GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy.

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal GDF15 gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant in GDF15 which strongly predisposes mothers to HG, particularly when the fetus is wild-type, was found to markedly impair cellular secretion of GDF15 and associate with low circulating levels of GDF15 in the non-pregnant state. Consistent with this, two common GDF15 haplotypes which predispose to HG were associated with lower circulating levels outside pregnancy. The administration of a long-acting form of GDF15 to wild-type mice markedly reduced subsequent responses to an acute dose, establishing that desensitisation is a feature of this system. GDF15 levels are known to be highly and chronically elevated in patients with beta thalassemia. In women with this disorder, reports of symptoms of nausea or vomiting in pregnancy were strikingly diminished. Our findings support a causal role for fetal derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to GDF15, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Neonatal outcomes of twins according to birth order, presentation and mode of delivery: a systematic review and meta-analysis.

BACKGROUND: The optimal mode of delivery for twins is undetermined. OBJECTIVE: To review literature regarding the neonatal outcomes following twin delivery. DATA SOURCES: Searches were conducted in PubMed, Medline, Embase, Cochrane library and reference lists. SELECTION CRITERIA: Studies selection criteria were: both twins alive at labour, outcomes stratified for birth order, presentation, planned and actual delivery mode. Eighteen articles were included in the meta-analysis (39, 571 twin sets). DATA COLLECTION AND ANALYSIS: The Meta-analysis of Observational Studies in Epidemiology guidelines were followed. Interstudy heterogeneity (I(2) ) was tested. A fixed model was generated whenever I(2)<25%. Pooled odds ratios (OR) with 95% CI were computed. Intergroup comparison was significant if 95% CI did not encompass 1. The first and second twins were indicated as Twin A (TA) and Twin B (TB), respectively. MAIN RESULTS: Neonatal morbidity was lower in TA than TB (3.0 versus 4.6%; OR 0.53; 95% CI 0.39-0.70). TA experienced neonatal death less often than TB (0.3 versus 0.6%; OR 0.55; 95% CI 0.38-0.81). No differences were noted between vertex and non-vertex and attempted vaginal delivery versus planned caesarean section in either TA or TB. In TA, neonatal morbidity was lower after vaginal delivery (1.1%) than caesarean section (2.2%; OR 0.47; 95% CI 0.27-0.82). Neonatal death was not associated with actual delivery mode. In TB, morbidity following combined delivery (19.8%) was higher than after vaginal delivery (9.5%; OR 0.55; 95% CI 0.41-0.74) or caesarean section (9.8%; OR 0.47; 95% CI 0.43-0.53). When outcomes were stratified for both presentation and delivery mode, mortality rate was lower after vaginal delivery than caesarean section for both vertex and nonvertex TB. AUTHOR'S CONCLUSION: An attempt at vaginal delivery should be considered in twin pregnancies with vertex/vertex presentation.

Labor induction utilizing the Foley balloon: a randomized trial comparing standard placement versus immediate removal.

OBJECTIVE: To compare time to delivery between two induction procedures. The Foley balloon is a mechanical method for cervical ripening. However, the device may also result in endogenous prostaglandin release following separation of the chorionic membrane and decidua. Prolonged Foley placement may therefore be unnecessary for successful labor induction. METHOD: Randomized controlled trial of labor induction at LAC+USC Medical Center between 2010 and 2013. Subjects were assigned to either (a) standard placement of the Foley balloon or (b) Foley balloon insufflation and immediate removal. Oxytocin was administered to all subjects not in active labor after 12 h. Delivery information and neonatal outcomes were documented and all patients were followed for 6 weeks for adverse events. RESULT: A total of 79 women were included in the analysis (37 standard and 42 immediate). Induction time was 8.6 h longer in the immediate removal group (23.5 vs 32.1, P=0.002), but the difference in delivery within 24 h did not meet the statistical significance (46.0 vs 28.6%, P=0.11). Similar rates of cesarean delivery, epidural use and abnormal APGAR scores were observed. After controlling for number of vaginal exams and duration of rupture, a decreased risk of infection was observed in the immediate removal group (odds ratio=0.08, 95% confidence interval=0.007 to 0.93, P=0.04). Further, when the analysis was stratified by parity, differences in induction time only persisted in nulliparous women. CONCLUSION: Immediate removal of the Foley balloon may lead to longer overall induction time, but a lower risk of infection. Parous women may be particularly good candidates for this type of induction.

No increased risk of psychological/behavioral disorders in siblings of women with hyperemesis gravidarum (HG) unless their mother had HG.

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, is characterized by prolonged maternal stress, undernutrition and dehydration. Maternal stress and malnutrition of pregnancy are linked to poor neonatal outcome and associated with poor adult health, and we recently showed that in utero exposure to HG may lead to increased risks of psychological and behavioral disorders in the offspring. In addition, we have shown familial aggregation of HG, which is strong evidence for a genetic component to the disease. In this study, we compare the rates of psychological and behavioral disorders in 172 adults with and 101 adults without a sibling with HG. The rate of emotional/behavioral disorders is identical (15%) in both groups. The results suggest that the etiology of HG is not likely to include genetic factors associated with emotional and behavioral disorders. In addition, this study provides evidence that the increased incidence of psychological/behavioral disorders among offspring of women with HG is attributable to the HG pregnancy itself, rather than to confounding genetic factors linked to HG.

Prenatal exposure to hyperemesis gravidarum linked to increased risk of psychological and behavioral disorders in adulthood.

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, is characterized by long-term maternal stress, undernutrition and dehydration. While maternal stress and malnutrition of pregnancy are linked to poor neonatal outcome and associated with poor adult health, long-term outcome of fetal exposure to HG has never been explored. The purpose of this study is to determine whether long-term emotional and behavioral diagnoses may be associated with fetal exposure to HG. Emotional and behavioral diagnoses of adults born of a pregnancy complicated by HG were compared to diagnoses from non-exposed controls. Offspring exposed to HG in utero were significantly more likely to have a psychological and behavioral disorder (OR = 3.6, P < 0.0001) with diagnoses primarily of depression, bipolar disorder and anxiety. In utero exposure to HG may lead to increased risks of psychological and behavioral disorders in the offspring.