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.

External validation of prognostic models to predict stillbirth using International Prediction of Pregnancy Complications (IPPIC) Network database: individual participant data meta-analysis.

OBJECTIVE: Stillbirth is a potentially preventable complication of pregnancy. Identifying women at high risk of stillbirth can guide decisions on the need for closer surveillance and timing of delivery in order to prevent fetal death. Prognostic models have been developed to predict the risk of stillbirth, but none has yet been validated externally. In this study, we externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance. METHODS: MEDLINE, EMBASE, DH-DATA and AMED databases were searched from inception to December 2020 to identify studies reporting stillbirth prediction models. Studies that developed or updated prediction models for stillbirth for use at any time during pregnancy were included. IPD from cohorts within the International Prediction of Pregnancy Complications (IPPIC) Network were used to validate externally the identified prediction models whose individual variables were available in the IPD. The risk of bias of the models and cohorts was assessed using the Prediction study Risk Of Bias ASsessment Tool (PROBAST). The discriminative performance of the models was evaluated using the C-statistic, and calibration was assessed using calibration plots, calibration slope and calibration-in-the-large. Performance measures were estimated separately in each cohort, as well as summarized across cohorts using random-effects meta-analysis. Clinical utility was assessed using net benefit. RESULTS: Seventeen studies reporting the development of 40 prognostic models for stillbirth were identified. None of the models had been previously validated externally, and the full model equation was reported for only one-fifth (20%, 8/40) of the models. External validation was possible for three of these models, using IPD from 19 cohorts (491 201 pregnant women) within the IPPIC Network database. Based on evaluation of the model development studies, all three models had an overall high risk of bias, according to PROBAST. In the IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65 and summary calibration slopes ranging from 0.40 to 0.88, with risk predictions that were generally too extreme compared with the observed risks. The models had little to no clinical utility, as assessed by net benefit. However, there remained uncertainty in the performance of some models due to small available sample sizes. CONCLUSIONS: The three validated stillbirth prediction models showed generally poor and uncertain predictive performance in new data, with limited evidence to support their clinical application. The findings suggest methodological shortcomings in their development, including overfitting. Further research is needed to further validate these and other models, identify stronger prognostic factors and develop more robust prediction models. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Risk stratification for early-onset fetal growth restriction in women with abnormal serum biomarkers: a retrospective cohort study.

Abnormal maternal serum biomarkers (AMSB), identified through the aneuploidy screening programme, are frequent incidental findings in pregnancy. They are associated with fetal growth restriction (FGR), but previous studies have not examined whether this association is with early-onset (< 34 weeks) or late-onset (> 34 weeks) FGR; as a result there is no consensus on management. The aims of this study were to determine the prevalence and phenotype of FGR in women with AMSB and test the predictive value of placental sonographic screening to predict early-onset FGR. 1196 pregnant women with AMSB underwent a 21-24 week "placental screen" comprising fetal and placental size, and uterine artery Doppler. Multivariable regression was used to calculate a predictive model for early-onset FGR (birthweight centile < 3rd/< 10th with absent umbilical end-diastolic flow, < 34 weeks). FGR prevalence was high (10.3%), however early-onset FGR was uncommon (2.3%). Placental screening effectively identified early-onset (area under the curve (AUC) 0.93, 95% confidence interval (CI) 0.87-1.00), but not late-onset FGR (AUC 0.70, 95% CI 0.64-0.75). Internal validation demonstrated robust performance for detection/exclusion of early-onset FGR. In this cohort, utilisation of our proposed algorithm with targeted fetal growth and Doppler surveillance, compared with universal comprehensive surveillance would have avoided 1044 scans, potentiating significant cost-saving for maternity services.

UK stillbirth trends in over 11 million births provide no evidence to support effectiveness of Growth Assessment Protocol program.

OBJECTIVE: Use of the Growth Assessment Protocol (GAP) has increased internationally under the assumption that it reduces the stillbirth rate. The evidence for this is limited and based largely on an ecological time-trend study. Discordance in the uptake of the GAP program between Scotland and England/Wales enabled us to assess the assertion that implementation of GAP leads to a reduced stillbirth rate. METHODS: We analyzed data from the National Records for Scotland and the Office for National Statistics on the number of singleton maternities and stillbirths in Scotland and in England and Wales, respectively, from 1 January 2000 to 31 December 2015. National uptake of the GAP program over time in each of the regions was recorded. Stillbirth rate per 1000 maternities was calculated, according to year of delivery, and compared between Scotland and England/Wales. RESULTS: During the study period, there were 870 632 singleton maternities in Scotland, of which 4243 were stillbirths, and there were 10 469 120 singleton maternities in England and Wales, of which 51 562 were stillbirths. There was a marked difference in uptake of the GAP program between the two regions, with substantially fewer maternity units in Scotland implementing the program. Stillbirth rates were static up to 2010, with a decline thereafter in both regions, to 3.75 (95% CI, 3.25-4.30) per 1000 maternities in Scotland and 4.30 (95% CI, 4.15-4.46) per 1000 maternities in England and Wales in 2015. From 2010 onwards, the decline in Scotland was faster, equating to 48 (95% CI, 47.9-48.1) fewer stillbirths per 100 000 maternities in Scotland than in England and Wales from 2010 to 2015 compared with 2000 to 2009. CONCLUSIONS: We observed a decline in stillbirth rate in England and Wales, which coincided with implementation of the GAP program. However, a concurrent decline in stillbirth rate was observed in Scotland in the absence of increased implementation of GAP. The secular rates of change in stillbirth rate in England and Wales cannot be used to infer efficacy of the GAP program. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Blinded ultrasound fetal biometry at 36 weeks and risk of emergency Cesarean delivery in a prospective cohort study of low-risk nulliparous women.

OBJECTIVES: To compare the association between risk of emergency Cesarean delivery (CD) and non-customized vs customized ultrasound estimated fetal weight (EFW) at 36 weeks' gestation, determine whether addition of ultrasound EFW to a model based on maternal characteristics alone improved prediction of emergency CD, assess the screening performance of a multivariable model using both EFW and maternal characteristics to predict emergency CD, and determine whether women at high predicted risk of emergency CD based on this model had higher risk of maternal and perinatal morbidity compared with screen-negative women. METHODS: We studied 3047 low-risk (no pre-existing medical conditions or acquired complications of pregnancy) nulliparous women from the prospective Pregnancy Outcome Prediction study (Cambridge, UK) cohort, who underwent ultrasound EFW at ∼36 weeks' gestation. Both the women and their clinicians were blinded to fetal biometry results. Emergency CD was defined as delivery by Cesarean section in pregnancies in which the date of delivery had not been prearranged. Additional candidate predictors of emergency CD evaluated were maternal age, height, body mass index (BMI), weight gain, fetal abdominal circumference growth velocity and fetal sex. External validation of the predictive model was performed using routinely collected data from 55 337 births in Scotland between 2003 and 2008. Women with an estimated risk of emergency CD ≥ 40% were defined as screen positive. RESULTS: Blinded EFW was associated strongly with the risk of emergency CD (coefficient for increase of 1 SD in EFW, 0.39 (95% CI, 0.30-0.48); odds ratio (OR), 1.48 (95% CI, 1.35-1.62)). The coefficient for customized EFW was similar (0.42 (95% CI, 0.33-0.51); OR, 1.53 (95% CI, 1.39-1.67)); hence, for simplicity, non-customized EFW was employed subsequently. A multivariable logistic regression model combining maternal characteristics (age, height, BMI and weight gain between 12 and 36 weeks) was moderately predictive of emergency CD (area under the receiver-operating characteristics curve (AUC) = 0.68). Addition of blinded EFW to the model increased the AUC to 0.71 and improved prediction (likelihood-ratio test P < 0.0001). Based on this model, 189 (6.2%) women were screen positive and 48% of these delivered by CD. Screen-positive women had elevated risks of severe postpartum hemorrhage (relative risk (RR), 2.49; 95% CI, 1.83-3.38), any adverse neonatal outcome (RR, 1.86; 95% CI, 1.22-2.82) and severe adverse neonatal outcome (RR, 4.03; 95% CI, 1.35-12.03) compared with screen-negative women. The risks of these events were also higher compared with women who had a term CD for breech presentation. The model was similarly predictive of the risk of emergency CD and perinatal morbidity when evaluated using the dataset from Scotland. CONCLUSIONS: Ultrasound EFW at 36 weeks, combined with maternal characteristics, can identify women who are at increased risk of subsequent emergency CD. These women are at increased risk of maternal and perinatal morbidity compared with women at low risk of emergency CD and those having CD for breech presentation at term. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Universal vs selective ultrasonography to screen for large-for-gestational-age infants and associated morbidity.

OBJECTIVES: To compare the diagnostic effectiveness of selective vs universal ultrasonography as a screening test for large-for-gestational-age (LGA) infants, and to determine whether previously described ultrasound markers of excessive fetal growth could identify suspected LGA fetuses that are at increased risk of adverse neonatal outcome. METHODS: Data from the Pregnancy Outcome Prediction study, a prospective cohort study of nulliparous women with a viable singleton pregnancy at the time of the dating ultrasound scan, were analyzed. Women were selected for clinically indicated ultrasound assessment in the third trimester as per routine clinical care, and the results of these scans were reported ('selective ultrasonography'). In addition, all participants underwent research ultrasound scans, including estimated fetal weight (EFW) assessment, at around 36 weeks' gestation, in which both the women and their clinicians were blinded to the results ('universal ultrasonography'). Participants who attended the 36-week research scan and had a live birth at the Rosie Hospital were included in the study. Screen positive for LGA was defined as EFW > 90th percentile at ≥ 34 weeks. RESULTS: The current analysis included 3866 eligible women, of whom 1354 (35%) had a clinically indicated ultrasound scan at or after 34 weeks' gestation. A total of 177 (4.6%) infants had a birth weight > 90th percentile. The sensitivity for detection of LGA infants was 27% for selective ultrasonography and 38% for universal ultrasonography. The specificity of both approaches was high (99% and 97%, respectively). Using universal ultrasonography, neonatal outcome differed (P for interaction) by abdominal circumference growth velocity (ACGV) for both any neonatal morbidity (P = 0.08) and severe adverse neonatal outcome (P = 0.03). LGA fetuses with increased ACGV had a relative risk of any neonatal morbidity of 2.0 (95% CI, 1.1-3.6; P = 0.04) and of severe adverse neonatal outcome of 6.5 (95% CI, 2.0-21.1; P = 0.01), whereas LGA fetuses with normal ACGV were not at increased risk. CONCLUSIONS: Third-trimester screening of nulliparous women by universal ultrasound fetal biometry increases the detection rate of LGA infants and, combined with ACGV, identifies those at increased risk of adverse neonatal outcome. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Birth weight to placenta weight ratio and its relationship to ultrasonic measurements, maternal and neonatal morbidity: A prospective cohort study of nulliparous women.

INTRODUCTION: Birth weight to placenta weight (BWPW)-ratio is an indicator of the ability of the placenta to maintain adequate nutrient supply to the fetus. We sought to investigate the relationship between BWPW-ratio with fetal growth, utero-placental Doppler and neonatal and maternal morbidity. METHODS: We studied a group of 3311 women recruited to a prospective cohort study of nulliparous women (Rosie Hospital, Cambridge, UK) who delivered a live born infant at term and whose placental weight and birth weight were known. Ultrasonic indices and BWPW ratio were converted to gestational age adjusted z scores. Analysis of continuous variables was by multivariable linear regression. BWPW ratio was also categorized (lowest or highest quintile, both referent to quintiles 2 to 4) and associations with adverse outcomes analyzed using multivariable logistic regression. RESULTS: Lowest quintile of BWPW-ratio was associated (adjusted odds ratio [95% CI], P) with both neonatal morbidity (1.55 [1.12-2.14], 0.007) and maternal diabetes (1.75 [1.18-2.59], 0.005). Highest quintile of BWPW ratio was associated with a reduced risk of maternal obesity (0.71 [0.53 to 0.95], 0.02) and preeclampsia (0.51 [0.31 to 0.84], 0.008), but higher (adjusted z score [95% CI], P) uterine artery Doppler mean pulsatility index (PI) at 20 weeks of gestation (0.09 [0.01-0.18], 0.04) and umbilical artery Doppler PI at 36 weeks of gestation (0.16 [0.07-0.25], <0.001). CONCLUSION: BWPW-ratio is related to ultrasonic measurements and both neonatal and maternal morbidity. Therefore, this ratio may be an indicative marker of immediate and longer term health risks for an individual.

Uterine artery pulsatility and resistivity indices in pregnancy: Comparison of MRI and Doppler US.

OBJECTIVE: The aim of this work was to evaluate whether the uterine arteries (UtA) could be identified and their flow profiles measured during a fetal MRI examination. A comparison was performed against same day sonographic Doppler assessment. METHODS: 35 normal, healthy, singleton pregnancies at 28-32 weeks gestation underwent routine Doppler examination, followed by MRI examination. The resistivity index (RI) and pulsatility index (PI) of the left and right UtA were measured using phase contrast MRI. Bland Altman statistics were used to compare MRI and ultrasound results. RESULTS: Sixty-nine comparable vessels were analysed. Six vessels were excluded due to artefact or technical error. Bland-Altman analysis demonstrated the ultrasound indices were comparable, although systematically lower than the MRI indices; Right UtA RI bias -0.03 (95% limits of agreement (LOA) -0.27 to +0.20), and left UtA RI bias -0.06 (95% LOA -0.26 to +0.14); Right UtA PI bias -0.06 (95% LOA -0.50 to +0.38), Left UtA PI bias -0.11 (95% LOA -0.54 to +0.32). The inter-rater agreement for the MRI derived PI and RI analysis was good. CONCLUSION: This study demonstrates that in the majority of early third trimester pregnancies, the uterine arteries can be identified, and their flow profiles measured using MRI, and that the derived PI and RI values are comparable with Doppler ultrasound values.

The relationship between human placental morphometry and ultrasonic measurements of utero-placental blood flow and fetal growth.

INTRODUCTION: Ultrasonic fetal biometry and arterial Doppler flow velocimetry are widely used to assess the risk of pregnancy complications. There is an extensive literature on the relationship between pregnancy outcomes and the size and shape of the placenta. However, ultrasonic fetal biometry and arterial Doppler flow velocimetry have not previously been studied in relation to postnatal placental morphometry in detail. METHODS: We conducted a prospective cohort study of nulliparous women in The Rosie Hospital, Cambridge (UK). We studied a group of 2120 women who had complete data on uterine and umbilical Doppler velocimetry and fetal biometry at 20, 28 and 36 weeks' gestational age, digital images of the placenta available, and delivered a liveborn infant at term. Associations were expressed as the difference in the standard deviation (SD) score of the gestational age adjusted ultrasound measurement (z-score) comparing the lowest and highest decile of the given placental morphometric measurement. RESULTS: The lowest decile of placental surface area was associated with 0.87 SD higher uterine artery Doppler mean pulsatility index (PI) at 20 weeks (95% CI: 0.68 to 1.07, P < 0.001). The lowest decile of placental weight was associated with 0.73 SD higher umbilical artery Doppler PI at 36 weeks (95% CI: 0.54 to 0.93, P < 0.001). The lowest decile of both placental weight and placental area were associated with reduced growth velocity of the fetal abdominal circumference between 20 and 36 weeks (both P < 0.001). CONCLUSION: Placental area and weight are associated with uterine and umbilical blood flow, respectively, and both are associated with fetal growth rate.

The tricipital aponeurosis--a reliable soft tissue landmark for humeral plating.

This study aims to identify the relationship of the radial nerve as it descends across the humerus with reference to a reliable soft tissue landmark, the tricipital aponeurosis. Following cadaveric dissection of 10 adult humerii, the radial nerve was located as it crossed the lateral midsagittal point of the humeral diaphysis. A horizontal line was then subtended medially from this point to another line subtended vertically from the lateral border of the tricipital aponeurosis. The vertical distance from this intersection to the lateral apex of the aponeurosis was recorded in three positions (full flexion, 90° of flexion and full extension). The location of the radial nerve on the posterior aspect of the humeral diaphysis to the medial apex of the tricipital aponeurosis was also noted. In 90° of flexion the radial nerve at the lateral midsagittal point of the humerus was 0.9 mm proximal to the lateral apex of the tricipital aponeurosis. Flexion and extension of the elbow changed the interval to 16.3 mm (nerve proximal) in full flexion and 7.1 mm in full extension (nerve distal). On the posterior aspect of the humerus the radial nerve was 21.8 mm proximal to the medial aspect of the tricipital aponeurosis. The aponeurosis provides a reference point from which the nerve can be easily located on the lateral aspect of the humerus intraoperatively in a range of positions, whilst the medial apex provides a guide to the location of the nerve on the posterior aspect of the arm.

Obstetric factors and different causes of special educational need: retrospective cohort study of 407,503 schoolchildren.

OBJECTIVE: To determine whether relationships with gestational age and birthweight centile vary between specific causes of special educational need (SEN). DESIGN: Retrospective cohort study. SETTING: Scotland. POPULATION: A cohort of 407,503 schoolchildren. METHODS: Polytomous logistic regression was used to examine the risk of each cause of SEN across the spectrum of gestation at delivery and birthweight centile, adjusting for potential confounding factors. MAIN OUTCOME MEASURES: Crude and adjusted odds ratios and confidence intervals. RESULTS: Of the 19,821 children with SEN, 557 (2.8%) had sensory impairments, 812 (4.1%) had physical or motor disabilities, 876 (4.4%) had language impairments, 2823 (14.2%) had social, emotional, or behavioural problems, 7018 (35.4%) had intellectual disabilities, 4404 (22.2%) had specific learning difficulties, and 1684 (8.5%) autistic spectrum disorder (ASD). Extreme preterm delivery (at 24-27 weeks of gestation) was a strong predictor of sensory (adjusted OR 23.64, 95% CI 12.03-46.45), physical or motor (adjusted OR 29.69, 95% CI 17.49-50.40), and intellectual (adjusted OR 11.67, 95% CI 8.46-16.10) impairments, with dose relationships across the range of gestation. Similarly, birthweight below the third centile was associated with sensory (adjusted OR 2.85, 95% CI 2.04-3.99), physical or motor (adjusted OR 2.47, 95% CI 1.82-3.37), and intellectual (adjusted OR 2.67, 95% CI 2.41-2.96) impairments. Together, gestation and birthweight centile accounted for 24.0% of SEN arising from sensory impairment, 34.3% arising from physical or motor disabilities, and 26.6% arising from intellectual disabilities. Obstetric factors were less strongly associated with specific learning difficulties and social or emotional problems, and there were no significant associations with ASD. CONCLUSIONS: The association between gestation and birthweight centile and overall risk of SEN is largely driven by very strong associations with sensory, physical or motor impairments, and intellectual impairments.

Maternal waist to hip ratio is a risk factor for macrosomia.

OBJECTIVE: Fetal growth during pregnancy may be affected by the metabolic activity and distribution of fat stores in women. This study investigates the association between waist to hip ratio (WHR) as a measure of the distribution of adiposity in primiparous mothers living in Avon, England, and macrosomia in their offspring. DESIGN: Prospective historical cohort study. SETTING: The Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort study in Avon, UK. POPULATION: A cohort of 3083 primiparous women with a term singleton delivery with expected dates of delivery from 1 April 1991 to 31 December 1992. METHODS: The distribution of WHR was categorised into quartiles. We compared the second, third and fourth quartiles against the first (reference) quartile with respect to whether the mother delivered a macrosomic newborn. We controlled for maternal age, gestational age, body mass index (BMI), marital status and racial group using multivariate logistic regression. MAIN OUTCOME MEASURES: Macrosomia defined in three ways: birthweight ≥ 4000 g; birthweight ≥ 4500 g; large for gestational age (LGA: ≥ 95th percentile of birth weight adjusted for sex and gestational age). RESULTS: Waist to hip ratios in the third and fourth quartiles were associated with a higher odds of delivering a macrosomic infant, defined as a birthweight ≥ 4000 g (third quartile, OR 1.59, 95% CI 1.12-2.26; fourth quartile, OR 1.69, 95% CI 1.18-2.42) or as LGA (≥95th percentile of the cohort; third quartile, OR 1.77, 95% CI 1.10-2.85; fourth quartile, OR 1.78, 95% CI 1.09-2.91). When defined as a birthweight ≥ 4500 g, the fourth quartile was associated with increased odds of macrosomia (OR 2.74, 95% CI 1.05-7.16). Odds ratios after adjustment for confounding factors followed a similar pattern. CONCLUSION: Independent of confounding factors, women with increased WHRs were significantly more likely to give birth to macrosomic newborns.

Meta-analysis of the association between preterm delivery and intelligence.

BACKGROUND: An increasing proportion of infants are born preterm, and their survival has improved. Therefore, their long-term sequelae are of increasing public health importance. METHODS: We conducted a systematic review covering a 30 year period (1980-2009). A random effects meta-analysis provided a pooled estimate of the difference in IQ score between individuals born preterm and term. Small-study bias was examined using a funnel plot and Egger's test, and meta-regression was used to investigate possible causes of heterogeneity. Cumulative meta-analysis was used to determine if the magnitude of the association had changed over time. RESULTS: The 27 eligible studies covered 7044 individuals; 3504 (50%) delivered preterm and 3540 (50%) at term. They provided 37 estimates of difference in IQ. All demonstrated a reduced IQ among those delivered preterm and all but four reached statistical significance. Overall, IQ score was 11.94 (95% CI: 10.47-13.42, P < 0.001) points lower among children born preterm. There was moderate heterogeneity (overall I(2) 74.2%, P < 0.001), but no significant small-study bias (P = 0.524). The association between preterm delivery and IQ did not change significantly over time. There was a statistically significant, linear association across the gestational age range (adjusted coefficient: -0.91, 95% CI: -1.64, -0.17, P = 0.018). CONCLUSIONS: There is a strong and consistent body of evidence suggesting an association between preterm delivery and reduced IQ, with evidence of a dose-response relationship with gestational age.

Recurrent miscarriage is associated with a family history of ischaemic heart disease: a retrospective cohort study.

OBJECTIVE: To determine whether women experiencing recurrent miscarriage were more likely to have a family history of cardiovascular disease. DESIGN: Retrospective cohort study. SETTING: Women having a first birth in Scotland between 1992 and 2006. SAMPLE: A total of 74, 730 first births were linked to the hospital admission and death certification data for the women's parents through the women's birth certificates. METHODS: The incidence of cardiovascular disease in the women's parents was related to the number of miscarriages experienced before their daughters' first births using a Cox proportional hazards model. MAIN OUTCOME MEASURES: Death or hospital admission of the women's parents for ischaemic heart disease (IHD), cerebrovascular disease (CVD) or venous thromboembolism (VTE). MAIN RESULTS: There was an increased incidence of IHD in the parents of women who experienced two miscarriages before their first birth (hazard ratio 1.25, 95% CI 1.04-1.49) and parents of women who experienced three or more miscarriages before their first birth (hazard ratio 1.56, 95% CI 1.14-2.15). Adjustment for the characteristics of the women at the time of the first birth was without material effect. There was no significant association between miscarriage and family history of CVD or VTE. There was no significant association between the number of therapeutic terminations of pregnancy before the first birth and the incidence of any type of cardiovascular disease in the women's parents. CONCLUSIONS: The parents of women who experience recurrent miscarriage are more likely to experience IHD. Recurrent miscarriage and IHD may have common patho-physiological pathways and genetic predispositions.

Age at menarche and the risk of operative first delivery.

OBJECTIVE: The risk of operative delivery at term increases linearly with age at first birth. It has been hypothesised that this is because of a deleterious effect of a prolonged interval between menarche and first birth on uterine function. The aim of this study was to test a prediction from the hypothesis, namely, that the risk of operative first delivery would decline with later age at menarche. DESIGN: Retrospective analysis of a prospective cohort study. SETTING: The ALSPAC prospective cohort study enrolled pregnant women resident in Avon, UK with expected dates of delivery from 1 April 1991 to 31 December 1992. POPULATION: A total of 3739 primipara recruited to the ALSPAC cohort who experienced labour at term with a singleton infant in a cephalic presentation. MAIN OUTCOME MEASURE: Operative delivery, defined as caesarean section or operative vaginal birth. RESULT: The rate of operative delivery was highest among women with age at menarche in the bottom quartile (32.4%, menarche aged or=15) quartiles (test for trend, P = 0.01). When adjusted for height, body mass index, marital status, smoking status, induction of labour, week of gestation of delivery and birthweight percentile; the odds ratio for operative delivery associated with a 5-year increase in age at menarche (0.78, 95% CI 0.61-0.99) was very similar to the odds ratio for a 5-year decrease in age at delivery (0.73, 95% CI 0.67-0.79). There was no association between age at menarche and the risk of operative delivery following adjustment for the interval between menarche and the first birth (adjusted odds ratio 0.98, 95% CI 0.77-1.25). CONCLUSION: Later menarche is associated with a decreased risk of operative delivery by decreasing the interval between menarche and first birth. The observation is consistent with the hypothesis that prolonged hormonal stimulation of the uterus prior to the first birth has a deleterious effect on uterine function.

Placental size and the prediction of severe early-onset intrauterine growth restriction in women with low pregnancy-associated plasma protein-A.

OBJECTIVES: Screening studies for trisomy 21 demonstrate that low maternal serum pregnancy-associated plasma protein-A (PAPP-A) at 11-13 weeks' gestation is associated with stillbirth, intrauterine growth restriction (IUGR) and pre-eclampsia in chromosomally normal fetuses. However, the strength of these associations is too weak to justify screening for these placental insufficiency syndromes. Our objective was to evaluate placental size and uterine artery (UtA) Doppler imaging as second-stage screening tests for women with low PAPP-A. METHODS: We prospectively studied 90 normal singleton pregnancies with first-trimester PAPP-A