Why women with low ovarian reserve have no greater chance of miscarriage than those with normal ovarian reserve

Study draws distinction between oocyte quantity and oocyte quality in risk of miscarriage.

Published 13 June 2022

A large study based on registry data suggests that the accelerated loss of oocytes seen in women with early ovarian ageing, while linked to decreased pregnancy and live birth rate, is not associated with a concomitant decline in oocyte quality as evident in pregnancy loss.

Young women with low ovarian reserve without a known cause are no more likely to miscarry after fertility treatment than those of a similar age who have a normal number of eggs. This is the reassuring conclusion from a register-based Danish cohort study based on data from more than 10,000 ART patients, including those experiencing prematurely accelerated follicle loss, and 21,400 embryo transfer cycles.(1) However, as expected, the chance of a clinical pregnancy or live birth per embryo transfer were lower for women with early ovarian ageing (EOA) than for those with normal ovarian reserve (NOA).

Data came from 10,027 women aged 37 or below who underwent IVF or ICSI treatment in public or private clinics in Denmark between 1995 and 2014. The authors identified suitable participants using national health registers; exclusion criteria were known causes which influence ovarian reserve (eg, chemotherapy and endometriosis).

Participants were divided into an EOA group (n = 1213) with five or fewer oocytes harvested in a first and second FSH-stimulated cycle (no more than a year between cycles) and an NOA group (n = 8814) with eight or more eggs from either a first or second FSH-stimulated cycle (minimum of two stimulated cycles).

The primary outcome for oocyte quality was an overall risk of pregnancy loss (22 weeks’ gestation or less) following a positive hCG test. Pregnancy loss was separated into non-visualised pregnancy loss, early miscarriage (12 weeks’ gestation or less), and late miscarriage (more than 12 weeks’ gestation). Secondary outcomes were chance of clinical pregnancy and live birth per embryo transfer.

Time to event was measured from the day of embryo transfer beginning with the second cycle and ending on day of miscarriage or end of follow-up; and adjustment was made for confounders (eg, BMI, age and smoking).

Results showed a comparable overall risk of pregnancy loss between both groups of women (adjusted OR 1.04) and for type of pregnancy loss (non-visualised, etc). However, compared with the NOA group, the odds for clinical pregnancy and live birth were lower per ET in the EOA group (adjusted OR 0.77 and 0.78).

Limitations of the study included the fact only women with at least two ART cycles were included, and the authors had no information on the total doses of gonadotrophin administered in each cycle. In addition, they say very early pregnancy losses may not have been recorded because information was register-based.

The findings shed new light on the mechanisms involved in early ovarian ageing. The authors say their evidence indicates that oocyte quality ‘does not strictly correlate with numerical ovarian reserve’ in younger women when evaluated by risk of miscarriage. These women may have fewer eggs, but the quality of their oocytes does not appear to be affected in the same way as quantity. This, they explain, may be because the oocytes have not yet been impacted significantly by ageing, unlike those of older women reaching natural menopause.

Hence, aneuploidy by itself may not be the cause of reduced implantation and the lower chance of pregnancy/live birth among EOA women. Instead, one hypothesis the researchers put forward is that fewer oocytes from EOA patients mean fewer embryos to choose between, and this ‘may lead to transfer of embryos with suboptimal morphology and implantation potential’.

They add that the results could prove valuable when counselling this specific group of patients.

1. Christensen MW, Ingerslev HJ, Kirkegaard K, Kesmodel US. Idiopathic early ovarian ageing: risk of miscarriage and chance of delivery following ART in a nationwide cohort study. Hum Reprod 2022; doi.org//10.1093/humrep/deac093

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