The paradox of pregnancy : an update on the immunology of early pregnancy

Pregnancy is an altered physiological state where an organism essentially foreign to the individual carrying it, grows, develops and at an appropriate time probably initiates a series of signals which lead to its safe expulsion from the woman's body. The immunological changes which allow this process are unique to pregnancy. Recent work in this field has led to a further understanding of the changes which operate to adapt the woman to the pregnant state. The concept that has developed over the years is one where a number of factors exert their effect both at the systemic but mostly at the local uterine level to modulate the immune response which will then refrain from mounting an inflammatory response against the invading trophoblast. The main protagonists of this immunomodulation are embryonic factors, uterine (endometrial) NK cells and, of course, the hormone progesterone. Progress has been made from the original observations of miscarriage rates in HLA sharing couples and with the possibility of research in couples undergoing IVF cycles, factors are being identified which initiate immunomodulation. Once implantation occurs the endometrial NK cells which are abundant from the late luteal phase are activated to control trophoblastic invasion and enhance the changes in blood vessels which allow for adequate feto-maternal perfusion. The immune response is controlled by PIBF under the influence of progesterone to bias towards a humoral response and suppress a cytotoxic response. All these processes are prone to fail at times and the clinical manifestation of such a failure is miscarriage along with other obstetric complications such as intra-uterine growth retardation, pre-eclampsia and placental abruption. Progress in the understanding of the immunological processes which protect pregnancy will help in elucidating the mechanisms whereby these processes fail. A consequence of this should be the explanation of those cases as yet classified as unexplained recurrent miscarriage. The literature indicates that the prognosis for this group of patients is not as encouraging as one would hope and that progress in this area is eagerly awaited by both patients and doctors working in this field.peer-reviewe

Alpha-foetoprotein in umbilical cord in relation to severe pre-eclampsia, birth weight and future breast cancer risk

Women born after pre-eclamptic pregnancies have been reported to be at reduced risk of breast cancer as adults, because of reduced intrauterine oestrogen influence on breast tissue; high levels of α-foetoprotein (a glycoprotein with anti-oestrogenic properties), however, could also be important. In severe pre-eclampsia, placental function and foetal growth are reduced, and umbilical cord plasma levels of α-foetoprotein could reflect the underlying processes. Umbilical cord blood was collected in 12 804 consecutive deliveries. Among 307 pregnancies with clinical pre-eclampsia, 66 singleton pregnancies were identified as clinically severe, and 610 singleton pregnancies were selected as controls. Oestradiol and α-foetoprotein were measured from umbilical plasma, and birth weight was standardized as the ratio between the observed and expected birth weight, adjusted for differences in gestation length and offspring sex. Cord plasma levels of α-foetoprotein were significantly higher in severe pre-eclampsia than controls (P<0.01) after adjustment for gestational age and birth weight. For oestradiol, there was no difference in cord plasma levels between the severe pre-eclampsia group and controls, after adjustment for length of gestation and birth weight. These results suggest that an anti-oestrogenic effect associated with pre-eclampsia may be mediated through high levels of α-foetoprotein rather than low levels of oestradiol

Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Preterm birth remains a common cause of neonatal mortality, with a disproportionately high burden in low-income and middle-income countries. Meta-analyses of low-dose aspirin to prevent pre-eclampsia suggest that the incidence of preterm birth might also be decreased, particularly if initiated before 16 weeks of gestation. METHODS: ASPIRIN was a randomised, multicountry, double-masked, placebo-controlled trial of low-dose aspirin (81 mg daily) initiated between 6 weeks and 0 days of pregnancy, and 13 weeks and 6 days of pregnancy, in nulliparous women with an ultrasound confirming gestational age and a singleton viable pregnancy. Participants were enrolled at seven community sites in six countries (two sites in India and one site each in the Democratic Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia). Participants were randomly assigned (1:1, stratified by site) to receive aspirin or placebo tablets of identical appearance, via a sequence generated centrally by the data coordinating centre at Research Triangle Institute International (Research Triangle Park, NC, USA). Treatment was masked to research staff, health providers, and patients, and continued until 36 weeks and 7 days of gestation or delivery. The primary outcome of incidence of preterm birth, defined as the number of deliveries before 37 weeks\u27 gestational age, was analysed in randomly assigned women with pregnancy outcomes at or after 20 weeks, according to a modified intention-to-treat (mITT) protocol. Analyses of our binary primary outcome involved a Cochran-Mantel-Haenszel test stratified by site, and generalised linear models to obtain relative risk (RR) estimates and associated confidence intervals. Serious adverse events were assessed in all women who received at least one dose of drug or placebo. This study is registered with ClinicalTrials.gov, NCT02409680, and the Clinical Trial Registry-India, CTRI/2016/05/006970. FINDINGS: From March 23, 2016 to June 30, 2018, 14 361 women were screened for inclusion and 11 976 women aged 14-40 years were randomly assigned to receive low-dose aspirin (5990 women) or placebo (5986 women). 5780 women in the aspirin group and 5764 in the placebo group were evaluable for the primary outcome. Preterm birth before 37 weeks occurred in 668 (11·6%) of the women who took aspirin and 754 (13·1%) of those who took placebo (RR 0·89 [95% CI 0·81 to 0·98], p=0·012). In women taking aspirin, we also observed significant reductions in perinatal mortality (0·86 [0·73-1·00], p=0·048), fetal loss (infant death after 16 weeks\u27 gestation and before 7 days post partum; 0·86 [0·74-1·00], p=0·039), early preterm delivery (\u3c34 \u3eweeks; 0·75 [0·61-0·93], p=0·039), and the incidence of women who delivered before 34 weeks with hypertensive disorders of pregnancy (0·38 [0·17-0·85], p=0·015). Other adverse maternal and neonatal events were similar between the two groups. INTERPRETATION: In populations of nulliparous women with singleton pregnancies from low-income and middle-income countries, low-dose aspirin initiated between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation resulted in a reduced incidence of preterm delivery before 37 weeks, and reduced perinatal mortality. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development

Early onset and late onset preeclampsia-maternal and perinatal outcomes in a rural teritiary health center

Background: Preeclampsia is main cause of morbidity and mortality both mother and fetus. Preeclampsia occurs in 10-17% of pregnancies. Preeclampsia was divided into early onset preeclampsia is occur at less 34 weeks of gestation age. Early and late onset preeclampsia have different etiology and should be considered as different disease as there are difference in clinical manifestation, maternal and perinatal outcome, prognosis and complication.Methods: An analytic observational study involving retrospective data done at RL Jalappa Hospital, Sri Devaraj Urs Medical College, Kolar. 217 women with singleton pregnancies with Pre eclampsia who were admitted and delivered in our hospital between June 2016 and May 2017 were recruited for this retrospective study.Results: The results showed that the incidence of EOPE (27.6%) was lower than LOPE (72.4%). Diastolic blood pressure is significantly higher in EOPE compared to LOPE. Complications in perinatal outcomes such as low birth weight (<2500 gram) are more in EOPE (98.3%) compared to LOPE (45.2%) and asphyxia is more on EOPE (11.7%) compared to LOPE (1.3%). Stillbirth in EOPE (15%) is more than LOPE group (3.2%).Conclusions: It is observed that EOPE incidence rate is lower than LOPE. Maternal and perinatal complications are greater in the EOPE group

Sixteen years of Collaborative Learning through Active Sense-making in Physics (CLASP) at UC Davis

This paper describes our large reformed introductory physics course at UC Davis, which bioscience students have been taking since 1996. The central feature of this course is a focus on sense-making by the students during the five hours per week discussion/labs in which the students take part in activities emphasizing peer-peer discussions, argumentation, and presentations of ideas. The course differs in many fundamental ways from traditionally taught introductory physics courses. After discussing the unique features of CLASP and its implementation at UC Davis, various student outcome measures are presented showing increased performance by students who took the CLASP course compared to students who took a traditionally taught introductory physics course. Measures we use include upper-division GPAs, MCAT scores, FCI gains, and MPEX-II scores.Comment: Also submitted to American Journal of Physic

Role of dydrogesterone in the treatment of idiopathic IUGR

Background: a) To evaluate the therapeutic efficacy of dydrogesterone in the treatment of pregnant women with idiopathic fetal growth restriction. b) To compare the outcome with the control group receiving conventional treatment in the form of rest and high protein diet.Methods: Pregnant women with idiopathic IUGR between 28-34 weeks gestation were randomized to eitherGroup 1: Control group receiving conventional treatment in the form of rest and high protein diet (n=41).Group 2: Study group receiving dydrogesterone (n=43)Primary outcome were compared in terms of fetal birth weight, apgar at birth, perinatal morbidity and mortality. Secondary outcomes in terms of changes in Doppler indices, gestational age at delivery, requirement for inductions, need for cesarean sections for IUGR, fetal distress in labour were compared.Results: Average fetal birth weight in kg were (1.71± 0.37 vs 2.03 ± 0.4, p=S), poor apgar scores (29.3% vs 20.9%, p=NS), nursery admissions (46% vs 18.6%, p=S), perinatal mortality (7.3% vs 4.7%, p=NS) in the control and study group respectively. Average gestational age at delivery was 36.4± 2.34 vs 36.9 ± 1.93 weeks (p=NS) in the control and study group respectively. Labour inductions were similar and cesarean section rates were significantly more in the control group as compared to the study group  receiving dydrogesterone (39% vs 23.3%, p=S).Conclusion: Dydrogesterone for the treatment of IUGR looks promising as it favourably affects the fetal birth weight and nursery stay

Hypertensive disorders in twin pregnancy

Objective: To compare the incidence and severity of pregnancy-induced hypertensive disorders in twin pregnancy and in singleton gestation. Study design: Case-control study in the setting of a University Hospital. Each pregnancy of a consecutive series of 187 twin pregnancies attending the antenatal clinic and booked before a gestational age of 24 weeks was matched for maternal age, parity, and gestational age at delivery with a singleton pregnancy delivered in the same year. Primary end points of the analysis of the course and outcome of pregnancy were pregnancy-induced hypertension and proteinuric pre-eclampsi. Results: In the twin pregnancy group, 21% of patients met the criteria for the diagnosis of a pregnancy-induced hypertensive disorder, compared with 13% in the singleton pregnancy group (P < 0.05). The difference was due to a significantly higher incidence of pregnancy-induced hypertension in twin (15%) than in singleton (6%) pregnancy (P < 0.05), in particular in nulliparous women. The incidence of pre-eclampsia was similar in twin (6%) and singleton pregnancies (6.5%), without a difference in severity and in the occurrence of the HELLP syndrome. Conclusion: The incidence of non-proteinuric pregnancy-induced hypertension, but not of proteinuric pre-eclampsia, is increased in twin pregnancy

A description of the methods of the aspirin supplementation for pregnancy indicated risk reduction in nulliparas (ASPIRIN) study

Background: Preterm birth (PTB) remains the leading cause of neonatal mortality and long term disability throughout the world. Though complex in its origins, a growing body of evidence suggests that first trimester administration of low dose aspirin (LDA) may substantially reduce the rate of PTB.Methods: Hypothesis: LDA initiated in the first trimester reduces the risk of preterm birth. Study Design Type: Prospective randomized, placebo-controlled, double-blinded multi-national clinical trial conducted in seven low and middle income countries. Trial will be individually randomized with one-to-one ratio (intervention/control) Population: Nulliparous women between the ages of 14 and 40, with a singleton pregnancy between 6 0/7 weeks and 13 6/7 weeks gestational age (GA) confirmed by ultrasound prior to enrollment, no more than two previous first trimester pregnancy losses, and no contraindications to aspirin.Intervention: Daily administration of low dose (81 mg) aspirin, initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA, compared to an identical appearing placebo. Compliance and outcomes will be assessed biweekly.Outcomes: Primary outcome: Incidence of PTB (birth prior to 37 0/7 weeks GA). Secondary outcomes Incidence of preeclampsia/eclampsia, small for gestational age and perinatal mortality.Discussion: This study is unique as it will examine the impact of LDA early in pregnancy in low-middle income countries with preterm birth as a primary outcome. The importance of developing low-cost, high impact interventions in low-middle income countries is magnified as they are often unable to bear the financial costs of treating illness

Rapid genotyping of the human renin (REN) gene by the LightCycler® instrument: Identification of unexpected nucleotide substitutions within the selected hybridization probe area

Preeclampsia is a serious disorder affecting nearly 3% of all in the Western world. It is associated with hypertension and proteinuria, and several lines of evidence suggest that the renin-angiotensin system (RAS) may be involved in the development of hypertension at different stages of a preeclamptic pregnancy. In this study, we developed rapid genotyping assays on the LightCycler® instrument to allow the detection of genetic variants in the renin gene (REN) that may predispose to preeclampsia. The method is based on real-time PCR and allele-specific hybridization probes, followed by fluorescent melting curve analysis to expose a change in melting temperature (Tm). Ninety-two mother-father-child triads (n=276) from preeclamptic pregnancies were genotyped for three haplotype-tagging single nucleotide polymorphisms (htSNPs) in REN. All three htSNPs (rs5705, rs1464816 and rs3795575) were successfully genotyped. Furthermore, two unexpected nucleotide substitutions (rs11571084 and rs61757041) were identified within the selected hybridization probe area of rs1464816 and rs3795575 due to aberrant melting peaks. In conclusion, genotyping on the LightCycler® instrument proved to be rapid and highly reproducible. The ability to uncover additional nucleotide substitutions is particularly important in that it allows the identification of potentially etiological variants that might otherwise be overlooked by other genotyping methods.publishedVersio