External Validation of a Frequently Used Prediction Model for Ongoing Pregnancy in Couples With Unexplained Recurrent Pregnancy Loss

A. Youssef; M.L.P. van der Hoorn; M. Dongen; J. Visser; K. Bloemenkamp; J. van Lith; N. van Geloven; E.E.L.O. Lashley


Hum Reprod. 2022;37(3):393-399. 

In This Article

Abstract and Introduction


Study Question: What is the predictive performance of a currently recommended prediction model in an external Dutch cohort of couples with unexplained recurrent pregnancy loss (RPL)?

Summary Answer: The model shows poor predictive performance on a new population; it overestimates, predicts too extremely and has a poor discriminative ability.

What is Known Already: In 50–75% of couples with RPL, no risk factor or cause can be determined and RPL remains unexplained. Clinical management in RPL is primarily focused on providing supportive care, in which counselling on prognosis is a main pillar. A frequently used prediction model for unexplained RPL, developed by Brigham et al. in 1999, estimates the chance of a successful pregnancy based on number of previous pregnancy losses and maternal age. This prediction model has never been externally validated.

Study Design, Size, Duration: This retrospective cohort study consisted of 739 couples with unexplained RPL who visited the RPL clinic of the Leiden University Medical Centre between 2004 and 2019.

Participants/Materials, Setting, Methods: Unexplained RPL was defined as the loss of two or more pregnancies before 24 weeks, without the presence of an identifiable cause for the pregnancy losses, according to the ESHRE guideline. Obstetrical history and maternal age were noted at intake at the RPL clinic. The outcome of the first pregnancy after intake was documented. The performance of Brigham's model was evaluated through calibration and discrimination, in which the predicted pregnancy rates were compared to the observed pregnancy rates.

Main Results and the Role of Chance: The cohort included 739 women with a mean age of 33.1 years (±4.7 years) and with a median of three pregnancy losses at intake (range 2–10). The mean predicted pregnancy success rate was 9.8 percentage points higher in the Brigham model than the observed pregnancy success rate in the dataset (73.9% vs 64.0% (95% CI for the 9.8% difference 6.3–13.3%)). Calibration showed overestimation of the model and too extreme predictions, with a negative calibration intercept of −0.46 (95% CI −0.62 to −0.31) and a calibration slope of 0.42 (95% CI 0.11–0.73). The discriminative ability of the model was very low with a concordance statistic of 0.55 (95% CI 0.51–0.59). Recalibration of the Brigham model hardly improved the c-statistic (0.57; 95% CI 0.53–0.62)

Limitations, Reasons for Caution: This is a retrospective study in which only the first pregnancy after intake was registered. There was no time frame as inclusion criterium, which is of importance in the counselling of couples with unexplained RPL. Only cases with a known pregnancy outcome were included.

Wider Implications of the Findings: This is the first study externally validating the Brigham prognostic model that estimates the chance of a successful pregnancy in couples with unexplained RPL. The results show that the frequently used model overestimates the chances of a successful pregnancy, that predictions are too extreme on both the high and low ends and that they are not much more discriminative than random luck. There is a need for revising the prediction model to estimate the chance of a successful pregnancy in couples with unexplained RPL more accurately.

Study Funding/Competing Interest(S): No external funding was used and no competing interests were declared.

Trial Registration Number: N/A.


Recurrent pregnancy loss (RPL) is defined as the loss of two or more conceptions (Bender Atik et al., 2018). This condition affects 1–3% of all fertile couples (Jauniaux et al., 2006; Rai and Regan, 2006). RPL is a highly heterogeneous condition with multiple known maternal and paternal risk factors (Nybo Andersen et al., 2004; Venners et al., 2004; McQueen et al., 2019). Despite extensive diagnostic work-ups offered to couples with RPL, an underlying risk factor may be identified in only 25–50% of couples (Stephenson, 1996; Jaslow et al., 2010). Limited understanding of mechanisms underlying RPL leads to the lack of options for effective treatment. As no evidence-based therapeutic options are available for couples with RPL, clinical management is primarily focused on providing supportive care. Supportive care and intensive pregnancy surveillance in the first trimester of gestation are assumed to be of influence in the prevention of new pregnancy loss (Liddell et al., 1991). An important aspect of this supportive care is counselling on the prognosis and success rate of subsequent pregnancies in couples with RPL.

Several prediction models for the estimation of the chance of live birth after RPL have been published (Cauchi et al., 1991, 1995; Quenby and Farquharson, 1993; Brigham et al., 1999; Sugiura-Ogasawara et al., 2009; Lund et al., 2012; Bashiri et al., 2020) and various international guidelines recommend the use of different prediction models (Youssef et al., 2019). The ESHRE RPL guideline recommends to use the prediction models of Brigham et al. or Lund et al. (hereafter called the 'Brigham model' and the 'Lund model') to estimate the chance of live birth in couples with unexplained RPL (Bender Atik et al., 2018). The Brigham model has been implemented in RPL care in the Netherlands and in the UK (NVOG, 2007; RCOG, 2011), while the American Society for Reproductive Medicine (ASRM) adapted the Lund model in their RPL guideline (Practice Committee of the American Society for Reproductive Medicine, 2012). The Lund model was not designed for individual risk assessment, given the descriptive scope of the study. Furthermore, the study does not discriminate between unexplained and explained RPL. Although the Brigham model and the Lund model were both reviewed with high methodological quality and both studies have consistent results, these models did not follow the nowadays recommended TRIPOD guideline in the development and reporting of a prediction model (Collins et al., 2015). This guideline provides a 22-item checklist consisting of items that assures transparent reporting and acts as a tool for reminding authors of all necessary prediction components, such as measuring the predictive performance of the study internally and/or externally. Both models were never internally nor externally validated, which leaves their predictive performance unknown.

As the Lund model was not intended for individual risk assessment, the aim of this study is to externally validate the Brigham model to assess its predictive performance in a Dutch cohort of couples with unexplained RPL.