Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes.

OBJECTIVE: Microbial invasion of the amniotic cavity (MIAC) is common in early preterm labor and is associated with maternal and neonatal infectious morbidity. MIAC is usually occult and is reliably detected only with amniocentesis. We sought to develop a noninvasive test to predict MIAC based on protein biomarkers in cervicovaginal fluid (CVF) in a cohort of women with preterm labor (phase 1) and to validate the test in an independent cohort (phase 2). STUDY DESIGN: This was a prospective study of women with preterm labor who had amniocentesis to screen for MIAC. MIAC was defined by positive culture and/or 16S ribosomal DNA results. Nine candidate CVF proteins were analyzed by enzyme-linked immunosorbent assay. Logistic regression was used to identify combinations of up to 3 proteins that could accurately classify the phase 1 cohort (N = 108) into those with or without MIAC. The best models, selected by area under the curve (AUC) of the receiver operating characteristic curve in phase 1, included various combinations of interleukin (IL)-6, chemokine (C-X-C motif) ligand 1 (CXCL1), alpha fetoprotein, and insulin-like growth factor binding protein-1. Model performance was then tested in the phase 2 cohort (N = 306). RESULTS: MIAC was present in 15% of cases in phase 1 and 9% in phase 2. A 3-marker CVF model using IL-6 plus CXCL1 plus insulin-like growth factor binding protein-1 had AUC 0.87 in phase 1 and 0.78 in phase 2. Two-marker models using IL-6 plus CXCL1 or alpha fetoprotein plus CXCL1 performed similarly in phase 2 (AUC 0.78 and 0.75, respectively), but were not superior to CVF IL-6 alone (AUC 0.80). A cutoff value of CVF IL-6 ≥463 pg/mL (which had 81% sensitivity in phase 1) predicted MIAC in phase 2 with sensitivity 79%, specificity 78%, positive predictive value 38%, and negative predictive value 97%. CONCLUSION: High levels of IL-6 in CVF are strongly associated with MIAC. If developed into a bedside test or rapid laboratory assay, cervicovaginal IL-6 might be useful in selecting patients in whom the probability of MIAC is high enough to warrant amniocentesis or transfer to a higher level of care. Such a test might also guide selection of potential subjects for treatment trials.

Timing of and outcomes after selective termination of anomalous fetuses in dichorionic twin pregnancies.

OBJECTIVE: The objective of this article is to determine if selective termination (ST) of an anomalous dichorionic twin at early gestational age (GA) is associated with a decreased risk of fetal loss and prematurity. METHOD: All patients who had ST for dichorionic twin pregnancies from 2004 through 2010 at Mount Sinai Medical Center were included. Data were collected via chart review and patient interview. Two case-control analyses were carried out: first, cases were nonviable deliveries, and controls were live births; and second, cases were live births <37 weeks' GA, and controls were live births ≥37 weeks' GA. Univariable and then multivariable analyses identified characteristics associated with pregnancy loss and prematurity. RESULTS: Among 80 participants, there were four (5%) fetal losses and 15 (19%) premature births. GA at ST was the only characteristic associated with pregnancy loss in multivariable exact logistic regression [OR = 1.43, 95% CI (1.03, 2.26), P = 0.03]. GA at ST was the only characteristic associated with premature delivery in multivariable exact logistic regression [OR = 1.18, 95% CI (1.02, 1.37), P = 0.03]. CONCLUSION: This study suggests that ST performed earlier in pregnancy is associated with decreased fetal loss and prematurity.

8p23.1 duplication syndrome; common, confirmed, and novel features in six further patients.

The 8p23.1 duplication syndrome is a relatively rare genomic condition that has been confirmed with molecular cytogenetic methods in only 11 probands and five family members. Here, we describe another prenatal and five postnatal patients with de novo 8p23.1 duplications analyzed with oligonucleotide array comparative genomic hybridization (oaCGH). Of the common features, mild or moderate developmental delays and/or learning difficulties have been found in 11/12 postnatal probands, a variable degree of mild dysmorphism in 8/12 and congenital heart disease (CHD) in 4/5 prenatal and 3/12 postnatal probands. Behavioral problems, cleft lip and/or palate, macrocephaly, and seizures were confirmed as additional features among the new patients, and novel features included neonatal respiratory distress, attention deficit hyperactivity disorder (ADHD), ocular anomalies, balance problems, hypotonia, and hydrocele. The core duplication of 3.68 Mb contains 31 genes and microRNAs of which only GATA4, TNKS, SOX7, and XKR6 are likely to be dosage sensitive genes and MIR124-1 and MIR598 have been implicated in neurocognitive phenotypes. A combination of the duplication of GATA4, SOX7, and related genes may account for the variable penetrance of CHD. Two of the duplications were maternal and intrachromosomal in origin with maternal heterozygosity for the common inversion between the repeats in 8p23.1. These additional patients and the absence of the 8p23.1 duplications in published controls, indicate that the 8p23.1 duplication syndrome may now be considered a pathogenic copy number variation (pCNV) with an estimated population prevalence of 1 in 58,000.

Prediction of patient-specific risk for fetal loss using maternal characteristics and first- and second-trimester maternal serum Down syndrome markers.

OBJECTIVE: To develop and evaluate a method of estimating patient-specific risk for fetal loss by combining maternal characteristics with serum markers. STUDY DESIGN: Data were obtained on 36,014 women from the FaSTER trial. Separate likelihood ratios were estimated for significant maternal characteristics and serum markers. Patient-specific risk was calculated by multiplying the incidence of fetal loss by the likelihood ratios for each maternal characteristic and for different serum marker combinations. RESULTS: Three hundred eighteen women had fetal loss < 24 weeks (early) and 103 > 24 weeks (late). Clinical characteristics evaluated included maternal age, body mass index, race, parity, threatened abortion, previous preterm delivery, and previous early loss. Serum markers studied as possible predictors of early loss included first-trimester pregnancy-associated plasma protein A and second-trimester alpha-fetoprotein, and unconjugated estriol. A risk assessment for early loss based on all of these factors yielded a 46% detection rate, for a fixed 10% false-positive rate, 39% for 5% and 28% for 1%. The only significant marker for late loss was inhibin A. The detection rate was 27% for a fixed 10% false-positive rate and only increased slightly when clinical characteristics were added to the model. CONCLUSION: Patient-specific risk assessment for early fetal loss using serum markers, with or without maternal characteristics, has a moderately high detection. Patient-specific risk assessment for late fetal loss has low detection rates.

The effect of low body mass index on the development of gestational hypertension and preeclampsia.

OBJECTIVES: To evaluate the relationship between low maternal body mass index (BMI) as calculated in the first trimester and the risk of preeclampsia and gestational hypertension. METHODS: Patients enrolled in the First And Second Trimester Evaluation of Risk for aneuploidy (FASTER) trial were grouped into three weight categories: low BMI (BMI <19.8 kg/m2), normal BMI (BMI 19.8 - 26 kg/m2), and overweight BMI (26.1 - 29 kg/m2). The incidences of gestational hypertension and preeclampsia were ascertained for each group. Tests for differences in crude incidence proportions were performed using Chi-square tests. Multiple logistic regression was used to adjust for maternal age, race, parity, obesity, use of assisted reproductive technology (ART), in vitro fertilization (IVF), gestational diabetes, pre-gestational diabetes, cocaine use, and smoking. RESULTS: The proportion of patients having gestational hypertension in the low BMI group was 2.0% compared to 3.2% for normal BMI and 6.0% for overweight BMI (p < 0.0001). Women with low BMI were also less likely to develop preeclampsia, 1.1% vs. 1.9% for normal BMI and 2.8% for overweight BMI (p < 0.0001). CONCLUSIONS: We found that women with low BMI in the first trimester were significantly less likely to develop gestational hypertension or preeclampsia than women with a normal BMI.

Pregnancy loss rates after midtrimester amniocentesis.

OBJECTIVE: The purpose of this study was to quantify the contemporary procedure-related loss rate after midtrimester amniocentesis using a database generated from patients who were recruited to the First And Second Trimester Evaluation of Risk for Aneuploidy trial. METHODS: A total of 35,003 unselected patients from the general population with viable singleton pregnancies were enrolled in the First And Second Trimester Evaluation of Risk for Aneuploidy trial between 10 3/7 and 13 6/7 weeks gestation and followed up prospectively for complete pregnancy outcome information. Patients who either did (study group, n=3,096) or did not (control group, n=31,907) undergo midtrimester amniocentesis were identified from the database. The rate of fetal loss less than 24 weeks of gestation was compared between the two groups, and multiple logistic regression analysis was used to adjust for potential confounders. RESULTS: The spontaneous fetal loss rate less than 24 weeks of gestation in the study group was 1.0% and was not statistically different from the background 0.94% rate seen in the control group (P=.74, 95% confidence interval -0.26%, 0.49%). The procedure-related loss rate after amniocentesis was 0.06% (1.0% minus the background rate of 0.94%). Women undergoing amniocentesis were 1.1 times more likely to have a spontaneous loss (95% confidence interval 0.7-1.5). CONCLUSION: The procedure-related fetal loss rate after midtrimester amniocentesis performed on patients in a contemporary prospective clinical trial was 0.06%. There was no significant difference in loss rates between those undergoing amniocentesis and those not undergoing amniocentesis. LEVEL OF EVIDENCE: II-2.

Is misoprostol safe for labor induction in twin gestations?

OBJECTIVE: To compare the safety and efficacy of intravaginal misoprostol to oxytocin for the induction of labor in twin gestations. METHODS: All twin gestations that underwent induction of labor with misoprostol or oxytocin during a 4-year period were identified from the Mount Sinai obstetrical database. Only twins > or = 34 weeks with a vertex presenting twin A were included. Labor and delivery characteristics, maternal complications and neonatal outcomes were compared between the two groups. RESULTS: Of 134 patients with twins, 57 initially received misoprostol and 77 received oxytocin. These groups had similar demographics, but women who received misoprostol had less cervical dilation (0.8 vs. 2.2 cm, p < 0.0001) and were less likely to be multiparous (19% vs. 44%, p = 0.003). There was a shorter length of induction to delivery (7.8 hours vs. 15.1 hours, p = 0.001) and a trend toward a lower cesarean section rate (16.9% vs. 31.6%, p = 0.06) in the oxytocin-only group. There were no cases of uterine rupture or maternal mortality in this series. There were no significant differences in neonatal outcomes between the two groups, but the sample size was underpowered to detect significant differences between the groups. CONCLUSIONS: Misoprostol and oxytocin both appear to be safe and efficacious for use in inductions of labor in twins in this limited retrospective investigation. The safety of these agents with regard to neonatal outcomes should be confirmed by larger studies.

Circulating Cell-Free DNA to Determine the Fetal RHD Status in All Three Trimesters of Pregnancy.

OBJECTIVE: To estimate the accuracy of a new assay to determine the fetal RHD status using circulating cell-free DNA. METHODS: This was a prospective, observational study. Maternal blood samples were collected in each trimester of pregnancy in 520 nonalloimmunized RhD-negative patients. Plasma samples were analyzed for circulating cell-free DNA using the SensiGENE RHD test, which used primers for exons 4 and 7 as previously described and incorporated a new primer design for exon 5 of the RHD gene. Neonatal serology for RhD typing using cord blood at birth was undertaken and results were stored in a separate clinical database. After unblinding the data, results of the DNA analysis were compared with the neonatal serology. RESULTS: Inconclusive results secondary to the presence of the RHD pseudogene or an RHD variant were noted in 5.6%, 5.7%, and 6.1% of the first-, second-, and third-trimester samples, respectively. The incidence of false-positive rates for RhD (an RhD-negative fetus with an RHD-positive result) was 1.54% (95% confidence interval [CI] 0.42-5.44%), 1.53% (CI 0.42-5.40%), and 0.82% (CI 0.04-4.50%), respectively. There was only one false-negative diagnosis (an RhD-positive fetus with an RHD-negative result), which occurred in the first trimester (0.32%; 95% CI 0.08-1.78%). Genotyping for mismatches across repeated samples revealed that this error was related to mislabeling of samples from two patients collected on the same day at one of the collection sites. Overall test results were in agreement across all three trimesters (P>.99). CONCLUSION: Circulating cell-free DNA can accurately predict the fetal RhD status in all three trimesters of pregnancy.

Impact of maternal age on obstetric outcome.

OBJECTIVE: To estimate the effect of maternal age on obstetric outcomes. METHODS: A prospective database from a multicenter investigation of singletons, the FASTER trial, was studied. Subjects were divided into 3 age groups: 1) less than 35 years, 2) 35-39 years, and 3) 40 years and older. Multivariable logistic regression analysis was used to assess the effect of age on outcomes after adjusting for race, parity, body mass index, education, marital status, smoking, medical history, use of assisted conception, and patient's study site. RESULTS: A total of 36,056 women with complete data were available: 28,398 (79%) less than 35 years of age; 6,294 (17%) 35-39 years; and 1,364 (4%) 40 years and older. Increasing age was significantly associated with miscarriage (adjusted odds ratio [adjOR]2.0 and 2.4 for ages 35-39 years and age 40 years and older, respectively), chromosomal abnormalities (adjOR 4.0 and 9.9), congenital anomalies (adjOR 1.4 and 1.7), gestational diabetes (adjOR 1.8 and 2.4), placenta previa (adjOR 1.8 and 2.8), and cesarean delivery (adjOR 1.6 and 2.0). Patients aged 35-39 years were at increased risk for macrosomia (adjOR 1.4). Increased risk for abruption (adjOR 2.3), preterm delivery (adjOR 1.4), low birth weight (adjOR 1.6), and perinatal mortality (adjOR 2.2) was noted in women aged 40 years and older. CONCLUSION: Increasing maternal age is independently associated with specific adverse pregnancy outcomes. Increasing age is a continuum rather than a threshold effect.

Invasive procedures in multifetal pregnancies.

This review discusses the various invasive techniques currently performed in multiple pregnancies.

Maternal complications of multifetal pregnancy.

This article reviews the common maternal complications encountered in multifetal gestations.

Long-term outcomes in multiple gestations.

Children born from a multiple gestation are at increased risk for cerebral palsy, learning disability, and language and neurobehavioral deficits. With the increased incidence of multiple pregnancies and use of assisted reproductive technology (ART), these issues are more commonly affecting parents. Long-term outcomes are a critical part of preconceptual and early pregnancy counseling for parents faced with a multiple gestation or considering ART, and the provider should be well versed on issues surrounding zygosity, gestational age, higher-order multiples, and the effects of options such as multifetal pregnancy reduction.

Multifetal pregnancy reduction and selective termination.

MPR and ST are important options for patients who have multifetal pregnancies. Both procedures have been shown to be technically safe and result in acceptable pregnancy loss rates and GAs at delivery. An important caveat is that these findings are observed in centers that have vast experience performing this type of procedure and should not be generalized to all centers. The authors believe that the good outcomes reported here and elsewhere are a result of having a relatively limited number of operators adhering to a strict common protocol and that they should not be generalized to all centers. Awareness of the ethical and psychological issues aids counseling of patients and their follow-up, but more information is needed in this area. Finally, it is the authors' hope that advances in ART will decrease the need for MPR procedures in the future.

Diagnosis and management of neonatal alloimmune thrombocytopenia in pregnancy.

Neonatal alloimmune thrombocytopenia (NAIT) is the most common cause of severe thrombocytopenia in the healthy newborn, occurring in 1 in 1000 live births. NAIT is analogous to rhesus alloimmunization in pathophysiology; however, it often presents unexpectedly in first pregnancies. Presentation of NAIT varies from mild thrombocytopenia to life-threatening intracranial hemorrhage. It has been observed to be more severe in subsequent affected pregnancies. It is important that the diagnosis of NAIT be considered in the work-up of all cases of neonatal thrombocytopenia to determine the risk to future pregnancies and corresponding management plans. This article discusses the pathogenesis and incidence of NAIT and the antenatal and postnatal management of this condition.

Does sonographic determination of placental location predict fetal birth weight in diamniotic-dichorionic twins?

OBJECTIVE: The purpose of this study was to determine the association between placental location in diamniotic-dichorionic twins as determined at the time of anatomic survey and birth weight. METHODS: We retrospectively identified all diamniotic-dichorionic twins in our Maternal-Fetal Medicine sonography database between 2000 and 2005 who had an anatomic survey, went on to be delivered at our hospital, and had records available for review (n = 304). Placental location for each twin was determined at the time of anatomic survey and grouped into both anterior or both posterior versus separate anterior and posterior. Maternal and fetal characteristics were collected from chart review. Placental pathologic findings were available for 249 (83%) patients. Outcomes analyzed were percent discordance, small size for gestational age of twin A or B, and difference in birth weight as a continuous variable. Multivariable logistic regression using stepwise backward elimination was used to adjust for potential confounders. RESULTS: There was no difference in discordance of 20% or greater or incidence of small size for gestational age when both placentas were both anterior and both posterior compared with separate anterior and posterior: adjusted odds ratio (AdjOR), 1.38 (95% confidence interval [CI], 0.64-2.95); and AdjOR, 1.29 (95% CI, 0.57-2.89). The actual birth weight difference (A - B) was not affected by placental location (P = .36). Opposite sex fetuses and nulliparity were significantly associated with birth weight discordance: AdjOR, 2.68 (95% CI, 1.39-5.17); and AdjOR, 0.34 (95% CI, 0.28-0.94). CONCLUSIONS: We did not find a correlation between birth weight and placental location in our cohort analysis. The presence of sex-discordant twins was associated with birth weight discordance of 20% or greater, whereas nulliparity was protective.

Selective termination of anomalous fetuses in multifetal pregnancies: two hundred cases at a single center.

OBJECTIVE: The objective of this study was to summarize the outcome of 200 selective termination (ST) procedures performed at a single center. STUDY DESIGN: Two hundred patients underwent ST at the Mt Sinai Medical Center from 1986 to 2000. The following data were collected for each patient: indication for the ST, gestational age (GA) at the time of the procedure, starting and ending number of fetuses, which fetus(es) underwent ST (presenting vs nonpresenting), and GA at delivery or at spontaneous pregnancy loss less than 24 weeks. RESULTS: ST was performed on 164 sets of twins, 32 triplets, and 4 quadruplets. Median GA at the time of ST was 19.6 weeks. The presenting fetus was terminated in 91 (45.5%) cases. There were 8 (4%) unintended pregnancy losses less than 24 weeks, 4 of 164 (2.4%) in twins, 4 of 32 (12.5%) in triplets, and none of the 4 in quadruplets. The median GA at delivery in the remaining 190 patients was 37.1 weeks. One hundred sixty (84.2%) patients were delivered at >or=32 weeks' gestation. CONCLUSION: ST at our institution has an overall unintended pregnancy loss rate of 4%. The loss rate is almost 5-fold higher in patients carrying 3 or more fetuses (11.1%) than for those carrying twins (2.4%). ST is a reasonable alternative in multifetal pregnancies in which 1 or more fetuses have a significant abnormality.