Maternal serum fructosamine levels and stillbirth: a case-control study of the Stillbirth Collaborative Research Network.

OBJECTIVE: To evaluate the association between maternal fructosamine levels at the time of delivery and stillbirth. DESIGN: Secondary analysis of a case-control study. SETTING: Multicentre study of five geographic catchment areas in the USA. POPULATION: All singleton stillbirths with known diabetes status and fructosamine measurement, and representative live birth controls. MAIN OUTCOME MEASURES: Fructosamine levels in stillbirths and live births among groups were adjusted for potential confounding factors, including diabetes. Optimal thresholds of fructosamine to discriminate stillbirth and live birth. RESULTS: A total of 529 women with a stillbirth and 1499 women with a live birth were included in the analysis. Mean fructosamine levels were significantly higher in women with a stillbirth than in women with a live birth after adjustment (177 ± 3.05 versus 165 ± 2.89 µmol/L, P < 0.001). The difference in fructosamine levels between stillbirths and live births was greater among women with diabetes (194 ± 8.54 versus 162 ± 3.21 µmol/L), compared with women without diabetes (171 ± 2.50 versus 162 ± 2.56 µmol/L). The area under the curve (AUC) for fructosamine level and stillbirth was 0.634 (0.605-0.663) overall, 0.713 (0.624-0.802) with diabetes and 0.625 (0.595-0.656) with no diabetes. CONCLUSIONS: Maternal fructosamine levels at the time of delivery were higher in women with stillbirth compared with women with live birth. Differences were substantial in women with diabetes, suggesting a potential benefit of glycaemic control in women with diabetes during pregnancy. The small differences noted in women without diabetes are not likely to justify routine screening in all cases of stillbirth. TWEETABLE ABSTRACT: Maternal serum fructosamine levels are higher in women with stillbirth than in women with live birth, especially in women with diabetes.

Stillbirth and fetal anomalies: secondary analysis of a case-control study.

OBJECTIVE: Approximately 10% of stillbirths are attributed to fetal anomalies, but anomalies are also common in live births. We aimed to assess the relationship between anomalies, by system and stillbirth. DESIGN: Secondary analysis of a prospective, case-control study. SETTING: Multicentre, 59 hospitals in five regional catchment areas in the USA. POPULATION OR SAMPLE: All stillbirths and representative live birth controls. METHODS: Standardised postmortem examinations performed in stillbirths, medical record abstraction for stillbirths and live births. MAIN OUTCOME MEASURES: Incidence of major anomalies, by type, compared between stillbirths and live births with univariable and multivariable analyses using weighted analysis to account for study design and differential consent. RESULTS: Of 465 singleton stillbirths included, 23.4% had one or more major anomalies compared with 4.3% of 1871 live births. Having an anomaly increased the odds of stillbirth; an increasing number of anomalies was more highly associated with stillbirth. Regardless of organ system affected, the presence of an anomaly increased the odds of stillbirth. These relationships remained significant if stillbirths with known genetic abnormalities were excluded. After multivariable analyses, the adjusted odds ratio (aOR) of stillbirth for any anomaly was 4.33 (95% CI 2.80-6.70) and the systems most strongly associated with stillbirth were cystic hygroma (aOR 29.97, 95% CI 5.85-153.57), and thoracic (aOR16.18, 95% CI 4.30-60.94) and craniofacial (aOR 35.25, 95% CI 9.22-134.68) systems. CONCLUSIONS: In pregnancies affected by anomalies, the odds of stillbirth are higher with increasing numbers of anomalies. Anomalies of nearly any organ system increased the odds of stillbirth even when adjusting for gestational age and maternal race. TWEETABLE ABSTRACT: Stillbirth risk increases with anomalies of nearly any organ system and with number of anomalies seen.

Localization of a major susceptibility locus influencing preterm birth.

Preterm birth (PTB) is a complex trait, but little is known regarding its major genetic determinants. The objective of this study is to localize genes that influence susceptibility to PTB in Mexican Americans (MAs), a minority population in the USA, using predominantly microfilmed birth certificate-based data obtained from the San Antonio Family Birth Weight Study. Only 1302 singleton births from 288 families with information on PTB and significant covariates were considered for genetic analysis. PTB is defined as a childbirth that occurs at <37 completed weeks of gestation, and the prevalence of PTB in this sample was 6.4%. An ∼10 cM genetic map was used to conduct a genome-wide linkage analysis using the program SOLAR. The heritability of PTB was high (h(2) ± SE: 0.75 ± 0.20) and significant (P = 4.5 × 10(-5)), after adjusting for the significant effects of birthweight and birth order. We found significant evidence for linkage of PTB (LOD = 3.6; nominal P = 2.3 × 10(-5); empirical P = 1.0 × 10(-5)) on chromosome 18q between markers D18S1364 and D18S541. Several other chromosomal regions (2q, 9p, 16q and 20q) were also potentially linked with PTB. A strong positional candidate gene in the 18q linked region is SERPINB2 or PAI-2, a member of the plasminogen activator system that is associated with various reproductive processes. In conclusion, to our knowledge, perhaps for the first time in MAs or US populations, we have localized a major susceptibility locus for PTB on chromosome 18q21.33-q23.

Placental amino acid transport and placental leptin resistance in pregnancies complicated by maternal obesity.

UNLABELLED: HYPOTHESIS AND STUDY OBJECTIVES: We hypothesized that maternal obesity is associated with increased placental amino acid transport and hyperleptinemia. Our objectives were to study placental amino acid transport and the effect of leptin on placental amino acid transport in vitro in the setting of maternal obesity. MATERIALS AND METHODS: Seven lean, BMI at entry 22.4, and seven obese, BMI at entry 31.5 (p < 0.001), pregnant women were studied at 39 weeks. We measured baseline and leptin-stimulated placental system A sodium-dependent neutral amino acid transporter (SNAT) activity, placental immunoreactive protein expression of SNAT, leptin and leptin receptor, and maternal and fetal plasma leptin concentrations, with significance set at p

Interrelationship of cytokines, hypothalamic-pituitary-adrenal axis hormones, and psychosocial variables in the prediction of preterm birth.

BACKGROUND/AIMS: To examine the relationship of biological mediators (cytokines, stress hormones), psychosocial, obstetric history, and demographic factors in the early prediction of preterm birth (PTB) using a comprehensive logistic regression model incorporating diverse risk factors. METHODS: In this prospective case-control study, maternal serum biomarkers were quantified at 9-23 weeks' gestation in 60 women delivering at <37 weeks compared to 123 women delivering at term. Biomarker data were combined with maternal sociodemographic factors and stress data into regression models encompassing 22 preterm risk factors and 1st-order interactions. RESULTS: Among individual biomarkers, we found that macrophage migration inhibitory factor (MIF), interleukin-10, C-reactive protein (CRP), and tumor necrosis factor-alpha were statistically significant predictors of PTB at all cutoff levels tested (75th, 85th, and 90th percentiles). We fit multifactor models for PTB prediction at each biomarker cutoff. Our best models revealed that MIF, CRP, risk-taking behavior, and low educational attainment were consistent predictors of PTB at all biomarker cutoffs. The 75th percentile cutoff yielded the best predicting model with an area under the ROC curve of 0.808 (95% CI 0.743-0.874). CONCLUSION: Our comprehensive models highlight the prominence of behavioral risk factors for PTB and point to MIF as a possible psychobiological mediator.

Feto-placental adaptations to maternal obesity in the baboon.

Maternal obesity is present in 20-34% of pregnant women and has been associated with both intrauterine growth restriction and large-for-gestational age fetuses. While fetal and placental functions have been extensively studied in the baboon, no data are available on the effect of maternal obesity on placental structure and function in this species. We hypothesize that maternal obesity in the baboon is associated with a maternal inflammatory state and induces structural and functional changes in the placenta. The major findings of this study were: 1) decreased placental syncytiotrophoblast amplification factor, intact syncytiotrophoblast endoplasmic reticulum structure and decreased system A placental amino acid transport in obese animals; 2) fetal serum amino acid composition and mononuclear cells (PBMC) transcriptome were different in fetuses from obese compared with non-obese animals; and 3) maternal obesity in humans and baboons is similar in regard to increased placental and adipose tissue macrophage infiltration, increased CD14 expression in maternal PBMC and maternal hyperleptinemia. In summary, these data demonstrate that in obese baboons in the absence of increased fetal weight, placental and fetal phenotype are consistent with those described for large-for-gestational age human fetuses.

Identification of biological/biochemical marker(s) for preterm delivery.

Fetal and neonatal mortality and morbidity rates are strongly associated with gestational age for delivery: the risk for poor outcome increases as gestational age decreases. Attempts to predict preterm delivery (PTD, spontaneous delivery before 37 weeks' gestation) have been largely unsuccessful, and rates of PTD have not improved in recent decades. More recently, the reported associations between infections in pregnancy and PTD suggest preventive initiatives that could be taken. The overall objective of the current study is to assess whether specific markers of infection (primarily interleukin (IL) 1beta, tumour necrosis factor (TNF) alpha, IL-6, and IL-10) obtained from maternal blood during pregnancy, alone or in combination with other risk factors for PTD, permit identification of women at risk for spontaneous PTD. To achieve this objective, data are obtained from two Danish prospective cohort studies involving serial collection of maternal blood samples, newborn cord blood samples, and relevant confounders and other risk factors for PTD. The first study consists of a completed Danish regional cohort of 3000 pregnant women enrolled in a study of microbiological causes of PTD, upon which a nested case-control study of PTD in 84 cases and 400 controls has been performed. The second study is a nested case-control study of 675 PTD cases (equally divided into three gestational age categories of 24-29 weeks' gestation, 30-33 weeks' gestation, and 34-36 weeks' gestation) and 675 controls drawn from the ongoing Danish National Birth Cohort study of 100 000 pregnant women enrolled during 1997-2001. The second study will provide the opportunity to refine and retest hypotheses from the first study, as well as to explore new hypotheses. Our preliminary work suggests that a single predictive marker effectively accounting for a large proportion of PTD is unlikely to be found. Rather, a search for multiple markers indicative of the multifactorial aetiology of PTD is likely to be more successful. Knowledge gained from the proposed studies will be implemented in a third, clinical intervention study against PTD. The first phase of the clinical intervention study will be to establish a risk-assessment model based on the "best" combination of biological/biochemical measures and other factors associated with PTD in order to identify pregnant women at very high risk of PTD. The second phase will be to apply an intervention model of tailored obstetric care to the very high-risk pregnant women for PTD identified in phase one. The intervention will be carried out against each specific risk factor associated with PTD identified for the individual. The aim is to reduce the risk for PTD attributed to the combination of risk factors included in the clinical intervention study.

Antenatal steroid treatment and adverse fetal effects: what is the evidence?

This article reviews current animal and human data regarding possible adverse fetal effects from antenatal steroid treatment. Although it is now well accepted that such treatment is of benefit to fetal lung development, the potential for adverse fetal outcomes as a result of single or multiple glucocorticoid dosing has not been widely recognized. There are now growing concerns, based on animal and some human data, that repeated antenatal doses could lead to a decrease in birth weight, a decrease in fetal brain and other organ size, and abnormal neuronal development. Previous investigations have been hampered by nonstandardization in the type of glucocorticoid, route of delivery, timing of administration, and number of treatment courses. It is recommended that these concerns be addressed through large randomized, controlled clinical trials. In the meantime, it would be prudent to minimize antenatal steroid treatments to a single course with repeated dosing only if there is a persistent threat of preterm delivery. The practice of giving weekly injections of steroids starting at fetal viability and continuing into the third trimester is not supported.