Reproductive outcomes following recurrent first-trimester miscarriage: a retrospective cohort study
Authors: Linehan L A , San Lazaro Campillo I , Hennessy M , Flannery C , O’Donoghue K 
Published: October 2022

Abstract

STUDY QUESTION
What are the subsequent reproductive outcomes (livebirths, miscarriages or other adverse pregnancy outcomes or no further pregnancy) of women with recurrent miscarriage (RM) attending a dedicated clinic?

SUMMARY ANSWER
Of women with RM, 77% had a subsequent pregnancy, and among these pregnancies, the livebirth rate was 63%.

WHAT IS KNOWN ALREADY
RM affects ∼1–3% of women of reproductive age. RM has known associations with advanced maternal age, obesity, diabetes, inherited thrombophilias, thyroid dysfunction, endometriosis and parental balanced translocations. However, ∼ 50% of women or couples will be left without an explanation for their pregnancy loss, even after completing investigations. RM is also associated with secondary infertility and adverse pregnancy outcomes including preterm birth and perinatal death.

STUDY DESIGN, SIZE, DURATION
We undertook a retrospective cohort study to identify subsequent pregnancy outcomes in women with RM, defined as three consecutive first-trimester miscarriages. Women attending the RM clinic at a tertiary university hospital in the Republic of Ireland over 12 years (2008–2020) with a confirmed diagnosis of primary or secondary first-trimester RM were eligible for inclusion. In total, 923 charts were identified for review against the eligibility criteria.

PARTICIPANTS/MATERIALS, SETTING, METHODS
Women with non-consecutive first-trimester miscarriages or ectopic pregnancy were excluded. Epidemiological and clinical information regarding medical history, investigation and management was gathered from paper and electronic medical records. Data were analysed using SPSS (Version 27). Associations between maternal characteristics and outcomes were explored using the χ2 test, with significance set at P &lt; 0.05. Multinomial regression analysis was performed using a stepwise approach.

MAIN RESULTS AND THE ROLE OF CHANCE
There were 748 women who were included; 332 (44%) had primary RM and 416 (56%) had secondary RM. The median age was 36 years (range 19–47). Foetal aneuploidy was the most common investigative finding (15%; n = 111/748); 60% had unexplained RM. In addition to supportive care, most women were prescribed aspirin (96%) and folic acid (75%). Of the 748 women, 573 had a subsequent pregnancy (77%) and 359 (48% of all women; 63% of pregnancies) had a livebirth, while 208 had a further pregnancy loss (28% of all women; 36% of pregnancies) and 6 were still pregnant at the end of the study. Women aged 35–39 years were more likely to have a livebirth than no further pregnancy (relative risk ratio (RRR): 2.29 (95% CI: 1.51–5.30)). Women aged 30–34 years were more likely to have a livebirth (RRR: 3.74 (95% CI: 1.80–7.79)) or a miscarriage (RRR: 2.32 (95% CI: 1.07–4.96)) than no further pregnancy. Smokers were less likely to have a livebirth (RRR: 0.37 (95% CI: 0.20–0.69)) or a miscarriage (RRR: 0.45 (95% CI: 0.22–0.90)) than no further pregnancy. Couples with an abnormal parental karyotype were less likely to have a miscarriage than no further pregnancy (RRR: 0.09 (95% CI: 0.01–0.79)). Including successive pregnancies conceived over the study period, the overall livebirth rate was 63% (n = 466/742), but this was reduced to 44% in women aged ≥40 years and 54% in women with infertility.

LIMITATIONS, REASONS FOR CAUTION
This work covers 13 years; however, those included in the later years have a shorter follow-up time. Although electronic health records have improved data availability, data collection in this cohort remains hampered by the absence of a formal booking visit for women presenting with miscarriage and a national miscarriage database or register.

WIDER IMPLICATIONS OF THE FINDINGS
Our findings are largely reassuring as most women with RM and hoping to conceive achieved a livebirth. In addition to older age, smoking and parental balanced translocations were associated with a reduced likelihood of further pregnancy. No investigation or treatment was associated with pregnancy outcome, reiterating the importance of the supportive aspects of care for women and their partners after RM and counselling regarding individual risk factors. This contributes to the limited international data on the investigative findings and treatment of women with RM. The high rate of prescribed medications merits greater scrutiny, in conjunction with other pregnancy outcomes, and reiterates the need for a national guideline on RM.

STUDY FUNDING/COMPETING INTEREST(S)
L.A.L. is a PhD scholar funded through the Pregnancy Loss Research Group, Department of Obstetrics and Gynaecology, University College Cork. M.H. and C.F. are Postdoctoral Researchers on a project funded by the Health Research Board Ireland [ILP-HSR-2019-011] and led by K.O.D., titled: ‘Study of the impact of dedicated recurrent miscarriage clinics in the Republic of Ireland’. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no conflicts of interests to declare.

TRIAL REGISTRATION NUMBER
N/A.