and women who had their research scan result were excluded. CONCLUSION: Replacing the Hadlock method by the INTERGROWTH-21st method may lead to less effective screening for extremes of birthweight percentile.

Slowing of fetal growth and elevated maternal serum sFLT1:PlGF are associated with early term spontaneous labor.

BACKGROUND: The physiological control of human parturition at term is unknown. OBJECTIVE: This study aimed to test the hypothesis that slowing of fetal growth or elevated maternal serum levels of markers of placental hypoxia in late gestation will be associated with earlier term labor. STUDY DESIGN: We observed 2208 women having first births and performed serial blinded ultrasonography and immunoassay of soluble fms-like tyrosine kinase-1 and placenta growth factor. We estimated the probability of spontaneous delivery from 37 weeks of gestational age concerning (1) fetal growth between 20 and 36 weeks of gestational age and (2) the maternal serum soluble fms-like tyrosine kinase-1-to-placenta growth factor ratio measured at approximately 36 weeks of gestational age. Data were analyzed using logistic regression and Cox regression. RESULTS: Fetal size at 36 weeks of gestational age was not independently associated with the timing of delivery at term. However, there was an inverse relationship between fetal growth between 20 weeks of gestational age and 36 weeks of gestational age and the probability of spontaneous labor at 37 to 38 weeks' gestation (hazard ratio [95% confidence interval] for a 50 percentile increase in abdominal circumference growth velocity, 0.60 [0.47-0.78]; P=.0001). This association was weaker at 39 to 40 weeks' gestation (0.83 [0.74-0.93]; P=.0013), and there was no association at ≥41 weeks' gestation. Very similar associations were observed for estimated fetal weight growth velocity. There was a positive relationship between soluble fms-like tyrosine kinase-1-to-placenta growth factor ratio and the probability of spontaneous labor at 37 to 38 weeks' gestation (hazard ratio [95% confidence interval] for a 50 percentile increase in soluble fms-like tyrosine kinase-1-to-placenta growth factor ratio, 3.05 [2.32-4.02]; P<.0001). This association was weaker at 39 to 40 weeks' gestation (1.46 [1.30-1.63]; P<.0001), and there was no association at ≥41 weeks' gestation. Adjustment for maternal characteristics was without material effect on any of these associations. CONCLUSION: Slowing of fetal growth and biomarkers of placental insufficiency were associated with an increased probability of early onset of spontaneous term labor. We speculated that progressive placental insufficiency may be a physiological phenomenon that occurs with advancing gestational age near and at term and promotes the initiation of labor.

Late Pregnancy Ultrasound to Screen for and Manage Potential Birth Complications in Nulliparous Women: A Cost-Effectiveness and Value of Information Analysis.

BACKGROUND: Fetal growth restriction is a major risk factor for stillbirth. A routine late-pregnancy ultrasound scan could help detect this, allowing intervention to reduce the risk of stillbirth. Such a scan could also detect fetal presentation and predict macrosomia. A trial powered to detect stillbirth differences would be extremely large and expensive. OBJECTIVES: It is therefore critical to know whether this would be a good investment of public research funds. The aim of this study is to estimate the cost-effectiveness of various late-pregnancy screening and management strategies based on current information and predict the return on investment from further research. METHODS: Synthesis of current evidence structured into a decision model reporting expected costs, quality-adjusted life-years, and net benefit over 20 years and value-of-information analysis reporting predicted return on investment from future clinical trials. RESULTS: Given a willingness to pay of £20 000 per quality-adjusted life-year gained, the most cost-effective strategy is a routine presentation-only scan for all women. Universal ultrasound screening for fetal size is unlikely to be cost-effective. Research exploring the cost implications of induction of labor has the greatest predicted return on investment. A randomized, controlled trial with an endpoint of stillbirth is extremely unlikely to be a value for money investment. CONCLUSION: Given current value-for-money thresholds in the United Kingdom, the most cost-effective strategy is to offer all pregnant women a presentation-only scan in late pregnancy. A randomized, controlled trial of screening and intervention to reduce the risk of stillbirth following universal ultrasound to detect macrosomia or fetal growth restriction is unlikely to represent a value for money investment.

Abnormal placental CD8+ T-cell infiltration is a feature of fetal growth restriction and pre-eclampsia.

KEY POINTS: Placental pathological abnormalities are more frequently observed in complicated pregnancies than in healthy pregnancies. Infiltration of CD8+ T-cells into the placental villous tissue occurred in both fetal growth restriction and pre-eclampsia, whereas CD79α+ B-cell infiltration was only apparent with reduced fetal growth. Vascularization, fibrin depositions, macrophage and neutrophil infiltration in the placenta did not differ between healthy and complicated pregnancies. ABSTRACT: Fetal growth restriction (FGR) and pre-eclampsia are severe, adverse pregnancy outcomes. Alterations in placental histology are frequently reported in these pregnancy complications and are often based upon scoring by pathologists. However, many alterations are also observed in placenta from uncomplicated pregnancies. Moreover, knowledge of disease state may bias assessment. We sought to perform an objective comparison of placental microscopic appearance in normal and complicated pregnancies. Placental villous tissue (n = 823) and edge biopsies (n = 488) from 871 individual, singleton pregnancies were collected after delivery. Cases of small-for-gestational age (SGA) or pre-eclampsia were matched with healthy controls. A subset of the SGA cases displayed signs of FGR. Cases of preterm delivery were also included. Tissue sections were stained with haematoxylin and eosin or antibodies for CD8, CD14, CD31, CD79α and elastase. Images were scored by two experienced pathologists for pathological features or analysed by image analysis and stereology. Analyses were performed blind to case-control status and gestational age. Volume fraction of T-cells increased in placentas from pregnancies complicated by pre-eclampsia (adjusted odds ratio (aOR) 1.46, 95% CI: 1.12-1.90) and FGR (aOR 1.64, 95% CI: 1.11-2.43), whereas B-cells only increased in FGR (aOR 1.65, 95% CI: 1.05-2.60). Pathological abnormalities in villous tissue were reported in 21.4% (88/411) of complicated pregnancies and 14.3% (52/363) of controls (OR 1.62, 95% CI: 1.12-2.37). There were no differences in the fractions of endothelial cells, fibrin deposition, macrophages and neutrophils when comparing normal and complicated pregnancies. In conclusion, FGR and pre-eclampsia are associated with T-cell infiltration of the placenta and placental pathological abnormalities.

Cesarean section and childhood infections: Causality for concern?

In this Perspective, Gordon Smith discusses the findings of Miller et al, and the balance of risks and benefits associated with different modes of delivery.