In the IVF world, the so called normal ovarian response to gonadotrophins stimulation is thought to be associated to the optimal reproductive success and several studies reported that the highest live birth rate is reached with the retrieval of 15 oocytes at pick up, as this number of oocytes ensures an adequate number of good embryos to transfer. On the contrary it is widely known that women with poor ovarian response to controlled ovarian stimulation have a poor prognosis with lower live birth rates and higher miscarriage rates (Sunkara et al., 2014). The increased rate of obstetrical complications has been related by many authors to the ovarian and vascular ageing in women with poor ovarian reserve. At the same time very little is known on any possible association between the opposite side of the spectrum of ovarian response, namely high ovarian response (i.e. high number of retrieved oocytes) and the obstetrical outcome after IVF.
An answer to this question can be found in a recently published study (Sunkara et al., 2015), where anonymous data were obtained from 402.185 stimulated fresh IVF+ICSI treatment cycles carried out between August 1991 and June 2008, and adverse obstetric outcomes were analyzed.
This large study found that the retrieval of >20 oocytes is the main risk factor for preterm birth (before 37weeks gestation) (OR 1.17, 95%CI 1.06–1.30) or low birth weight (<2.500g) (OR 1.20, 95%CI 1.08–1.33). For very low birth weight (<1.500g) the association was not statistically significant (OR 1.24, 95%CI 0.99–1.56). The higher risk for the above mentioned adverse outcomes is maintained after adjusting for the major predictors: female age, cause of infertility (endometriosis, male factor, unexplained) and number of transferred embryos are not associated to preterm birth or low birth weight.
On the other hand, although the difficulty in conception and the high risk of abortion, women with poor ovarian response (≤3 oocytes) seem to not have an increased risk of adverse obstetric outcomes, when the pregnancy is established, compared with women with a very good ovarian response (i.e. 10–15 oocytes). When pregnancy is achieved and ongoing, no effect on duration of gestation or fetal weight has been found in these poor responder women.
It is known that excessive ovarian response has its own underlying pathogenesis based on high ovarian reserve and without doubt a high prevalence of women with polycystic ovary syndrome (PCOS) can be found in this category. Likely reasons for the higher incidence of adverse obstetric outcomes in women with very high number of oocytes could be related indeed to PCOS itself or to the effect of the supraphysiological estradiol levels: the excessive hormonal exposure might influence negatively the implanting embryos or the endometrium. Indeed the complex relationship existing between impaired implantation of the trophoblast and future feto-placental complications has been widely recognized.
Actually the mentioned study has weaknesses, i.e the absence of information on likely confounders such as smoking, BMI and medical history (e.g. presence of diabetes, hypertension) of women during pregnancy.
Although some weaknesses can be found in the study, some conclusions can nonetheless be drown: first, women with >20 oocytes have a higher risk of adverse obstetric outcomes; second, women with poor ovarian response do not have an increased risk of adverse obstetric outcomes; third, female age is not the only important cause of adverse obstetric outcomes.
These findings are the umpteenth demonstration that controlled ovarian stimulation regimens must be individualized. For women with high ovarian reserve is important to avoid the excessive ovarian response, which leads to the risk of OHSS and to adverse obstetric outcomes. If then a high ovarian response is obtained and pregnancy is achieved, this pregnancy should be carefully monitored, in the assumption that it is already beyond the boundaries of physiology.
Sunkara SK, La Marca A, Seed PT, Khalaf Y. Increased risk of preterm birth and low birthweight with very high number of oocytes following IVF: an analysis of 65 868 singleton live birth outcomes. Hum Reprod. 2015 ;30:1473-80.
Prof. Antonio La Marca
Clinica Eugin Modena and Università degli Studi di Modena e Reggio Emilia