First-trimester screening for trisomies in pregnancies with vanishing twin.

OBJECTIVES: To examine multiples of the median (MoM) values of serum free beta-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in a large series of pregnancies with a vanishing twin, determine the association of these values with the interval between embryonic death and blood sampling, and develop a model that would allow incorporation of these metabolites in first-trimester combined screening for trisomy. METHODS: This was a retrospective study comparing maternal serum free ß-hCG and PAPP-A levels at 11-13 weeks' gestation in 528 dichorionic pregnancies with a vanishing twin, including 194 (36.7%) with an empty gestational sac and 334 (63.3%) with a dead embryo, with those in 5280 normal singleton pregnancies matched for method of conception and date of examination. In vanishing-twin pregnancies with a dead embryo, marker levels were examined in relation to the estimated time between embryonic death and maternal blood sampling. RESULTS: First, in pregnancies with a vanishing twin, median free ß-hCG MoM was not significantly different from that in normal singleton pregnancies (1.000; 95% CI, 0.985-1.016 vs 0.995; 95% CI, 0.948-1.044; P = 0.849). Second, PAPP-A MoM was higher in vanishing-twin pregnancies than in normal singleton pregnancies (1.000; 95% CI, 0.985-1.015), both in the group with an empty gestational sac (1.165; 95% CI, 1.080-1.256; P = 0.0001) and in that with a dead embryo (1.175; 95% CI, 1.105-1.249; P < 0.0001). Third, in vanishing-twin pregnancies with a dead embryo, PAPP-A MoM was related inversely to the interval between estimated gestational age at embryonic demise and blood sampling (P < 0.0001). Fourth, in first-trimester screening for trisomy 21 in singleton pregnancies, the estimated detection rate, at a 5% false-positive rate, was 82% in screening by a combination of maternal age and fetal nuchal translucency thickness, and this increased to 86% with the addition of serum free ß-hCG and to 91% with the addition of serum PAPP-A. Fifth, similar performance of screening can be achieved in pregnancies with a vanishing twin, provided the appropriate adjustments are made to the level of PAPP-A for the interval between estimated gestational age at embryonic demise and blood sampling. CONCLUSIONS: First-trimester screening for trisomy in pregnancies with a vanishing twin should rely on a combination of maternal age, fetal nuchal translucency thickness and serum free ß-hCG, as in singleton pregnancy, without the use of serum PAPP-A. Alternatively, PAPP-A can be included but only after appropriate adjustment for the interval between estimated gestational age at fetal demise and blood sampling. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Comparing effect levels of regulatory studies with endpoints derived in targeted anti-androgenic studies: example prochloraz.

Prochloraz is an imidazole fungicide, and its regulatory toxicological data package has been primarily generated in the 1990s. More recently, studies have been published demonstrating an interaction with hormone receptors/steroidogenesis and effects with an endocrine mode of action. In the present study, prochloraz has been investigated in a comprehensive in vivo study including relevant elements of current regulatory reproduction toxicity studies and additional mechanistic parameters. Prochloraz was administered per gavage in oil from GD 6 to PND 83 to pregnant and lactating Wistar rats and their respective offspring, at doses of 0.01 mg/kg bw/day (acceptable daily intake of prochloraz), 5 mg/kg bw/day [expected no-observed-effect-level (NOEL)] and 30 mg/kg bw/day. At 30 mg/kg bw/day maternal and offspring effects (decreased viability, lower number of live offspring) were seen including a delayed entry into male puberty (+1 day) accompanied by lower male offspring body weights, increased anogenital distance/index in females and transiently retained nipples in males at PND 12 (not seen at PND 20). The only finding at the "expected NOEL" was increased incidences of transiently retained nipples in males which are not considered adverse. No effects were seen in the low-dose group. There was no evidence for a non-monotonic dose-response curve or effects at low levels.

Maternal N-Carbamylglutamate Supplementation during Early Pregnancy Enhances Embryonic Survival and Development through Modulation of the Endometrial Proteome in Gilts.

BACKGROUND: Early pregnancy loss is a major concern in humans and animals. N-carbamylglutamate (NCG) has been found to enhance embryonic survival during early pregnancy in rats. However, little is known about the key factors in the endometrium involved in the improvement of embryonic implantation and development induced by maternal NCG supplementation. OBJECTIVES: Our objectives were to investigate whether NCG supplementation during early gestation enhanced embryonic survival and development in gilts and to uncover the related factors using the approach of endometrium proteome analysis with isobaric tags for relative and absolute quantification (iTRAQ). METHODS: Uteruses and embryos/fetuses were obtained on days 14 and 28 of gestation from gilts fed a basal diet that was or was not supplemented with 0.05% NCG. The iTRAQ-based quantitative proteomics approach was performed to explore the endometrium proteome altered by NCG supplementation. RESULTS: Maternal NCG supplementation significantly increased the number of total fetuses and live fetuses on day 28 of gestation by 1.32 and 1.29, respectively (P < 0.05), with a significant decrease in embryonic mortality (P < 0.05). iTRAQ results indicated that a total of 59 proteins showed at least 2-fold differences (P < 0.05), including 52 proteins that were present at higher abundance and 7 proteins present at lower abundance in NCG-supplemented gilts. The differentially expressed proteins primarily are involved in cell adhesion, energy metabolism, lipid metabolism, protein metabolism, antioxidative stress, and immune response. On day 14 of gestation, several proteins closely related to embryonic implantation and development, such as integrin-αv, integrin-ß3, talin, and endothelial nitric oxide synthase, were upregulated (3.7-, 4.1-, 2.4-, and 5.4-fold increases, respectively) by NCG supplementation. CONCLUSION: To our knowledge, our results provide the first evidence that altered abundance of the endometrial proteome induced by NCG supplementation is highly associated with the improvement of embryonic survival and development in gilts.

First and second trimester maternal serum markers in pregnancies with a vanishing twin.

OBJECTIVE: The aim of this study was to assess the concentration of the first and second trimester maternal serum markers in pregnancies with a vanishing twin. METHODS: This is a retrospective case-control study of pregnancies screened for Down syndrome in one Ontario center. Singleton pregnancies with ultrasound evidence of a vanishing twin were identified, and each was matched with five normal singleton controls for ethnicity, maternal age, gestational age, and blood sampling date. The median MoM of the first and second trimester serum markers was compared between cases and controls. The differences were assessed using the Mann-Whitney U-test. RESULTS: The study included 174 pregnancies that had a vanishing twin. Compared with control pregnancies, pregnancy associated plasma protein A increased by 21% (p = 0.0026), alpha-fetoprotein (AFP) increased by 10% (p < 0.0001), and dimeric inhibin A (DIA) increased by 13% (p = 0.0470) in pregnancies with a vanishing twin. Unconjugated oestriol and total human chorionic gonadotrophin were not significantly changed in these pregnancies. CONCLUSIONS: Pregnancy associated plasma protein A is not an adequate marker for pregnancies with a vanishing twin. The impact of elevated AFP on risk estimation is offset by that of DIA to certain extent. Further studies are needed to establish an adequate adjustment method for AFP and DIA to improve the accuracy of screening results for these pregnancies.

Vanishing twin as a potential source of bias in non-invasive fetal sex determination: a case report.

Detection of fetal sex based on fetal DNA present in maternal plasma is already in clinical use. Here we present a case of false positivity during the first trimester which may be attributable to a vanishing twin. The presence of Y-chromosome-specific sequences is used as a marker to indicate a male fetus and the absence of a female fetus. Fetal sex determination was conducted in a pregnant woman at gestational week 10. The sample was positive in all triplicates. Ultrasonography at gestational week 20 revealed female sex. Analysis of sample taken at gestational week 22 indicated a female fetus. According to recently published meta-analyses, non-invasive prenatal diagnosis of fetal sex has high sensitivity and specificity values. Nevertheless, false negative and false positive cases occur. Future studies focusing on the dynamics of fetal DNA are needed. Vanishing twin might be one of the possible causes of false positivity in fetal sex determination.

Human chorionic gonadotropin rise in normal and vanishing twin pregnancies.

OBJECTIVE: The purpose of the study was to describe and to compare the rate of rise of human chorionic gonadotropin (hCG) in vanishing twin and normally progressing twin pregnancies during the first trimester. DESIGN: All patients with twin pregnancies between 1985 and 1989 were prospectively studied. Human chorionic gonadotropin was measured one to three times per week between days 12 and 52 after luteinizing hormone (LH) surge or day of hCG administration (day 0). Pelvic ultrasound (US) was performed weekly beginning on day 24. SETTING: The study was performed at Rush-Presbyterian-St. Luke's Medical Center in an academic private practice setting of the Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology. PATIENTS: Forty patients who conceived after treatment of infertility and who had two gestational sacs on US examination were included in the study after the following criteria were met: (1) both sacs progressed to exhibit a fetal pole and (2) day of LH surge and/or day of hCG administration was known. MAIN OUTCOME MEASURE: The rate of rise of hCG was slower in vanishing twin pregnancies than in normally progressing twin gestations for the entire time period studied (P less than 0.05). RESULTS: A vanishing twin occurred in one third of the twin pregnancies. Forty-six percent of these losses occurred after fetal heart activity had been established. CONCLUSIONS: Vanishing twin phenomenon occurred in a large proportion of twin pregnancies in this infertility population. Fetal heart activity was not a reliable predictor of continuing fetal viability in early twin gestations. Vanishing twin conceptions were characterized by a slower rate of rise of hCG than normally progressing twin pregnancies.

Progesterone levels and socially-induced implantation failure and fetal resorption in golden hamsters (Mesocricetus auratus).

Levels of circulating progesterone (P) were significantly reduced in socially subordinate female golden hamsters following brief exposures to another female. Reduced P levels were accompanied by an increased incidence of implantation failure when social interactions occurred on days 2-4 after mating and by increased fetal mortality when interactions occurred later during pregnancy (days 5-7 or 10-12). P levels, the incidence of implantation failure and rate of fetal resorption were highly correlated with the number of attacks and chases sustained by subordinate females. Smaller reductions in plasma P levels and marginally significant decreases in fecundity were also noted among dominant animals and among females paired with unfamiliar males later in pregnancy. The fact that these effects occurred even with relatively brief exposure periods suggests that they could occur in the wild.

Early ß-human chorionic gonadotropin trends in vanishing twin pregnancies.

OBJECTIVE: To describe the early ß-hCG trends in vanishing twins compared with normally progressing singleton and twin pregnancies. DESIGN: Retrospective cohort study. SETTING: University-based infertility clinic. PATIENT(S): Women undergoing fresh IVF/intracytoplasmic sperm injection (ICSI) cycles between 1998 and 2010. INTERVENTION(S): Early ß-hCG level increase in vanished twin pregnancies was compared with the level increase in normally progressing singleton and twin pregnancies. MAIN OUTCOME MEASURE(S): Two-day percent increase in ß-hCG level. RESULT(S): Pregnancies with vanishing twins demonstrated a significantly lower mean 2-day percent increase in ß-hCG level than singletons and twins (114.3% vs. 128.8% and 125.4%, respectively). Vanishing twins arresting at earlier developmental stages demonstrated significantly further reduced ß-hCG level increases. Infrequently, all groups had ß-hCG level increases less than previously established clinical thresholds that led to a live birth. CONCLUSION(S): Early ß-hCG level increases are slower in vanishing twins than in singleton and twin pregnancies, with the slowest increases seen when the spontaneous fetal losses occur at earlier developmental stages. All increases, however, are within clinically accepted normal limits. Therefore, abnormal ß-hCG level increases should not be attributed to a vanishing twin. Of note, an abnormal ß-hCG level trend--even an initial decrease--does not preclude live birth, even in a singleton pregnancy.

Pregnancy failure in cats associated with long-term dietary taurine insufficiency.

The effect of long-term dietary taurine insufficiency on reproductive function was studied in adult female domestic cats (n = 11). Cats were time-mated during taurine-deficient (6 months) and refed (6 months) states, and the outcome of ovulatory cycles and breeding was analysed. Serum progesterone and relaxin concentrations were evaluated in order to characterize pregnancies, including those resulting in resorption of fetuses, and pseudopregnancies. Increased resorption of fetuses, reduced litter size, and increased incidence of stillborn kittens was observed in queens while on taurine-deficient diets, as well as after refeeding of a taurine-enriched diet. Overall, 30% of the ovulatory cycles resulted in the delivery of kittens, with mean live and stillborn litter sizes of 2.2 +/- 0.4 and 0.8 +/- 0.4 kittens (mean +/- SEM), respectively. The remaining ovulatory cycles resulted either in pregnancies in which fetuses were resorbed (38%), or in pseudopregnancies (32%). Ovulatory cycles resulting in resorbed fetuses were characterized by the appearance of relaxin on day 20 of gestation, but with a subsequent decrease to non-pregnant concentrations by day 25 of gestation. These results suggest that reproductive failure in domestic cats exposed to long-term nutritional taurine deficiency is associated with a postovulatory defect manifest within the first 10 days after implantation, and that this defect is not reversible upon refeeding of a taurine-enriched diet for 6 months.