External validation and clinical usefulness of first-trimester prediction models for small- and large-for-gestational-age infants: a prospective cohort study.

OBJECTIVE: To assess the external validity of all published first-trimester prediction models based on routinely collected maternal predictors for the risk of small- and large-for-gestational-age (SGA and LGA) infants. Furthermore, the clinical potential of the best-performing models was evaluated. DESIGN: Multicentre prospective cohort. SETTING: Thirty-six midwifery practices and six hospitals (in the Netherlands). POPULATION: Pregnant women were recruited at <16 weeks of gestation between 1 July 2013 and 31 December 2015. METHODS: Prediction models were systematically selected from the literature. Information on predictors was obtained by a web-based questionnaire. Birthweight centiles were corrected for gestational age, parity, fetal sex, and ethnicity. MAIN OUTCOME MEASURES: Predictive performance was assessed by means of discrimination (C-statistic) and calibration. RESULTS: The validation cohort consisted of 2582 pregnant women. The outcomes of SGA <10th percentile and LGA >90th percentile occurred in 203 and 224 women, respectively. The C-statistics of the included models ranged from 0.52 to 0.64 for SGA (n = 6), and from 0.60 to 0.69 for LGA (n = 6). All models yielded higher C-statistics for more severe cases of SGA (<5th percentile) and LGA (>95th percentile). Initial calibration showed poor-to-moderate agreement between the predicted probabilities and the observed outcomes, but this improved substantially after recalibration. CONCLUSION: The clinical relevance of the models is limited because of their moderate predictive performance, and because the definitions of SGA and LGA do not exclude constitutionally small or large infants. As most clinically relevant fetal growth deviations are related to 'vascular' or 'metabolic' factors, models predicting hypertensive disorders and gestational diabetes are likely to be more specific. TWEETABLE ABSTRACT: The clinical relevance of prediction models for the risk of small- and large-for-gestational-age is limited.

Predicting successful intended vaginal delivery after previous caesarean section: external validation of two predictive models in a Dutch nationwide registration-based cohort with a high intended vaginal delivery rate.

OBJECTIVE: To externally validate two models from the USA (entry-to-care [ETC] and close-to-delivery [CTD]) that predict successful intended vaginal birth after caesarean (VBAC) for the Dutch population. DESIGN: A nationwide registration-based cohort study. SETTING: Seventeen hospitals in the Netherlands. POPULATION: Seven hundred and sixty-three pregnant women, each with one previous caesarean section and a viable singleton cephalic pregnancy without a contraindication for an intended VBAC. METHODS: The ETC model comprises the variables maternal age, prepregnancy body mass index (BMI), ethnicity, previous vaginal delivery, previous VBAC and previous nonprogressive labour. The CTD model replaces prepregnancy BMI with third-trimester BMI and adds estimated gestational age at delivery, hypertensive disease of pregnancy, cervical examination and induction of labour. We included consecutive medical records of eligible women who delivered in 2010. For validation, individual probabilities of women who had an intended VBAC were calculated. MAIN OUTCOME MEASURES: Discriminative performance was assessed with the area under the curve (AUC) of the receiver operating characteristic and predictive performance was assessed with calibration plots and the Hosmer-Lemeshow (H-L) statistic. RESULTS: Five hundred and fifteen (67%) of the 763 women had an intended VBAC; 72% of these (371) had an actual VBAC. The AUCs of the ETC and CTD models were 68% (95% CI 63-72%) and 72% (95% CI 67-76%), respectively. The H-L statistic showed a P-value of 0.167 for the ETC model and P = 0.356 for the CTD model, indicating no lack of fit. CONCLUSION: External validation of two predictive models developed in the USA revealed an adequate performance within the Dutch population.

Vaginal birth after a caesarean section: the development of a Western European population-based prediction model for deliveries at term.

OBJECTIVE: To develop and internally validate a model that predicts the outcome of an intended vaginal birth after caesarean (VBAC) for a Western European population that can be used to personalise counselling for deliveries at term. DESIGN: Registration-based retrospective cohort study. SETTING: Five university teaching hospitals, seven non-university teaching hospitals, and five non-university non-teaching hospitals in the Netherlands. POPULATION: A cohort of 515 women with a history of one caesarean section and a viable singleton pregnancy, without a contraindication for intended VBAC, who delivered at term. METHODS: Potential predictors for a vaginal delivery after caesarean section were chosen based on literature and expert opinions. We internally validated the prediction model using bootstrapping techniques. MAIN OUTCOME MEASURES: Predictors for VBAC. For model validation, the area under the receiver operating characteristic curve (AUC) for discriminative capacity and calibration-per-risk-quantile for accuracy were calculated. RESULTS: A total of 371 out of 515 women had a VBAC (72%). Variables included in the model were: estimated fetal weight greater than the 90(th) percentile in the third trimester; previous non-progressive labour; previous vaginal delivery; induction of labour; pre-pregnancy body mass index; and ethnicity. The AUC was 71% (95% confidence interval, 95% CI = 69-73%), indicating a good discriminative ability. The calibration plot shows that the predicted probabilities are well calibrated, especially from 65% up, which accounts for 77% of the total study population. CONCLUSION: We developed an appropriate Western European population-based prediction model that is aimed to personalise counselling for term deliveries.

Involving women in personalised decision-making on mode of delivery after caesarean section: the development and pilot testing of a patient decision aid.

OBJECTIVE: To develop a patient decision aid (PtDA) for mode of delivery after caesarean section that integrates personalised prediction of vaginal birth after caesarean (VBAC) with the elicitation of patient preferences and evidence-based information. DESIGN: A PtDA was developed and pilot tested using the International Patients Decision Aid Standards (IPDAS) criteria. SETTING: Obstetric health care in the Netherlands. POPULATION: A multidisciplinary steering group, an expert panel, and 25 future users of the PtDA, i.e. women with a previous caesarean section. METHODS: The development consisted of a construction phase (definition of scope and purpose, and selection of content, framework, and format) and a pilot testing phase by interview. The process was supervised by a multidisciplinary steering group. MAIN OUTCOME MEASURES: Usability, clarity, and relevance. RESULTS: The construction phase resulted in a booklet including unbiased balanced information on mode of birth after caesarean section, a preference elicitation exercise, and tailored risk information, including a prediction model for successful VBAC. During pilot testing, visualisation of risks and clarity formed the main basis for revisions. Pilot testing showed the availability of tailored structured information to be the main factor involving women in decision-making. The PtDA meets 39 out of 50 IPDAS criteria (78%): 23 out of 23 criteria for content (100%) and 16 out of 20 criteria for the development process (80%). Criteria for effectiveness (n = 7) were not evaluated. CONCLUSIONS: An evidence-based PtDA was developed, with the probability of successful VBAC and the availability of structured information as key items. It is likely that the PtDA enhances the quality of decision-making on mode of birth after caesarean section.

Mechanisms leading to increased vasodilator responses to calcitonin-gene-related peptide in mesenteric resistance arteries of early pregnant rats.

The objective of this study was to explore the mechanism responsible for the higher relaxing responses of mesenteric arteries to calcitonin-gene-related peptide (CGRP) in pregnancy. We performed myograph and ligand binding studies to determine the role of matrix metalloproteinase-2 (MMP-2) and CGRP receptor density. MMP activity was manipulated in isolated arteries by exposing them to the blocking effects of doxycycline. Vascular activity of MMP-2 was studied by gelatin zymography, and CGRP receptor density was determined by ligand binding analysis. Compared to nonpregnant rats, CGRP elicited stronger arterial relaxation in pregnant rats. The latter effect was neither accompanied by a change in relaxing responses to direct activation of adenylyl cyclase by forskolin nor by a change in the response to stimulation of G-protein-coupled adrenergic receptors by isoproterenol. Doxycycline did not affect the stronger arterial relaxation in pregnancy in spite of the observed more than threefold higher arterial MMP-2 activity. Density of binding sites for [(125)I]CGRP in arteries from pregnant rats (64 +/- 14 fmol/mg protein) and from virgin rats (54 +/- 5 fmol/mg protein) were comparable. The results of this study provide evidence for increased coupling of CGRP receptors to adenylyl cyclase in early pregnancy.

Pregnancy enhances the prejunctional vasodilator response to adrenomedullin in selective regions of the arterial bed of Wistar rats.

The objective of this study is to determine whether the vascular response to adrenomedullin is modulated by pregnancy. To this end, the authors study the effect of adrenomedullin on different contractile responses of mesenteric, uterine, renal, and saphenous arteries of 10-day pregnant and nonpregnant rats in myographs. Adrenomedullin inhibited contractile responses induced by electrical field stimulation in only the mesenteric and uterine arteries. This effect was more pronounced during pregnancy than in the nonpregnant state. Adrenomedullin did not modify concentration response curves to noradrenaline. The reduction of contractile responses to 40 mmol/L K(+) by adrenomedullin was similar in arteries of pregnant and nonpregnant rats. However, after incubation with capsaicin, this effect was significantly increased in mesenteric arteries of the pregnant group. The authors conclude that pregnancy is associated with a rise in the prejunctional inhibitory effect of adrenomedullin in some regions of the arterial system.

Vasodilator reactivity to calcitonin gene-related peptide is increased in mesenteric arteries of rats during early pregnancy.

The objective of the present study was to determine the effect of early pregnancy on the sensitivity to, and endogenous production of calcitonin gene-related peptide (CGRP). Contractile responses of arteries of 10-day pregnant and nonpregnant rats were studied in myographs. During contractions induced by 40 mmol/l K(+), exogenous CGRP elicited an approximately 30% stronger relaxation in mesenteric arteries in pregnancy, an effect not seen in renal and uterine arteries. Capsaicin treatment during K(+)-induced contractions caused a persistent potentiation of the contractile response in mesenteric arteries, indicating that K(+) stimulates the endogenous release of CGRP. This potentiation was similar in the pregnant and nonpregnant state (+81 +/- 23% and +82 +/- 23%, respectively), suggesting no effect of pregnancy on the endogenous CGRP release. The latter was paralleled by comparable CGRP content in the arteries of both groups, indicating similar tissue CGRP availability. The results of this study support the concept that early pregnancy is associated with a rise in the vascular sensitivity to CGRP in selected areas of the vascular bed without concomitant increase in the vascular CGRP production and release.

Non-pregnant circulatory volume status predicts subsequent pregnancy outcome in normotensive thrombophilic formerly preeclamptic women.

BACKGROUND: Preeclampsia seems to be superimposed upon a preexisting hemodynamic, hemostatic, autoimmune or metabolic disorder. We tested the hypothesis that in normotensive thrombophilic formerly preeclamptic subjects, the non-pregnant circulatory volume status predicts the development of subsequent hypertensive pregnancy and/or fetal growth restriction. METHODS: In 250 non-diabetic formerly preeclamptic women and 15 normal parous controls, we measured and calculated the following variables at least 5 months postpartum at day 5 (+/-2) of the menstrual cycle: mean arterial pressure, body mass index, plasma volume and the clotting function. In the subsequent pregnancy we determined, birth weight, birth-weight centile and the incidence of preterm birth, fetal growth restriction, pregnancy-induced hypertension, preeclampsia and HELLP-syndrome. We only included in the final analysis normotensive subjects with a thrombophilic phenotype at the time of the pre-pregnant screening, who had a subsequent singleton pregnancy, ongoing beyond 16 weeks gestation within 1 year after pre-pregnant evaluation. As a consequence, 23 formerly preeclamptic women and 12 controls were eligible for final analysis. The thrombophilic formerly preeclamptic participants received aspirin in combination with low-molecular-weight heparin throughout pregnancy. If thrombophilia was diagnosed on the basis of hyperhomocysteinemia, the treatment consisted of aspirin, pyridoxine and folic acid, instead. RESULTS: Among 250 formerly preeclamptic 131/250 (52%) had a normotensive thrombophilic phenotype. Only 23 (18%) of these 131 participants had an ongoing pregnancy within 1 year. They were allocated to subgroup THROMB. None of the controls had hypertension or thrombophilia. In contrast, 12/15 (80%) controls had an ongoing pregnancy within a year. The observations in the THROMB subgroup were compared with those in the control group. None of the baseline demographic and blood pressure variables differed between THROMB and controls. With respect to pregnancy outcome, the incidence of the following pregnancy complications were observed in THROMB subjects: preterm birth: 9%, pregnancy-induced hypertension: 44%, preeclampsia: 13%, HELLP-syndrome: 13%, and fetal growth restriction: 30%. A low non-pregnant plasma volume was found to predispose for hypertensive complications in a subsequent pregnancy. CONCLUSION: Pre-pregnant plasma volume in normotensive thrombophilic formerly preeclamptic women have predictive value with respect to hypertensive complications in the subsequent pregnancy.

Maternal position and ultrasonic cervical assessment in multiple pregnancy. Preliminary observations.

OBJECTIVE: To evaluate the influence of position on the functional anatomy of the cervix. STUDY DESIGN: Cervical length and width of the internal os were measured by transvaginal ultrasound in the recumbent and standing position from 15 gestational weeks to term in 15 twin and 3 triplet pregnancies. Measurements on asymptomatic primigravidae with twins who delivered vaginally after 36 weeks were made to calculate trends in normal twin pregnancies. These data were compared with that obtained in patients who had threatened preterm labor. RESULTS: As the total observation period progressed, the mean cervical length decreased from 50 to 27 mm in the recumbent position and from 48 to 21 mm in the standing position (P < .001). The differences between the values obtained in the recumbent and standing position increased from 5% to 31% as pregnancy progressed (P < .001). Funnelling was observed from 20 weeks onwards in the erect position but only after 35 weeks in the recumbent position. CONCLUSION: Our preliminary observations support a policy aimed at prevention of prematurity by reducing physical activity and standing work in patients who have multiple gestations. The full impact of these observations on the early detection of special risk groups and the prescription of preventive interventions have yet to be evaluated.