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Objective To examine the predictive performance of the competing‐risks model in screening for pre‐eclampsia (PE) by maternal demographic characteristics and medical history in twin pregnancy, in a training dataset used for development of the model and a validation dataset. Methods The data for this study were derived from two prospective non‐intervention multicenter screening studies for PE in twin pregnancies at 11 + 0 to 13 + 6 weeks' gestation. The first study of 2219 women, which was reported previously, was used to develop the competing‐risks model for prediction of PE and is therefore considered to be the training set. The validation study comprised 2999 women. Patient‐specific risks of delivery with PE at < 34 (early), < 37 (preterm) and < 41 + 3 (all) weeks' gestation were calculated using the competing‐risks model and the performance of screening for PE in the training and validation datasets was assessed. We examined the predictive performance of the model by, first, its ability to discriminate between the PE and no‐PE groups using the area under the receiver–operating characteristics curve (AUC) and, second, calibration, which assesses agreement between the predicted risk and observed incidence of PE. Results The incidence of early PE, preterm PE and all PE in the training and validation datasets was similar (1.8% vs 1.4%, 5.6% vs 5.6% and 7.7% vs 7.2%, respectively) and this was substantially higher than in our previous studies in singleton pregnancies. The training and validation datasets had similar AUCs for early PE (0.670 (95% CI, 0.593–0.747) vs 0.677 (95% CI, 0.594–0.760)), preterm PE (0.666 (95% CI, (0.617–0.715) vs 0.652 (95% CI, 0.609–0.694)) and all PE (0.656 (95% CI, 0.615–0.697) vs 0.644 (95% CI, 0.606–0.682)). Calibration plots of the predictive performance of the competing‐risks model demonstrated that, in both the training and validation datasets, the observed incidence of PE was lower than the predicted one and such overestimation of risk was particularly marked for early PE. Conclusions Discrimination and calibration of the competing‐risks model for PE in a validation dataset are consistent with those in the training dataset. However, the model needs to be adjusted to correct the observed overestimation of risk for early PE. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

RFamide-related peptide-3 (RFRP-3), the orthologue of avian gonadotrophin-inhibitory hormone, and its receptor GPR147 have been recently identified in the human hypothalamus, and their roles in the regulation of reproductive axis has been studied. The present study aimed to investigate whether the presence of variants in the genes encoding human RFRP-3 (NPVF gene) and its receptor, GPR147 (NPFFR1 gene), is associated with the occurrence of gonadotrophin-releasing hormone-dependent pubertal disorders. Seventy-eight patients with idiopathic central precocious puberty (CPP) and 51 with normosmic isolated hypogonadotrophic hypogonadism (nIHH) were investigated. Fifty healthy subjects comprised the control group. The coding sequences of the NPVF and NPFFR1 genes were amplified and sequenced. Odds ratios (OR) were used to estimate the likelihood of CPP or nIHH in the presence of the described polymorphisms. All such polymorphisms have already been registered in the National Center for Biotechnology Information database. A three-nucleotide in frame deletion was identified in the NPVF gene (p.I71_K72), with a smaller proportion in the CPP (5%) compared to the nIHH (15%) group (P = 0.06). This results in the deletion of the isoleucine at position 71, adjacent to lysine at an endoproteolytic cleavage site of the precursor peptide. This polymorphism was associated with a lower risk of CPP (OR = 0.33; 95% confidence interval = 0.08-0.88); interestingly, only two men with nIHH were homozygotes for this variant. A total of five missense polymorphisms were found in the NPFFR1 gene, which encodes GPR147, with similar frequencies among groups and no association with pubertal timing. Our data suggest that RFRP-3/GPR147 may play secondary, modulatory roles on the regulation of pubertal development; a restraining modulatory effect of the NPVF p.I71_K72 variant on the activation of the gonadotrophic axis cannot be ruled out and deserves further investigation.