Raj Rai

Anti-inflammatory and immunosuppressive drugs and reproduction

Rheumatic diseases in women of childbearing years may necessitate drug treatment during a pregnancy, to control maternal disease activity and to ensure a successful pregnancy outcome. This survey is based on a consensus workshop of international experts discussing effects of anti-inflammatory, immunosuppressive and biological drugs during pregnancy and lactation. In addition, effects of these drugs on male and female fertility and possible long-term effects on infants exposed to drugs antenatally are discussed where data were available. Recommendations for drug treatment during pregnancy and lactation are given.

A Meta-analysis on the Influence of Inflammatory Bowel Disease on Pregnancy

Background: Inflammatory bowel disease (IBD) has a typical onset during the peak reproductive years. Evidence of the risk of adverse pregnancy outcomes in IBD is important for the management of pregnancy to assist in its management. Aim: To provide a clear assessment of risk of adverse outcomes during pregnancy in women with IBD. Design: The Medline literature was searched to identify studies reporting outcomes of pregnancy in patients with IBD. Random-effect meta-analysis was used to compare outcomes between women with IBD and normal controls. Patients and setting: A total of 3907 patients with IBD (Crohn’s disease 1952 (63%), ulcerative colitis 1113 (36%)) and 320 531 controls were reported in 12 studies that satisfied the inclusion criteria. Results: For women with IBD, there was a 1.87-fold increase in incidence of prematurity (<37 weeks gestation; 95% CI 1.52 to 2.31; p<0.001) compared with controls. The incidence of low birth weight (<2500 g) was over twice that of normal controls (95% CI 1.38 to 3.19; p<0.001). Women with IBD were 1.5 times more likely to undergo caesarean section (95% CI 1.26 to 1.79; p<0.001), and the risk of congenital abnormalities was found to be 2.37-fold increased (95% CI 1.47 to 3.82; p<0.001). Conclusion: The study has shown a higher incidence of adverse pregnancy outcomes in patients with IBD. Further studies are required to clarify which women are at higher risk, as this was not determined in the present study. This has an effect on the management of patients with IBD during pregnancy, who should be treated as a potentially high-risk group.

Natural Selection of Human Embryos: Impaired Decidualization of Endometrium Disables Embryo-Maternal Interactions and Causes Recurrent Pregnancy Loss

Background Recurrent pregnancy loss (RPL), defined as 3 or more consecutive miscarriages, is widely attributed either to repeated chromosomal instability in the conceptus or to uterine factors that are poorly defined. We tested the hypothesis that abnormal cyclic differentiation of endometrial stromal cells (ESCs) into specialized decidual cells predisposes to RPL, based on the observation that this process may not only be indispensable for placenta formation in pregnancy but also for embryo recognition and selection at time of implantation. Methodology/Principal Findings Analysis of mid-secretory endometrial biopsies demonstrated that RPL is associated with decreased expression of the decidual marker prolactin (PRL) but increased levels of prokineticin-1 (PROK1), a cytokine that promotes implantation. These in vivo findings were entirely recapitulated when ESCs were purified from patients with and without a history of RPL and decidualized in culture. In addition to attenuated PRL production and prolonged and enhanced PROK1 expression, RPL was further associated with a complete dysregulation of both markers upon treatment of ESC cultures with human chorionic gonadotropin, a glycoprotein hormone abundantly expressed by the implanting embryo. We postulated that impaired embryo recognition and selection would clinically be associated with increased fecundity, defined by short time-to-pregnancy (TTP) intervals. Woman-based analysis of the mean and mode TTP in a cohort of 560 RPL patients showed that 40% can be considered “superfertile”, defined by a mean TTP of 3 months or less. Conclusions Impaired cyclic decidualization of the endometrium facilitates implantation yet predisposes to subsequent pregnancy failure by disabling natural embryo selection and by disrupting the maternal responses to embryonic signals. These findings suggest a novel pathological pathway that unifies maternal and embryonic causes of RPL.

Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin

Objective To study the obstetric course of women with a history of recurrent miscarriage associated with antiphospholipid antibodies, lupus anticoagulant and anticardiolipin antibodies, treated with low dose aspirin and low dose heparin.

NATURAL SELECTION OF HUMAN EMBRYOS: DECIDUALIZING ENDOMETRIAL STROMAL CELLS SERVE AS SENSORS OF EMBRYO QUALITY UPON IMPLANTATION

Background Pregnancy is widely viewed as dependent upon an intimate dialogue, mediated by locally secreted factors between a developmentally competent embryo and a receptive endometrium. Reproductive success in humans is however limited, largely because of the high prevalence of chromosomally abnormal preimplantation embryos. Moreover, the transient period of endometrial receptivity in humans uniquely coincides with differentiation of endometrial stromal cells (ESCs) into highly specialized decidual cells, which in the absence of pregnancy invariably triggers menstruation. The role of cyclic decidualization of the endometrium in the implantation process and the nature of the decidual cytokines and growth factors that mediate the crosstalk with the embryo are unknown. Methodology/Principal Findings We employed a human co-culture model, consisting of decidualizing ESCs and single hatched blastocysts, to identify the soluble factors involved in implantation. Over the 3-day co-culture period, approximately 75% of embryos arrested whereas the remainder showed normal development. The levels of 14 implantation factors secreted by the stromal cells were determined by multiplex immunoassay. Surprisingly, the presence of a developing embryo had no significant effect on decidual secretions, apart from a modest reduction in IL-5 levels. In contrast, arresting embryos triggered a strong response, characterized by selective inhibition of IL-1β, -6, -10, -17, -18, eotaxin, and HB-EGF secretion. Co-cultures were repeated with undifferentiated ESCs but none of the secreted cytokines were affected by the presence of a developing or arresting embryo. Conclusions Human ESCs become biosensors of embryo quality upon differentiation into decidual cells. In view of the high incidence of gross chromosomal errors in human preimplantation embryos, cyclic decidualization followed by menstrual shedding may represent a mechanism of natural embryo selection that limits maternal investment in developmentally impaired pregnancies.

The effect of restorative proctocolectomy on sexual function, urinary function, fertility, pregnancy and delivery: a systematic review.

PurposeThis study was designed to evaluate the effect of restorative proctocolectomy on sexual function, urinary function, fertility, pregnancy, and delivery in patients with ulcerative colitis.MethodsA systematic literature search was performed of articles published between 1980 and 2005 on patients undergoing restorative proctocolectomy for ulcerative colitis reporting data on the outcomes of interest. A random-effect, meta-analytical model was used for pooled estimates and 95 percent confidence intervals.ResultsA total of 22 studies, with 1,852 females, were included. Infertility rate was 12 percent before restorative proctocolectomy and 26 percent after, among 945 patients in seven studies. The incidence of sexual dysfunction was 8 percent preoperatively and 25 percent postoperatively (7 studies, n = 419). Two studies (n = 62) reported no urinary dysfunction in patients undergoing restorative proctocolectomy. There was an increased incidence of cesarean section after restorative proctocolectomy. During the third trimester of pregnancy, there was an increase in stool frequency by 1.15 stools per day compared with before pregnancy frequency (n = 49 95 percent confidence interval, 0.28–2.03 P = 0.01 chi-squared statistic, 0.04 P = 0.84). No significant differences were seen in pouch function after vaginal delivery (n = 456; weighted mean difference, 0.23; 95 percent confidence interval, 0.43–0.88; P = 0.49; chi-squared statistic, 1.29; P = 0.26).ConclusionsThe incidence of dyspareunia increases after restorative proctocolectomy. There was a decrease in fertility after restorative proctocolectomy. Pregnancy after restorative proctocolectomy was not associated with an increase in complications. There was an increase in stool frequency and pad usage during the third trimester. Vaginal delivery is safe after restorative proctocolectomy. Pouch function after delivery returns to pregestational function within six months.

Second-trimester pregnancy loss is associated with activated protein C resistance

We have investigated whether activated protein C resistance (APCR) is associated with second‐trimester miscarriage. The prevalence of APCR was significantly higher amongst women with a history of second‐trimester miscarriage (10/50; 20%) compared with either women with a history of first‐trimester miscarriages only (4/70; 5.7%) or a control group of parous women with no previous history of pregnancy losses (3/70; 4.3%) (P < 0.02). These results suggest that APCR may be an important mechanism of second‐trimester pregnancy loss, possibly related to the increase in intravascular coagulation that occurs during pregnancy.

CMOS Vertical Multiple Independent Gate Field Effect Transistor (MIGFET)

Perfectly self aligned vertical multiple independent gate field effect transistor (MIGFET) CMOS devices have been fabricated. The unique process used to fabricate these devices allow them to be integrated with FinFET devices. Device and circuit simulations have been used to explain the device and explore new applications using this device. A novel application of the MIGFET as a signal mixer has been demonstrated. The undoped channel, very thin body, perfectly matched gates allows charge coupling of the two signals and provide a new family of applications using the MIGFET mixer. Since the process allows integration of regular CMOS double gate devices and MIGFET devices this technology has potential for various digital and analog mixed-signal applications.

Does suppressing luteinising hormone secretion reduce the miscarriage rate? Results of a randomised controlled trial

Abstract Objective: To determine whether prepregnancy pituitary suppression of luteinising hormone secretion with a luteinising hormone releasing hormone analogue improves the outcome of pregnancy in ovulatory women with a history of recurrent miscarriage, polycystic ovaries, and hypersecretion of luteinising hormone. Design: Randomised controlled trial. Setting: Specialist recurrent miscarriage clinic. Subjects: 106 women with a history of three or more consecutive first trimester miscarriages, polycystic ovaries, and hypersecretion of luteinising hormone. Interventions: Women were randomised before conception to receive pituitary suppression with a luteinising hormone releasing hormone analogue followed by low dose ovulation induction and luteal phase progesterone (group 1) or were allowed to ovulate spontaneously and then given luteal phase progesterone alone or luteal phase placebo alone (group 2). No drugs were prescribed in pregnancy. Main outcome measures: Conception and live birth rates over six cycles. Results: Conception rates in the pituitary suppression and luteal phase support groups were 80% (40/50 women) and 82% (46/56) respectively (NS). Live birth rates were 65% (26/40) and 76% (35/46) respectively (NS). In the luteal phase support group there was no difference in the outcome of pregnancy between women given progesterone and those given placebo pessaries. Live birth rates from an intention to treat analysis were 52% (26/50 pregnancies) in the group given pituitary suppression and 63% (35/56) in the controls (NS). Conclusions: Prepregnancy suppression of high luteinising hormone concentrations in ovulatory women with recurrent miscarriage and hypersecretion of luteinising hormone does not improve the outcome of pregnancy. The outcome of pregnancy without pituitary suppression is excellent. Key messages Hypersecretion of luteinising hormone seems not to be causally related to early pregnancy loss Further research should be directed at other endocrine factors controlling implantation Excellent live birth rates can be achieved with supportive care alone in a specialised clinic

Impact of titanium addition on film characteristics of HfO2 gate dielectrics deposited by atomic layer deposition

The impact of 8-to45-at.% Ti on physical and electrical characteristics of atomic-layer-deposited and annealed hafnium dioxide was studied using vacuum-ultraviolet spectroscopic ellipsometry, secondary ion mass spectroscopy, transmission electron microscopy, atomic force microscopy, x-ray diffraction, Rutherford backscattering spectroscopy, x-ray photoelectron spectroscopy, and x-ray reflectometry. The role of Ti addition on the electrical performance is investigated using molybdenum (Mo)-gated capacitors. The film density decreases with increasing Ti addition. Ti addition stabilizes the amorphous phase of HfO2, resulting in amorphous films as deposited. After a high-temperature annealing, the films transition from an amorphous to a polycrystalline phase. Orthorhombic Hf–Ti–O peaks are detected in polycrystalline films containing 33-at.% or higher Ti content. As Ti content is decreased, monoclinic HfO2 becomes the predominant microstructure. No TiSi is formed at the dielectric/Si interface, indicating fil...