James J. Walker

Combinations of Maternal KIR and Fetal HLA-C Genes Influence the Risk of Preeclampsia and Reproductive Success

Preeclampsia is a serious complication of pregnancy in which the fetus receives an inadequate supply of blood due to failure of trophoblast invasion. There is evidence that the condition has an immunological basis. The only known polymorphic histocompatibility antigens on the fetal trophoblast are HLA-C molecules. We tested the idea that recognition of these molecules by killer immunoglobulin receptors (KIRs) on maternal decidual NK cells is a key factor in the development of preeclampsia. Striking differences were observed when these polymorphic ligand: receptor pairs were considered in combination. Mothers lacking most or all activating KIR (AA genotype) when the fetus possessed HLA-C belonging to the HLA-C2 group were at a greatly increased risk of preeclampsia. This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative. Thus, this interaction between maternal KIR and trophoblast appears not to have an immune function, but instead plays a physiological role related to placental development. Different human populations have a reciprocal relationship between AA frequency and HLA-C2 frequency, suggesting selection against this combination. In light of our findings, reproductive success may have been a factor in the evolution and maintenance of human HLA-C and KIR polymorphisms.

Trends in postpartum hemorrhage in high resource countries: a review and recommendations from the International Postpartum Hemorrhage Collaborative Group

AbstractBackgroundPostpartum hemorrhage (PPH) is a major cause of maternal mortality and morbidity worldwide. Several recent publications have noted an increasing trend in incidence over time. The international PPH collaboration was convened to explore the observed trends and to set out actions to address the factors identified.MethodsWe reviewed available data sources on the incidence of PPH over time in Australia, Belgium, Canada, France, the United Kingdom and the USA. Where information was available, the incidence of PPH was stratified by cause.ResultsWe observed an increasing trend in PPH, using heterogeneous definitions, in Australia, Canada, the UK and the USA. The observed increase in PPH in Australia, Canada and the USA was limited solely to immediate/atonic PPH. We noted increasing rates of severe adverse outcomes due to hemorrhage in Australia, Canada, the UK and the USA.ConclusionKey Recommendations 1. Future revisions of the International Classification of Diseases should include separate codes for atonic PPH and PPH immediately following childbirth that is due to other causes. Also, additional codes are required for placenta accreta/percreta/increta.2. Definitions of PPH should be unified; further research is required to investigate how definitions are applied in practice to the coding of data.3. Additional improvement in the collection of data concerning PPH is required, specifically including a measure of severity.4. Further research is required to determine whether an increased rate of reported PPH is also observed in other countries, and to further investigate potential risk factors including increased duration of labor, obesity and changes in second and third stage management practice.5. Training should be provided to all staff involved in maternity care concerning assessment of blood loss and the monitoring of women after childbirth. This is key to reducing the severity of PPH and preventing any adverse outcomes.6. Clinicians should be more vigilant given the possibility that the frequency and severity of PPH has in fact increased. This applies particularly to small hospitals with relatively few deliveries where management protocols may not be defined adequately and drugs or equipment may not be on hand to deal with unexpected severe PPH.

Randomised clinical trials of fish oil supplementation in high risk pregnancies

Objective To test the postulated preventive effects of dietary n‐3 fatty acids on pre‐term delivery, intrauterine growth retardation, and pregnancy induced hypertension.

Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2

Many common disorders of pregnancy are attributed to insufficient invasion of the uterine lining by trophoblast, fetal cells that are the major cell type of the placenta. Interactions between fetal trophoblast and maternal uterine NK (uNK) cells--specifically interactions between HLA-C molecules expressed by the fetal trophoblast cells and killer Ig-like receptors (KIRs) on the maternal uNK cells--influence placentation in human pregnancy. Consistent with this, pregnancies are at increased risk of preeclampsia in mothers homozygous for KIR haplotype A (KIR AA). In this study, we have demonstrated that trophoblast expresses both paternally and maternally inherited HLA-C surface proteins and that maternal KIR AA frequencies are increased in affected pregnancies only when the fetus has more group 2 HLA-C genes (C2) than the mother. These data raise the possibility that there is a deleterious allogeneic effect stemming from paternal C2. We found that this effect also occurred in other pregnancy disorders (fetal growth restriction and recurrent miscarriage), indicating a role early in gestation for these receptor/ligand pairs in the pathogenesis of reproductive failure. Notably, pregnancy disorders were less frequent in mothers that possessed the telomeric end of the KIR B haplotype, which contains activating KIR2DS1. In addition, uNK cells expressed KIR2DS1, which bound specifically to C2+ trophoblast cells. These findings highlight the complexity and central importance of specific combinations of activating KIR and HLA-C in maternal-fetal immune interactions that determine reproductive success.

Genetic and familial predisposition to eclampsia and pre‐eclampsia in a defined population

Summary. Familial predisposition and patterns of genetic inheritance of eclampsia and pre‐eclampsia were investigated through three or four generations in 94 families from the homogenous island population of Iceland. The families descended from index women delivered in the years 1931–47 and who had either eclampsia (n = 38) or severe preeclampsia (n = 69). Inheritance was followed both through sons and daughters. The prevalence of pre‐eclampsia and eclampsia in daughters was significantly higher (23%) than that in daughters‐in‐law (10%). No difference was noted in the prevalence of these diseases by whether the daughter was born of an eclamptic or pre‐eclamptic mother or whether she was a first or later born daughter. There was a non‐significantly higher occurrence of pre‐eclampsia among grand‐daughters than in grand‐daughters‐in‐law. No difference was seen by whether granddaughters descended through sons or daughters. With increasing numbers of affected daughters or grand‐daughters the probability rose of finding more affected women in a family. Hypotheses of single recessive and dominant gene inheritance were compared and maximum likelihood estimates for gene frequency obtained. For a single recessive gene model this was 0.31 reflecting a population prevalence of 9.6%, whereas a dominant model with incomplete penetrance gave 0.14 at 48% gene penetrance, corresponding to a population prevalence of 0.9% homozygous expression of severe disease and 11% heterozygous expression of milder disease. Either genetic model could fit the data.

Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort

Objectives To develop a predictive model for pre-eclampsia based on clinical risk factors for nulliparous women and to identify a subgroup at increased risk, in whom specialist referral might be indicated. Design Prospective multicentre cohort. Setting Five centres in Auckland, New Zealand; Adelaide, Australia; Manchester and London, United Kingdom; and Cork, Republic of Ireland. Participants 3572 “healthy” nulliparous women with a singleton pregnancy from a large international study; data on pregnancy outcome were available for 3529 (99%). Main outcome measure Pre-eclampsia defined as ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both, on at least two occasions four hours apart after 20 weeks’ gestation but before the onset of labour, or postpartum, with either proteinuria or any multisystem complication. Preterm pre-eclampsia was defined as women with pre-eclampsia delivered before 37+0 weeks’ gestation. In the stepwise logistic regression the comparison group was women without pre-eclampsia. Results Of the 3529 women, 186 (5.3%) developed pre-eclampsia, including 47 (1.3%) with preterm pre-eclampsia. Clinical risk factors at 14-16 weeks’ gestation were age, mean arterial blood pressure, body mass index (BMI), family history of pre-eclampsia, family history of coronary heart disease, maternal birth weight, and vaginal bleeding for at least five days. Factors associated with reduced risk were a previous single miscarriage with the same partner, taking at least 12 months to conceive, high intake of fruit, cigarette smoking, and alcohol use in the first trimester. The area under the receiver operating characteristics curve (AUC), under internal validation, was 0.71. Addition of uterine artery Doppler indices did not improve performance (internal validation AUC 0.71). A framework for specialist referral was developed based on a probability of pre-eclampsia generated by the model of at least 15% or an abnormal uterine artery Doppler waveform in a subset of women with single risk factors. Nine per cent of nulliparous women would be referred for a specialist opinion, of whom 21% would develop pre-eclampsia. The relative risk for developing pre-eclampsia and preterm pre-eclampsia in women referred to a specialist compared with standard care was 5.5 and 12.2, respectively. Conclusions The ability to predict pre-eclampsia in healthy nulliparous women using clinical phenotype is modest and requires external validation in other populations. If validated, it could provide a personalised clinical risk profile for nulliparous women to which biomarkers could be added. Trial registration ACTRN12607000551493.

Randomised comparative trial of the levonorgestrel intrauterine system and norethisterone for treatment of idiopathic menorrhagia.

Objective To compare the efficacy and acceptability of the levonorgestrel intrauterine system and norethisterone for the treatment of idiopathic menorrhagia.

Antioxidant systems in normal pregnancy and in pregnancy-induced hypertension

Increased free radical activity has been implicated in the pathogenesis of pregnancy-induced hypertension. This article investigates whether changes in antioxidant systems contribute to this condition. Two extracellular (plasma thiols and ceruloplasmin) and two intracellular (red blood cell lysate thiols and red blood cell superoxide dismutase) antioxidant markers were assayed in 25 nonpregnant women, 16 pregnant women with normal blood pressure, 19 women with pregnancy-induced hypertension, and 13 women with proteinuric pregnancy-induced hypertension. In the normotensive pregnant group (in comparison with the nonpregnant group) the plasma thiol level was reduced (p less than 0.001) and the ceruloplasmin level raised (p less than 0.005), suggesting increased free radical activity. The lysate thiol level increased (p less than 0.005), which may reflect a compensatory protective response. In the hypertensive pregnant groups the lysate thiol rise was not present. These red blood cells may be more prone to oxidative stress. Whether this situation is a cause or an effect of oxidative stress in pregnancy-induced hypertension has yet to be elucidated.

Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model

BACKGROUND Pre-eclampsia is a leading cause of maternal deaths. These deaths mainly result from eclampsia, uncontrolled hypertension, or systemic inflammation. We developed and validated the fullPIERS model with the aim of identifying the risk of fatal or life-threatening complications in women with pre-eclampsia within 48 h of hospital admission for the disorder. METHODS We developed and internally validated the fullPIERS model in a prospective, multicentre study in women who were admitted to tertiary obstetric centres with pre-eclampsia or who developed pre-eclampsia after admission. The outcome of interest was maternal mortality or other serious complications of pre-eclampsia. Routinely reported and informative variables were included in a stepwise backward elimination regression model to predict the adverse maternal outcome. We assessed performance using the area under the curve (AUC) of the receiver operating characteristic (ROC). Standard bootstrapping techniques were used to assess potential overfitting. FINDINGS 261 of 2023 women with pre-eclampsia had adverse outcomes at any time after hospital admission (106 [5%] within 48 h of admission). Predictors of adverse maternal outcome included gestational age, chest pain or dyspnoea, oxygen saturation, platelet count, and creatinine and aspartate transaminase concentrations. The fullPIERS model predicted adverse maternal outcomes within 48 h of study eligibility (AUC ROC 0·88, 95% CI 0·84-0·92). There was no significant overfitting. fullPIERS performed well (AUC ROC >0·7) up to 7 days after eligibility. INTERPRETATION The fullPIERS model identifies women at increased risk of adverse outcomes up to 7 days before complications arise and can thereby modify direct patient care (eg, timing of delivery, place of care), improve the design of clinical trials, and inform biomedical investigations related to pre-eclampsia. FUNDING Canadian Institutes of Health Research; UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction; Preeclampsia Foundation; International Federation of Obstetricians and Gynecologists; Michael Smith Foundation for Health Research; and Child and Family Research Institute.

Haemorrhagic problems in obstetrics and gynaecology in patients with congenital coagulopathies

Objective— To review the obstetric and gynaecological problems in women with congenital coagulopathies.