Non-visualized pregnancy losses are prognostically important for unexplained recurrent miscarriage

STUDY QUESTION: Are non-visualized pregnancy losses (biochemical pregnancy loss and failed pregnancy of unknown location combined) in the reproductive history of women with unexplained recurrent miscarriage (RM) negatively associated with the chance of live birth in a subsequent pregnancy? SUMMARY ANSWER: Non-visualized pregnancy losses contribute negatively to the chance for live birth: each non-visualized pregnancy loss confers a relative risk (RR) for live birth of 0.90 (95% CI 0.83; 0.97), equivalent to the RR conferred by each additional clinical miscarriage. WHAT IS KNOWN ALREADY: The number of clinical miscarriages prior to referral is an important determinant for live birth in women with RM, whereas the significance of non-visualized pregnancy losses is unknown. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study comprising 587 women with RM seen in a tertiary RM unit 2000-2010. Data on the outcome of the first pregnancy after referral were analysed for 499 women. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in the RM Unit at Rigshospitalet, Copenhagen, Denmark. We included all women with unexplained RM, defined as ≥3 consecutive clinical miscarriages or non-visualized pregnancy losses following spontaneous conception or homologous insemination. The category 'non-visualized pregnancy losses' combines biochemical pregnancy loss (positive hCG, no ultrasound performed) and failed PUL (pregnancy of unknown location, positive hCG, but on ultrasound, no pregnancy location established). Demographics were collected, including BMI, age at first pregnancy after referral and outcome of pregnancies prior to referral. Using our own records and records from other Danish hospitals, we verified the outcome of the first pregnancy after referral. For each non-visualized pregnancy loss and miscarriage in the women's reproductive history, the RR for live birth in the first pregnancy after referral was determined by robust Poisson regression analysis, adjusting for risk factors for negative pregnancy outcome. MAIN RESULTS AND THE ROLE OF CHANCE: Non-visualized pregnancy losses constituted 37% of reported pregnancies prior to referral among women with RM. Each additional non-visualized pregnancy loss conferred an RR for live birth of 0.90 (95% CI 0.83; 0.97), which was not statistically significantly different from the corresponding RR of 0.87 (95% CI 0.80; 0.94) conferred by each clinical miscarriage. Among women with ≥2 clinical miscarriages, a reduced RR for live birth was also shown: 0.82 (95% CI 0.74; 0.92) for each clinical miscarriage and 0.89 (95% CI 0.80; 0.98) for each non-visualized pregnancy loss, respectively. Surgically treated ectopic pregnancies (EPs) were significantly more common for women with primary RM and no confirmed clinical miscarriages, compared with women with primary RM and ≥1 clinical miscarriage (22 versus 6%, difference 16% (95% CI 9.1%; 28.7%); RR for ectopic pregnancy was 4.0 (95% CI 1.92; 8.20). LIMITATIONS, REASONS FOR CAUTION: RM was defined as ≥3 consecutive pregnancy losses before 12 weeks' gestation, and we included only women with unexplained RM after thorough evaluation. It is uncertain whether the findings apply to other definitions of RM and among women with known causes for their miscarriages. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first comprehensive investigation of prior non-visualized pregnancy losses and their prognostic significance for live birth in a subsequent pregnancy in women with unexplained RM. We show that a prior non-visualized pregnancy loss has a negative prognostic impact on subsequent live birth and is thus clinically significant. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.