Customized versus Population Growth Standards for Morbidity and Mortality Risk Stratification Using Ultrasonographic Fetal Growth Assessment at 22 to 29 Weeks' Gestation.

OBJECTIVE: The aim of study is to compare the performance of ultrasonographic customized and population fetal growth standards for prediction adverse perinatal outcomes. STUDY DESIGN: This was a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be, in which l data were collected at visits throughout pregnancy and after delivery. Percentiles were assigned to estimated fetal weights (EFWs) measured at 22 to 29 weeks using the Hadlock population standard and a customized standard (www.gestation.net). Areas under the curve were compared for the prediction of composite and severe composite perinatal morbidity using EFW percentile. RESULTS: Among 8,701 eligible study participants, the population standard diagnosed more fetuses with fetal growth restriction (FGR) than the customized standard (5.5 vs. 3.5%, p < 0.001). Neither standard performed better than chance to predict composite perinatal morbidity. Although the customized performed better than the population standard to predict severe perinatal morbidity (areas under the curve: 0.56 vs. 0.54, p = 0.003), both were poor. Fetuses considered FGR by the population standard but normal by the customized standard had morbidity rates similar to fetuses considered normally grown by both standards.The population standard diagnosed FGR among black women and Hispanic women at nearly double the rate it did among white women (p < 0.001 for both comparisons), even though morbidity was not different across racial/ethnic groups. The customized standard diagnosed FGR at similar rates across groups. Using the population standard, 77% of FGR cases were diagnosed among female fetuses even though morbidity among females was lower (p < 0.001). The customized model diagnosed FGR at similar rates in male and female fetuses. CONCLUSION: At 22 to 29 weeks' gestation, EFW percentile alone poorly predicts perinatal morbidity whether using customized or population fetal growth standards. The population standard diagnoses FGR at increased rates in subgroups not at increased risk of morbidity and at lower rates in subgroups at increased risk of morbidity, whereas the customized standard does not.

Effect of parental origin of damaging variants in pro-angiogenic genes on fetal growth in patients with congenital heart defects: Data and analyses.

The placenta is a highly vascular structure composed of both maternal and fetal elements. We have determined that damaging variants in genes responsible for the positive regulation of angiogenesis (PRA) (GO:0045766) that are inherited by the fetus impair fetal growth and placental function in pregnancies involving critical congenital cardiac defects (Russell et al., 2019). In this dataset, we present the specific genetic variants identified, describe the parental origin of each variant where possible and present the analyses regarding the potential effects of parental origin of the variant on placental function and fetal growth. The data presented are related to the research article "Damaging variants in pro-angiogenic genes impair growth in fetuses with cardiac defects" (Russell et al., 2019).

Damaging Variants in Proangiogenic Genes Impair Growth in Fetuses with Cardiac Defects.

OBJECTIVE: To determine the impact of damaging genetic variation in proangiogenic pathways on placental function, complications of pregnancy, fetal growth, and clinical outcomes in pregnancies with fetal congenital heart defect. STUDY DESIGN: Families delivering a baby with a congenital heart defect requiring surgical repair in infancy were recruited. The placenta and neonate were weighed and measured. Hemodynamic variables were recorded from a third trimester (36.4 ± 1.7 weeks) fetal echocardiogram. Exome sequencing was performed on the probands (N = 133) and consented parents (114 parent-child trios, and 15 parent-child duos) and the GeneVetter analysis tool used to identify damaging coding sequence variants in 163 genes associated with the positive regulation of angiogenesis (PRA) (GO:0045766). RESULTS: In total, 117 damaging variants were identified in PRA genes in 133 congenital heart defect probands with 73 subjects having at least 1 variant. Presence of a damaging PRA variant was associated with increased umbilical artery pulsatility index (mean 1.11 with variant vs 1.00 without; P = .01). The presence of a damaging PRA variant was also associated with lower neonatal length and head circumference for age z score at birth (mean -0.44 and -0.47 with variant vs 0.23 and -0.05 without; P = .01 and .04, respectively). During median 3.1 years (IQR 2.0-4.1 years) of follow-up, deaths occurred in 2 of 60 (3.3%) subjects with no PRA variant and in 9 of 73 (12.3%) subjects with 1 or more PRA variants (P = .06). CONCLUSIONS: Damaging variants in proangiogenic genes may impact placental function and are associated with impaired fetal growth in pregnancies involving a fetus with congenital heart defect.

The Effect of Early Excessive Weight Gain on the Development of Hypertension in Pregnancy.

Background Previous studies have shown an association between total excessive gestational weight gain and hypertension in pregnancy. However, this may be a reflection of excessive water retention associated with the pathophysiology of hypertensive disorders of pregnancy. Early excessive weight gain, prior to the third trimester, results in greater maternal fat deposition and inflammation, which has also been associated with the development of hypertension. By focusing on early excessive weight gain, the association between maternal weight gain and the future development of hypertension can be examined. Objective To evaluate the association between early excessive maternal weight gain and the development of hypertension during pregnancy. Study Design This was a secondary analysis of a longitudinal cohort study of 1,441 women without chronic hypertension who were enrolled in a prospective study evaluating maternal angiogenic factors and the prediction of preeclampsia. Initial body mass index (BMI) was calculated by weight and height at the first study visit. Early excessive maternal weight gain was defined as weight gain by 28 weeks that exceeded the Institute of Medicine (IOM) guidelines and was calculated utilizing the maximum amount of weight gain per week recommended by the IOM based on the patient's starting BMI (normal: 0.45 kg; overweight: 0.32 kg; obese: 0.27 kg). Hypertension was defined as a sustained systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg. Logistic regression was used to determine the association between early excessive weight gain, initial BMI, and the development of hypertension, including gestational hypertension and preeclampsia, during pregnancy. Results Of 1,441 women, 767 (53.2%) had weight gain that exceeded the IOM guidelines in the first 28 weeks and 154 (10.8%) developed hypertension during pregnancy. Women whose weight gain exceeded the IOM guidelines were more likely to develop hypertension even after adjusting for relevant confounders (12.5 vs. 8.6%; p = 0.02; adjusted odds ratio [OR] = 1.70; 95% confidence interval [CI]: 1.18-2.44; p < 0.01). Obese women had a 2.4-fold increased risk of developing hypertension, even after controlling for excessive weight gain (adjusted OR = 2.44; 95% CI: 1.66-3.59; p < 0.01) Conclusions Early excessive maternal weight gain and initial BMI are independently associated with the diagnosis of a hypertensive disorder of pregnancy. Women should be counseled regarding the benefits of achieving a normal BMI prior to pregnancy and appropriate weight gain during pregnancy, as well as the potential harms of excessive weight gain related to perinatal outcomes.

Urinary tract infection during pregnancy, angiogenic factor profiles, and risk of preeclampsia.

BACKGROUND: Despite decades of research, and much progress in discernment of biomarkers in the maternal circulation, the pathogenesis of preeclampsia (PE) remains elusive. The pathophysiology of PE is believed to involve aberrant placentation and an associated increase in systemic inflammation. In this conceptualization, PE becomes more likely when the level of systemic inflammatory burden inherent in pregnancy itself exceeds the maternal capacity to compensate for this additional stress. If this is the case, then it is possible to hypothesize that conditions, such as infectious disease, that increase systemic inflammatory burden should also increase the risk of PE. As urinary tract infection (UTI) represents a common source of inflammation during pregnancy, we tested whether presence of UTI during pregnancy increased the odds of developing PE. Prior work has documented this association. However many of these studies were limited by small cohort sizes and insufficient control for covariates. OBJECTIVE: The present study is a secondary analysis of a robust contemporary obstetrical cohort recruited to examine the ability of longitudinally sampled maternal angiogenic concentrations to predict PE. We hypothesize that the occurrence of UTI during a pregnancy is associated with the later occurrence of PE in that pregnancy. As PE is believed to be associated with aberrations in systemic angiogenic levels (placental growth factor and soluble isoform of VEGF receptor), we further hypothesize that there will be significant interactions between maternal angiogenic protein levels and the occurrence of UTI. STUDY DESIGN: Women aged ≥18 years (n = 2607) were recruited and followed up prospectively from the initiation of prenatal care through delivery at 3 regional academic centers. PE was defined by American Congress of Obstetricians and Gynecologists criteria and was independently validated by a panel of physicians. UTI was defined by the presence of clinical symptoms necessitating treatment in addition to supportive laboratory evidence. Multivariate logistic regression models were used and controlled for maternal age, race, parity, body mass index, hypertension, diabetes, in vitro fertilization, and smoking status. RESULTS: There were 129 women with diagnosed UTIs and 235 with PE. Patients with UTI in pregnancy had higher rates of PE (31.1% vs 7.8%, P < .001) compared to those without reported UTI. The mean gestational age (SD) for UTI diagnosis in PE cases and controls was 25.6 (10.4) and 21.9 (10.9) weeks, respectively (P = .08). The unadjusted odds ratio for PE in the setting of UTI was 5.29 (95% confidence interval, 3.54-7.89). After controlling for confounders, UTI was associated with an odds ratio for PE of 3.2 (95% confidence interval, 2.0-5.1). CONCLUSION: Presence of UTI in pregnancy, particularly in the third trimester, is strongly associated with PE. This association supports the hypothesis that the risk of PE is enhanced by an increased maternal inflammatory burden. Prophylaxis against UTI represents a potentially low-cost global intervention to slow or halt the development of PE.

Angiogenic markers in pregnancies conceived through in vitro fertilization.

OBJECTIVE: Pregnancies that have been conceived through in vitro fertilization (IVF) have been associated with higher rates of preeclampsia and other complications that are associated with placental dysfunction. We evaluated whether IVF pregnancies, when compared with those conceived spontaneously, would be associated with alterations in serum angiogenic markers. STUDY DESIGN: This was a retrospective cohort study from 3 US academic institutions (2006-2008). Women with singleton pregnancies who conceived via IVF or spontaneously were included. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured at 4 time points throughout gestation. Pregnancy outcomes that included diagnosis of preeclampsia or other obstetric complications were ascertained from the medical record. The relationship among IVF status, PlGF, and sFlt-1 were modeled over gestation and stratified by clinical pregnancy outcome. RESULTS: Of the included 2392 singleton pregnancies, 4.5% (108 pregnancies) were conceived though IVF. IVF pregnancies were significantly more likely to be complicated by preeclampsia (15.7% vs 7.7%). IVF pregnancies had significantly higher levels of sFlt-1 at 18, 26, and 35 weeks of gestation (P = .04, P = .004, P < .0001, respectively) and lower levels of PlGF at 18 and 35 weeks of gestation (P = .007 and .0006, respectively). These differences persisted even after being controlled for maternal comorbidities or obstetric outcomes such as preeclampsia. CONCLUSION: Pregnancies conceived via IVF were found to have an increased antiangiogenic profile (elevated sFlt-1 and decreased PlGF) at multiple time points throughout gestation when compared with spontaneously conceived pregnancies. Alterations in the angiogenic profile persisted even after we controlled for maternal comorbidities of clinically evident disorders of abnormal placentation such as preeclampsia. The increased antiangiogenic profile suggests fundamentally aberrant placentation related to in vitro fertilization, which may warrant closer fetal surveillance in these pregnancies.

The association of body mass index with serum angiogenic markers in normal and abnormal pregnancies.

OBJECTIVE: Because obesity is a risk factor for placental dysfunction, we hypothesized that maternal body mass index (BMI) would be associated with alterations in serum angiogenic markers. STUDY DESIGN: We included 2399 singleton pregnancies with and without placental dysfunction in a prospective longitudinal cohort study of angiogenic markers. We modeled the relationship between categorical and continuous BMI, soluble fms-like tyrosine kinase-1 (sFlt-1), and placental growth factor (PlGF) over gestation, stratified by pregnancy outcome. RESULTS: In women with normal pregnancies, a higher BMI was associated with lower sFlt-1 values across gestation (P < .0001), lower PlGF in the second and third trimesters (P < .0001), and lower rate of change in PlGF (P < .0001). Similar relationships were seen between maternal BMI, sFlt-1 (P < .0001), and PlGF (P = .0005) in women with clinically evident placental dysfunction. CONCLUSION: The sFlt-1 value is inversely associated with maternal BMI. The pattern of change in PlGF is also dependent on maternal BMI, indicating that obese women may have abnormalities in angiogenesis near term.

Advancing research transdisciplinarity within our discipline.

Advancing biomedical knowledge is crucial to the understanding of disease pathophysiology, diagnosis, treatment, and the maintenance of health. Whereas collaborative pursuits among basic and translational scientists, clinical researchers, and clinicians should advance biomedical progress and its translation to better medicine. The field of obstetrics and gynecology and its subspecialties has not escaped this problem. Obstetrics and gynecology specialists and subspecialists have limited opportunities to interact with translational or basic investigators, and cross-fertilization and collaborations are further challenged by the current healthcare and funding climate. This opinion manuscript focuses on the field of maternal-fetal medicine, serving as an example that illustrates the risks and opportunities that might exist within our obstetrics and gynecology academic community. A Pregnancy Task Force recently sought to identify ways to overcome hurdles related to research training, and ensure a sufficient pool of physician-scientists pursuing pertinent questions in the field. The group discussed strategies to promote a culture of intellectual curiosity and research excellence, securing additional resources for trainees, and attracting current and next generation basic, translational, and clinical scholars to our field. Recommendations encompassed activities within annual academic meetings, training initiatives, and additional funding opportunities. Inferences from these discussions can be made to all obstetrics and gynecology subspecialty areas.

Identification and quantification of preterm birth biomarkers in human cervicovaginal fluid by liquid chromatography/tandem mass spectrometry.

Spontaneous preterm birth (PTB) before 37 completed weeks of gestation resulting from preterm labor (PTL) is a leading contributor of perinatal morbidity and mortality. Early identification of at-risk women by reliable screening tests could alleviate this health issue; however, conventional methods such as obstetric history and clinical risk factors, uterine activity monitoring, biochemical markers, and cervical sonography for screening women at risk for PTB have proven unsuccessful in lowering the rate of PTB. Cervicovaginal fluid (CVF) might prove to be a useful, readily available biological fluid for identifying diagnostic PTB biomarkers. Human columnar epithelial endocervical-1 (End1) and vaginal (Vk2) cell secretomes were employed to generate a stable isotope labeled proteome (SILAP) standard to facilitate characterization and relative quantification of proteins present in CVF. The SILAP standard was prepared using stable isotope labeling by amino acids in cell culture (SILAC) of End1 and Vk2 through seven passages. The labeled secreted proteins from both cell lines were combined and characterized by liquid-chromatography-tandem mass spectrometry (LC-MS/MS). In total, 1211 proteins were identified in the End1-Vk2 SILAP standard, with 236 proteins being consistently identified in each of the replicates analyzed. Individual proteins were found to contain <0.5% of the endogenous unlabeled forms. Identified proteins were screened to provide a set of 15 candidates that have either previously been identified as potential PTB biomarkers or could be linked mechanistically to PTB. Stable isotope dilution LC-multiple reaction monitoring (MRM/MS) assays were then developed for conducting relative quantification of the 15 candidate biomarkers in human CVF samples from term and PTB cases. Three proteins were significantly elevated in PTB cases (desmoplakin isoform 1, stratifin, and thrombospondin 1 precursor), providing a foundation for further validation in larger patient cohorts.