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.

A critical review of the Cochrane meta-analysis of routine late-pregnancy ultrasound.

A Cochrane review of universal late-pregnancy ultrasound has been highly influential in guiding UK practice, concluding that it does not improve outcome. However, the meta-analysis combines trials that used diverse definitions of screen positive, were designed in the absence of high-quality data on diagnostic effectiveness and did not couple screening to an effective intervention. Moreover, even if the trials had combined a highly effective screening test with a highly effective intervention, the sample size was 15% of that required to study perinatal death. It is not known whether universal late-pregnancy ultrasound confers benefit on the mother or baby. TWEETABLE ABSTRACT: Despite >50 years of research, we do not know whether universal late-pregnancy ultrasound confers benefit on the mother or baby.

Can risk prediction models help us individualise stillbirth prevention? A systematic review and critical appraisal of published risk models.

BACKGROUND: Stillbirth prevention is an international priority - risk prediction models could individualise care and reduce unnecessary intervention, but their use requires evaluation. OBJECTIVES: To identify risk prediction models for stillbirth, and assess their potential accuracy and clinical benefit in practice. SEARCH STRATEGY: MEDLINE, Embase, DH-DATA and AMED databases were searched from inception to June 2019 using terms relevant to stillbirth, perinatal mortality and prediction models. The search was compliant with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. SELECTION CRITERIA: Studies developing and/or validating prediction models for risk of stillbirth developed for application during pregnancy. DATA COLLECTION AND ANALYSIS: Study screening and data extraction were conducted in duplicate, using the CHARMS checklist. Risk of bias was appraised using the PROBAST tool. RESULTS: The search identified 2751 citations. Fourteen studies reporting development of 69 models were included. Variables consistently included were: ethnicity, body mass index, uterine artery Doppler, pregnancy-associated plasma protein and placental growth factor. For almost all models there were significant concerns about risk of bias. Apparent model performance (i.e. in the development dataset) was highest in models developed for use later in pregnancy and including maternal characteristics, and ultrasound and biochemical variables, but few were internally validated and none were externally validated. CONCLUSIONS: Almost all models identified were at high risk of bias. There are first-trimester models of possible clinical benefit in early risk stratification; these require validation and clinical evaluation. There were few later pregnancy models but, if validated, these could be most relevant to individualised discussions around timing of birth. TWEETABLE ABSTRACT: Prediction models using maternal factors, blood tests and ultrasound could individualise stillbirth prevention, but existing models are at high risk of bias.

Prediction of stillbirth: an umbrella review of evaluation of prognostic variables.

BACKGROUND: Stillbirth accounts for over 2 million deaths a year worldwide and rates remains stubbornly high. Multivariable prediction models may be key to individualised monitoring, intervention or early birth in pregnancy to prevent stillbirth. OBJECTIVES: To collate and evaluate systematic reviews of factors associated with stillbirth in order to identify variables relevant to prediction model development. SEARCH STRATEGY: MEDLINE, Embase, DARE and Cochrane Library databases and reference lists were searched up to November 2019. SELECTION CRITERIA: We included systematic reviews of association of individual variables with stillbirth without language restriction. DATA COLLECTION AND ANALYSIS: Abstract screening and data extraction were conducted in duplicate. Methodological quality was assessed using AMSTAR and QUIPS criteria. The evidence supporting association with each variable was graded. RESULTS: The search identified 1198 citations. Sixty-nine systematic reviews reporting 64 variables were included. The most frequently reported were maternal age (n = 5), body mass index (n = 6) and maternal diabetes (n = 5). Uterine artery Doppler appeared to have the best performance of any single test for stillbirth. The strongest evidence of association was for nulliparity and pre-existing hypertension. CONCLUSION: We have identified variables relevant to the development of prediction models for stillbirth. Age, parity and prior adverse pregnancy outcomes had a more convincing association than the best performing tests, which were PAPP-A, PlGF and UtAD. The evidence was limited by high heterogeneity and lack of data on intervention bias. TWEETABLE ABSTRACT: Review shows key predictors for use in developing models predicting stillbirth include age, prior pregnancy outcome and PAPP-A, PLGF and Uterine artery Doppler.

The cost-effectiveness of universal late-pregnancy screening for macrosomia in nulliparous women: a decision analysis.

OBJECTIVE: To identify the most cost-effective policy for detection and management of fetal macrosomia in late-stage pregnancy. DESIGN: Health economic simulation model. SETTING: All English NHS antenatal services. POPULATION: Nulliparous women in the third trimester treated within the UK NHS. METHODS: A health economic simulation model was used to compare long-term maternal-fetal health and cost outcomes for two detection strategies (universal ultrasound scanning at approximately 36 weeks of gestation versus selective ultrasound scanning), combined with three management strategies (planned caesarean section versus induction of labour versus expectant management) of suspected fetal macrosomia. Probabilities, costs and health outcomes were taken from literature. MAIN OUTCOME MEASURES: Expected costs to the NHS and quality-adjusted life-years (QALYs) gained from each strategy, calculation of net benefit and hence identification of most cost-effective strategy. RESULTS: Compared with selective ultrasound, universal ultrasound increased QALYs by 0.0038 (95% CI 0.0012-0.0076), but also costs by £123.50 (95% CI 99.6-149.9). Overall, the health gains were too small to justify the cost increase given current UK thresholds cost-effective policy was selective ultrasound coupled with induction of labour where macrosomia was suspected. CONCLUSIONS: The most cost-effective policy for detection and management of fetal macrosomia is selective ultrasound scanning coupled with induction of labour for all suspected cases of macrosomia. Universal ultrasound scanning for macrosomia in late-stage pregnancy is not cost-effective. TWEETABLE ABSTRACT: Universal late-pregnancy ultrasound screening for fetal macrosomia is not warranted.

Evaluation of a simple risk score to predict preterm pre-eclampsia using maternal characteristics: a prospective cohort study.

OBJECTIVES: (1) To derive a simple risk score for preterm pre-eclampsia based on the model used in the ASPRE trial, and (2) to compare it (i) with the original ASPRE algorithm, (ii) with the NICE Guideline score, and (iii) with and without biochemical and ultrasonic predictors. DESIGN: Prospective cohort study. SETTING: Cambridge, UK. POPULATION OR SAMPLE: 4184 nulliparous women from the Pregnancy Outcome Prediction study. METHODS: Maternal history model coefficients from the ASPRE algorithm were translated into a risk score, preserving the relative weight of each coefficient. MAIN OUTCOME MEASURES: Preterm delivery with a diagnosis of pre-eclampsia. RESULTS: The area under the ROC curve (AUC) for preterm pre-eclampsia was 0.846 (95% CI 0.787-0.906) for the risk score and 0.854 (95% CI 0.795-0.914) for the original ASPRE algorithm (P = 0.14). In all, 9.1% of women had a risk score of ≥30 and their risk ratio for preterm pre-eclampsia was 13.3 (95% CI 6.3-27.8), sensitivity 57.1% (37.5-74.8%), false-positive rate (1-specificity) 8.8% (8.0-9.7%), and LR+ 6.5 (4.6-9.1). The score had higher specificity than the NICE Guideline criteria. First trimester levels of PAPP-A and PlGF were not predictive when included in a model with the risk score. In contrast, mean arterial pressure at booking and 20-week uterine artery Doppler were independently associated with preterm pre-eclampsia and the latter modestly increased the AUC (by ~0.02). CONCLUSIONS: A simple risk score derived from the ASPRE screening study predictive model provided clinically useful prediction of the risk of preterm pre-eclampsia. TWEETABLE ABSTRACT: A simple risk score derived from the ASPRE screening study provided clinically useful prediction of the risk of preterm pre-eclampsia.

Making stillbirths visible: a systematic review of globally reported causes of stillbirth.

BACKGROUND: Stillbirth is a global health problem. The World Health Organization (WHO) application of the International Classification of Diseases for perinatal mortality (ICD-PM) aims to improve data on stillbirth to enable prevention. OBJECTIVES: To identify globally reported causes of stillbirth, classification systems, and alignment with the ICD-PM. SEARCH STRATEGY: We searched CINAHL, EMBASE, Medline, Global Health, and Pubmed from 2009 to 2016. SELECTION CRITERIA: Reports of stillbirth causes in unselective cohorts. DATA COLLECTION AND ANALYSIS: Pooled estimates of causes were derived for country representative reports. Systems and causes were assessed for alignment with the ICD-PM. Data are presented by income setting (low, middle, and high income countries; LIC, MIC, HIC). MAIN RESULTS: Eighty-five reports from 50 countries (489 089 stillbirths) were included. The most frequent categories were Unexplained, Antepartum haemorrhage, and Other (all settings); Infection and Hypoxic peripartum (LIC), and Placental (MIC, HIC). Overall report quality was low. Only one classification system fully aligned with ICD-PM. All stillbirth causes mapped to ICD-PM. In a subset from HIC, mapping obscured major causes. CONCLUSIONS: There is a paucity of quality information on causes of stillbirth globally. Improving investigation of stillbirths and standardisation of audit and classification is urgently needed and should be achievable in all well-resourced settings. Implementation of the WHO Perinatal Mortality Audit and Review guide is needed, particularly across high burden settings. FUNDING: HR, SH, SHL, and AW were supported by an NHMRC-CRE grant (APP1116640). VF was funded by an NHMRC-CDF (APP1123611). TWEETABLE ABSTRACT: Urgent need to improve data on causes of stillbirths across all settings to meet global targets. PLAIN LANGUAGE SUMMARY: Background and methods Nearly three million babies are stillborn every year. These deaths have deep and long-lasting effects on parents, healthcare providers, and the society. One of the major challenges to preventing stillbirths is the lack of information about why they happen. In this study, we collected reports on the causes of stillbirth from high-, middle-, and low-income countries to: (1) Understand the causes of stillbirth, and (2) Understand how to improve reporting of stillbirths. Findings We found 85 reports from 50 different countries. The information available from the reports was inconsistent and often of poor quality, so it was hard to get a clear picture about what are the causes of stillbirth across the world. Many different definitions of stillbirth were used. There was also wide variation in what investigations of the mother and baby were undertaken to identify the cause of stillbirth. Stillbirths in all income settings (low-, middle-, and high-income countries) were most frequently reported as Unexplained, Other, and Haemorrhage (bleeding). Unexplained and Other are not helpful in understanding why a baby was stillborn. In low-income countries, stillbirths were often attributed to Infection and Complications during labour and birth. In middle- and high-income countries, stillbirths were often reported as Placental complications. Limitations We may have missed some reports as searches were carried out in English only. The available reports were of poor quality. Implications Many countries, particularly those where the majority of stillbirths occur, do not report any information about these deaths. Where there are reports, the quality is often poor. It is important to improve the investigation and reporting of stillbirth using a standardised system so that policy makers and healthcare workers can develop effective stillbirth prevention programs. All stillbirths should be investigated and reported in line with the World Health Organization standards.

Labour induction near term for women aged 35 or over: an economic evaluation.

OBJECTIVE: Induction of labour at 39 weeks for nulliparous women aged 35 years and over may prevent stillbirths and does not increase caesarean births, so it may be popular. But the overall costs and benefits of such a policy have not been compared. DESIGN: A cost-utility analysis alongside a randomised controlled trial (the 35/39 trial). SETTING: Obstetric departments of 38 UK National Health Service hospitals and one UK primary-care trust. POPULATION: Nulliparous women aged 35 years or over on their expected due date, with a singleton live fetus in a cephalic presentation. METHODS: Costs were estimated from the National Health Service and Personal Social Services perspective and quality-adjusted life-years (QALYs) were calculated based on patient responses to the EQ-5D at baseline and 4 weeks. MAIN OUTCOME MEASURES: Data on antenatal care, mode of delivery, analgesia in labour, method of induction, EQ-5D (baseline and 4 weeks postnatal) and participant-administered postnatal health resource use data were collected. RESULTS: The intervention was associated with a mean cost saving of £263 and a small additional gain in QALYs (though this was not statistically significant), even without considering any possible QALY gains from stillbirth prevention. CONCLUSION: A policy of induction of labour at 39 weeks for women of advanced maternal age would save money. TWEETABLE ABSTRACT: A policy of induction of labour at 39 weeks of gestation for women of advanced maternal age would save money.

Previous caesarean delivery and the risk of unexplained stillbirth: retrospective cohort study and meta-analysis.

OBJECTIVE: To determine whether caesarean delivery in the first pregnancy is a risk factor for unexplained antepartum stillbirth in a second pregnancy. DESIGN: A population-based retrospective cohort study and meta-analysis. SETTING: All maternity units in Scotland. PARTICIPANTS: A cohort of 128 585 second births, 1999-2008. METHODS: Time-to-event analysis and random-effects meta-analysis. MAIN OUTCOME MEASURE: Risk of unexplained antepartum stillbirth in a second pregnancy. RESULTS: There were 88 stillbirths among 23 688 women with a previous caesarean delivery (2.34 per 10 000 women per week) and 288 stillbirths in 104 897 women who had previously delivered vaginally (1.67 per 10 000 women per week, P = 0.002). When analysed by cause, women with a previous caesarean delivery had an increased risk of unexplained stillbirth (hazard ratio, HR 1.47; 95% confidence interval, 95% CI 1.12-1.94; P = 0.006) and, as previously observed, the excess risk was apparent from 34 weeks of gestation onwards. The risk did not differ in relation to the indication of the caesarean delivery, and was independent of maternal characteristics and previous obstetric complications. We identified three other comparable studies (two in North America and one in Europe), and meta-analysis of these studies showed a statistically significant association between previous caesarean delivery and the risk of antepartum stillbirth in the second pregnancy (pooled HR 1.40; 95% CI 1.10-1.77; P = 0.006). CONCLUSIONS: Women who have had a previous caesarean delivery are at increased risk of unexplained stillbirth in the second pregnancy. TWEETABLE ABSTRACT: Caesarean first delivery is associated with an increased risk of unexplained stillbirth in the next pregnancy.

Previous miscarriage and the subsequent risk of preterm birth in Scotland, 1980-2008: a historical cohort study.

OBJECTIVE: To determine whether the relationship between previous miscarriage and risk of preterm birth changed over the period 1980-2008, and to determine whether the pattern varied according to the cause of the preterm birth. DESIGN: Linked birth databases. SETTING: All Scottish NHS hospitals. POPULATION: A total of 732 719 nulliparous women with a first live birth between 1980 and 2008. METHODS: Risk was estimated using logistic regression. MAIN OUTCOME MEASURES: Preterm birth, subdivided by cause (spontaneous, induced with a diagnosis of pre-eclampsia, or induced without a diagnosis of pre-eclampsia) and severity [extreme (24-28 weeks of gestation), moderate (29-32 weeks of gestation), and mild (33-36 weeks of gestation)]. RESULTS: Consistent with previous studies, previous miscarriage was associated with an increased risk of all-cause preterm birth (adjusted odds ratio, aOR 1.26; 95% confidence interval, 95% CI 1.22-1.29). This arose from associations with all subtypes. The strongest association was found with extreme preterm birth (aOR 1.73; 95% CI 1.57-1.90). Risk increased with the number of miscarriages. Women with three or more miscarriages had the greatest risk of all-cause preterm birth (aOR 2.14; 95% CI 1.93-2.38), and the strongest association was with extreme preterm birth (aOR 3.87; 95% CI 2.85-5.26). The strength of the association between miscarriage and preterm birth decreased from 1980 to 2008. This was because of weakening associations with spontaneous preterm birth and induced preterm birth without a diagnosis of pre-eclampsia. CONCLUSIONS: The association between a prior history of miscarriage and the risk of preterm birth declined in Scotland over the period 1980-2008. We speculate that changes in the methods of managing incomplete termination of pregnancy might explain the trend, through reduced cervical damage.