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OBJECTIVES: In-vivo studies of the bioavailability of major components of the tumor necrosis factor alpha (TNFα) biosystem inside the gestational sac during embryogenesis have not been reported. We sought to determine the concentration of TNFα, soluble (s) TNFα receptors (sTNFR1, sTNFR2), and RANTES in the primate extraembryonic celomic fluid (ECF). METHODS: A validated timed-pregnant baboon animal model (N: 10) for experimental research in pregnancy was used to collect paired maternal blood and ECF samples in ongoing pregnancies. The concentrations (pg/dL) of TNFα, sTNFR1, sTNFR2, and RANTES were then determined by ELISA immunoassays. RESULTS: All animals delivered at term healthy newborns. The differential concentration of TNFα, sTNFR1, sTNFR2, and RANTES between the maternal plasma and the ECF could be determined with ratios for TNFα (5.4), sTNFR2 (1.85) and RANTES (3.59) that contrasted with that of sTNFR1 (0.07), which favored the gestational sac compartment. No significant correlations were noted between maternal plasma and ECF TNFR1, sTNFR2 and RANTES. There was a trend for a correlation between TNFα in maternal plasma and ECF (R=0.74; p=0.07). CONCLUSIONS: We report the physiological concentrations of TNFα, sTNFR1, sTNFR2, and RANTES in extraembryonic celomic fluid during embryogenesis in primates.

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A 50-year-old non-Hispanic white Caucasian female was diagnosed with breast cancer and was subsequently found to possess the tumorigenic ataxia telangiectasia mutated (ATM) and PALB2 variants but not the BRCA1 and BRCA2 variants. She visited the gynecologic oncology office for routine counseling about risk-reducing salpingo-oophorectomy (RRSO). Although the patient was asymptomatic, an adnexal mass was discovered in the physical examination performed by palpation. Upon using pre-operative imaging techniques, an 8 cm complex adnexal mass was identified. Her CA-125 level was elevated. She underwent complete cytoreductive surgery. Pathological analysis showed a stage IC clear cell carcinoma of the left ovary; subsequently, she received 6 cycles of adjuvant chemotherapy with a combination of carboplatin and paclitaxel. The patient exhibited no signs ovarian cancer in a follow-up appointment after 32 months of treatment. However, bilateral RRSO is not recommended for patients positive for ATM and PALB2. Breast cancer patients with PALB2 and ATM mutations should extensively discuss the risks and benefits of RRSO in light of current data.

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Objective To evaluate the possible association between antenatal magnesium sulfate treatment with histological chorioamnionitis in patients with singleton or dichorionic twins that had preterm premature rupture of the membranes. Methods This was an observational study performed in patients admitted to the hospital with rupture of membranes before 34 weeks' gestation. The primary outcome was histological chorioamnionitis and the primary predictor was antenatal magnesium sulfate treatment. A logistic regression model was used without consideration of other antenatal medical treatments. Results Among 107 patients with preterm deliveries, 57 were admitted to the hospital before 34 weeks' gestation with preterm premature rupture of membranes. Fifty-cases were excluded from the analysis because they were admitted after 34 weeks' gestation, delivered before 24 weeks' gestation or had intrauterine fetal demise or monochorionic twins. The logistic regression analysis adjusting for maternal age, gravidity, parity, multiple gestation, gestational age at delivery, and birthweight, indicated that patients with singleton pregnancies and histological chorioamnionitis had received magnesium sulfate antenatally more frequently (χ2=6.46; P=0.01). The association between histological chorioamnionitis and magnesium sulfate treatment was not found among patients with dichorionic twin pregnancies with one intact gestational sac. Conclusions In this cohort of patients with preterm premature rupture of membranes admitted to the hospital before 34 week's gestation, those with singleton pregnancies treated antenatally with magnesium sulfate for neonatal neuroprotection had a greater rate of histological chorioamnionitis.

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Obstetricians offer prenatal screening for most common chromosomal abnormalities to all pregnant women including those that had in vitro fertilization (IVF) and preimplantation genetic screening/diagnosis (PGS/D). We propose that free fetal DNA in maternal circulation together with the second trimester maternal serum alfa feto protein (MSAFP) and ultrasound imaging is the best prenatal screening test for chromosomal abnormalities and congenital anomalies in IVF-PGD/S patients because risk estimations from all other prenatal screening algorithms for chromosomal abnormalities depend heavily on maternal age which is irrelevant in PGS/D patients.

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OBJECTIVE: There are no national reports on the mode of delivery in pregnancies that end in stillbirth. We aimed at analyzing the cesarean delivery rates in pregnancies resulting in stillbirth over a 10-year period in the United States. MATERIALS AND METHODS: This was a retrospective analysis evaluating data from the 1995 to 2004 US linked live birth-infant death files reported by the National Center for Health Statistics to examine the cesarean delivery rates in singleton pregnancies with and without stillbirth. RESULTS: There were 39 797 616 singleton births registered in the database after the 20th week of gestation. During the study period, there were 243 979 stillbirths (0.61 per 100). Significant differences in stillbirths were noted in the African American population, nonmarried patients, in mothers who smoked, and at the extremes of the patients reproductive age (P < .01). The overall cesarean delivery rate in liveborn was 23.54% (9 309 961 cases) and 10.5% in stillbirth (25 558 cases; P < .01). The rate of cesarean delivery increased in liveborn (from 20.8% in 1995 to 28.9% in 2004; 28% overall increase) and in stillbirth (9.5% in 1995 to 11.23% in 2004; 15% overall increase). The rates of primary and repeat cesarean operations increased with gestational age in the stillbirth group. This pattern was not observed in the liveborn group. CONCLUSION: This analysis indicates that the cesarean delivery rates increased both in liveborn and in stillbirth from 1995 to 2004. This epidemiological observation deserves new clinical investigations to understand the clinical reasons, driving this obstetrical practice and the financial and societal impact that it portends.

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The maternal microbiota has long been considered a potential cause for adverse perinatal outcomes. Gene expression regulators in prokaryotic and eukaryotic cells are influenced by changes in their microenvironments. We propose the novel idea that during in utero development, an adaptive and dynamic gene-regulatory cross talk might exist between the host genome and the maternal microbiota. Understanding these cross talks could increase the appreciation for the discovery of new diagnostics and therapeutics in maternal-fetal medicine.

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OBJECTIVE: Placental abruption is a clinical term used when premature separation of the placenta from the uterine wall occurs prior to delivery of the fetus. Hypertension, substance abuse, smoking, intrauterine infection and recent trauma are risk factors for placental abruption. In this study, we sought for clinical factors that increase the risk for perinatal mortality in patients admitted to the hospital with the clinical diagnosis of placental abruption. MATERIALS AND METHODS: We identified all placental abruption cases managed over the past 6 years at our Center. Those with singleton pregnancies and a diagnosis of abruption based on strict clinical criteria were selected. Eleven clinical variables that had potential for increasing the risk for perinatal mortality were selected, logistic regression analysis was used to identify variables associated with perinatal death. RESULTS: Sixty-one patients were included in the study with 16 ending in perinatal death (26.2%). Ethnicity, maternal age, gravidity, parity, use of tobacco, use of cocaine, hypertension, asthma, diabetes, hepatitis C, sickle cell disease and abnormalities of amniotic fluid volume were not the main factors for perinatal mortality. Gestational age at delivery, birthweight and history of recent trauma were significantly associated with perinatal mortality. The perinatal mortality rate was 42% in patients who delivered prior to 30 weeks of gestation compared to 15% in patients who delivered after 30 weeks of gestation (p < 0.05). A three-fold increase in severe trauma was reported in the group of patients with perinatal mortality than in the group with perinatal survivors (25% versus 7%, respectively, p < 0.05). CONCLUSIONS: In patients admitted to hospital for placental abruption delivery prior to 30 weeks of gestation and a history of abdominal trauma are independent risk factors for perinatal death.

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OBJECTIVE: We sought to evaluate the types of genetic screening tests that are performed in women of childbearing ages in New Jersey. METHOD: Data from patients who had a reproductive genetics consultation between January 1, 2012, and July 31, 2012, were stratified according to the referring providers, i.e., those from academic or private practices, and descriptive analyses performed. Unconventional genetic screening was defined as any test ordered by the referring health care provider outside the recommendations from the American Congress of Obstetricians and Gynecologists or the American College of Medical Genetics and Genomics. RESULTS: Overall, 30% of 371 patients referred for a genetic consultation underwent unconventional screening. As compared to patients from academic practices, the relative rate of unconventional screening was 10-fold higher among patients from private practices, resulting in a relative 34-fold increase in the estimated cost in genetic screening (P<0.01). CONCLUSION: This set of preliminary observations highlight the need for further state, nationwide, and international studies to understand the financial, personal, and societal impact that this discrepancy health care system in the use of genetic carrier screening portends.

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Introduction Prenatal counseling with regards to the prognosis of a cerebellar abnormality is hindered not only by the diverse clinical presentations but also by the presence of subtle findings. We present a case of a distinct combination of asymmetric cerebellar hypoplasia secondary to an anterior meningoencephalocele through a clival defect that caused a severe airway obstruction in the newborn. Case Description A 21-year-old gravida 4 para 0 mother with a dichorionic-diamniotic twin pregnancy was referred for a second trimester sonographic survey. An asymmetric cerebellar hypoplasia, mega cisterna magna, and a pharyngeal cystic mass were noted on twin A. Magnetic resonance imaging report confirmed posterior fossa abnormalities and shed no light on the differential diagnosis of the cystic mass. The pregnancy ended by Cesarean delivery at 32 weeks' gestation after a preterm premature rupture of the membranes. Twin A had a severe airway obstruction. Postnatal evaluation confirmed a midline anterior meningoencephalocele through a defect in the clivus. The microarray chromosomal analysis demonstrated a 5q15 variant with uncertain clinical significance. Conclusion Antenatal recognition of the unique combination of a cerebellar hypoplasia with a pharyngeal cyst can impact the prenatal counseling as well as neonatal management.

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PURPOSE: The corrections necessary to estimate the risk for Down syndrome in twin pregnancies have been pointed out. We performed a nested controlled study to evaluate the validity of these corrections in dichorionic twins conceived by IVF. METHODS: Detailed clinical data was collected from the medical records. Twins were matched with a contemporaneous cohort of spontaneously conceived singleton pregnancies that serve as reference in a 1 to 4 ratio. All patients had their entire obstetrical care at our Hospital. The Student t-test was used for group comparisons and a p-value <0.05 was considered significant. RESULTS: Nineteen sets of normal twins concordant in size and with appropriate weight for gestational age were matched with 80 normal and mature newborns. Significant differences between groups were found for maternal age, gestational age at delivery and newborn weight (all p < 0.01). No statistical differences were noted for the levels of the biochemical markers expressed as multiples of the median. However, a 15 % closer approximation to the laboratory median for PAPP-A and a 10 % closer approximation to the laboratory median for free ß-hCG was evident in twins when compared to the reference group. CONCLUSIONS: These findings support the methods used to estimate the risk for Down syndrome in dichorionic twin pregnancies conceived after IVF. A future study with a larger sample size could confirm if the laboratory corrections done on the combined screening test improve the predictability of Down syndrome in dichorionic twin pregnancy conceived by IVF when compared to singleton pregnancies.

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OBJECTIVE: In this study, we sought to characterize the tumor necrosis factor α (TNFα) baseline operational capacity in mature fetuses and their mothers prior to the onset of labor. MATERIALS AND METHODS: We used an experimental pregnant nonhuman primate model to measure the plasma concentration of TNFα, TNF transmembrane receptor I (TNFRI), and TNFRII with validated enzyme-linked immunosorbent assays. Coefficients of correlations between the maternal and the fetal values and the soluble TNFα, TNFRI, or TNFRII concentrations and ratios were calculated. RESULTS: The TNFα/TNFRI ratio was 3 times lower in fetal circulation than in maternal circulation. No correlations were noted between the maternal and the fetal TNFα, TNFRI, or TNFRII plasma concentrations. CONCLUSIONS: These findings suggest that the fetal and maternal baseline circulatory operational capacities of TNFα are independent of each other and tuned differently. This differential regulation of TNFα in fetal and maternal circulation at the end of pregnancy may be guided to protect the fetus from the systemic inflammatory response that is essential for the mechanisms of labor to proceed in the mother.

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OBJECTIVE: To determine whether advanced paternal age is associated with increased risk for cesarean delivery. STUDY DESIGN: We used the 1990-2002 US linked live birth and infant death data files restricted to primiparous Caucasian and African-American women that delivered a singleton birth at ≥20 week's gestation (12.5 million). We examined temporal trends and risk ratios of cesarean birth in relation to paternal age before and after adjustments for known confounders. RESULTS: Among Caucasians, the cesarean delivery rates were 21.1%, 26.7% and 31.8% in fathers aged 20-29, 30-39 and ≥40 years, respectively. Among African-Americans, the corresponding rates were 24.1%, 33.2%, and 38.1%, respectively. These increased cesarean delivery rates persisted in analyses stratified by maternal age before and after adjustment for a variety of confounders. CONCLUSIONS: These findings suggest that increasing paternal age may be associated with an increased risk for cesarean delivery in primiparous women.

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PROBLEM: A maternal serum biomarker profile analysis was performed to determine potential indicators of acute rejection of pregnancy following in-utero cell-based treatments in pre-immune embryos. METHOD OF STUDY: We used an established non-human primate model for in-utero stem cell therapy at 38-42 days from fertilization. The maternal serum concentrations of nine candidate biomarkers for acute rejection of pregnancy were determined before and after the injection of different cocktails of human umbilical cord blood stem cells into the gestational sac. All animals were then followed until delivery. RESULTS: Twenty-four hours after celocentesis, two of the animals aborted. These two animals received a cocktail of haemopoietic stem cells with the highest concentration of human CD3(+) cells and showed a twofold increase in maternal serum IL-6 and a threefold increase in prolactin after the procedure. The remaining six animals delivered at term live and normal newborns and only demonstrated an increase in prolactin after the celocentesis procedure. CONCLUSION: IL-6 and prolactin are master immunoregulators with pleiotropic biological functions that have different maternal serum concentrations depending on pregnancy outcome. These findings suggest that increases in maternal serum prolactin and IL-6 concentration may be associated with acute rejection of pregnancy after in-utero stem cell therapy.

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OBJECTIVES: In vitro preparations have provided evidence suggesting that acute and chronic exposure to very high glucose concentrations can lead to embryonic demise via disruption of the extra-celomic membranes and yolk sac. In this study, we sought to determine, in vivo, if an acute increase in extra-embryonic fluid glucose concentration could cause spontaneous abortion. MATERIALS AND METHODS: We employed a pregnant non-human primate model and ultrasound-guided celocentesis at 38-42 days from conception. In three control animals, partial replacement of the extra-embryonic celomic fluid was performed using normal saline containing 0.6 mg/mL of glucose. In four study animals, the extra-celomic fluid was replaced with a similar solution containing high glucose concentrations. All animals were then followed until delivery. RESULTS: Immediately after celocentesis, the estimated celomic fluid glucose concentration in experimental animals ranged between 5 mg/mL and 83.8 mg/mL (8-140 times the physiologic glucose concentration of 0.6 mg/mL). All animals delivered live newborns at term without congenital abnormalities. CONCLUSIONS: These findings suggest that transitory increases in the extra-celomic fluid glucose concentration are not likely to cause a spontaneous abortion detectable with the sample size of our study.

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OBJECTIVE: To determine the ability to assess the fetal anatomy and ultrasound screening markers using three-dimensional (3D) volumes acquired during the 11th to 13th week scan, in relation to whether a fetal profile could be used as a starting section. METHODS: Post hoc analysis of 3D ultrasound volumes acquired at 11 to 13 weeks in 223 pregnancies was performed to identify the appropriate sections for evaluation of three screening markers and ten fetal anatomy landmarks. When possible, the fetal profile was used as the starting section for volume acquisition. RESULTS: When the fetal profile was used, satisfactory images for assessment were obtained in 90% of cases for nuchal translucency and 72% for the nasal bone, whereas successful evaluation of the ten anatomical landmarks ranged from 0 to 99%. In alternative starting sections, the corresponding success rates were 65%, 48%, and 0-95%. CONCLUSION: Although performance of post hoc analysis of 3D volumes is best when carried out from a profile starting section and quicker than two-dimensional analysis, it appears to be not ready for clinical use because nuchal translucency could not be examined in 10% of the fetuses.

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PURPOSE: To compare measurements of the fetal thymus obtained by magnetic resonance imaging (MRI) and ultrasound (US). MATERIALS AND METHODS: Written informed consent was obtained from the patients that participated in this Institutional Review Board-approved observational study. The study population consisted of 17 pregnant women carrying fetuses between 21 and 34 weeks of gestation with suspected abnormalities. The transverse diameter and perimeter of the thymus were measured in these fetuses at the level of an axial view of the thorax that includes the pulmonary, aorta, and superior vena cava. The degree of agreement between MRI and US measurements was determined using Lin's concordance correlation coefficient and Bland-Altman analysis. RESULTS: The mean (standard deviation, SD) gestational age at the time of the prenatal evaluation was 28.4 weeks (3.6). The thymus was measured by MRI and US in all cases. Comparison of the measurements from these two imaging modalities demonstrated a relatively good reproducibility with no evidence of systematic error. CONCLUSION: MRI and US measurements of the fetal thymus during the second half of pregnancy are comparable. This finding suggests that MRI can become a useful adjuvant to US for assessment of the fetal thymus.

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We sought to determine the clinical value of the 11- to 13(+6)-week ultrasound evaluation for diagnosis of congenital abnormalities. A literature search was conducted for publications concerning the use of the 11- to 13(+6)-week ultrasound evaluation for prenatal diagnosis of congenital abnormalities. Series with more than 1000 cases published in the English language were selected. The reported data were integrated and a pooled analysis was performed to provide meaningful clinical interpretations. Our analysis of data from 36,237 pregnancies generated by eight centers suggests that the overall detection rate of major congenital anomalies during the 11- to 13(+6)-week ultrasound evaluation is 29% (95% confidence interval 25 to 33). Prenatal diagnosis at these stages of development could improve if evaluations are implemented in accordance to very well delineated protocols.

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