Excessive gonadotropins in IVF: Effects on mosaicism and live birth


A recent study revealed a correlation between high doses and prolonged duration of exogenous gonadotropin use during in vitro fertilization and increased embryonic mosaicism alongside diminished live birth rates, prompting reconsideration of dosage and duration protocols.

Excessive gonadotropins in IVF: Effects on mosaicism and live birth | Image Credit: © Seventyfour - © Seventyfour - stock.adobe.com.

Excessive gonadotropins in IVF: Effects on mosaicism and live birth | Image Credit: © Seventyfour - © Seventyfour - stock.adobe.com.

Embryonic mosaicism is increased by administration of excessive exogenous gonadotropin, while cumulative live birth rates are decreased, according to a recent study published in JAMA Network Open.


  1. Excessive administration of exogenous gonadotropins during controlled ovarian hyperstimulation (COH) is associated with increased rates of embryonic mosaicism, particularly when treatment duration is under 10 days.
  2. Cumulative live birth rates are significantly decreased when gonadotropin dosage exceeds 1500 IU and/or treatment duration extends beyond 10 days. This suggests that prolonged exposure to high gonadotropin levels may adversely affect pregnancy outcomes.
  3. The study highlights the lack of conclusive data regarding the safety of COH on embryonic and pregnancy outcomes. This underscores the importance of further research to better understand the potential risks associated with fertility treatments.
  4. Different COH protocols were employed, including GnRH agonist long protocol, GnRH short protocol, and GnRH antagonist protocol. These variations were considered based on factors such as patient age, body mass index, and ovarian reserve.
  5. The findings suggest the need for cautious consideration of gonadotropin dosage and duration in fertility treatment protocols. Lowering exogenous gonadotropin levels and treatment duration may mitigate the risks of increased embryonic mosaicism and decreased live birth rates.

Gonadotropins are the primary medication used for controlled ovarian hyperstimulation (COH) during in vitro fertilization, with continued administration linked to follicle growth. However, embryonic development and pregnancy outcomes may be adversely impacted by high estrogen concentrations from the development of multiple follicles.

There is a lack of conclusive data about the safety of COH for embryonic and pregnancy outcomes. The accuracy of available data may also be impacted by high embryonic abnormality risk in patients, such as those with advanced maternal age or recurrent miscarriages.

To determine the impact of gonadotropin dosage and treatment duration on embryonic and pregnancy outcomes, investigators conducted a post hoc analysis of a randomized clinical trial. Participants included couples with infertility and a good prognosis.

Good prognosis was determined by at least 3 available good-quality blastocytes for a mother aged 20 to 37 years with a day 5 embryo culture score of 4BC or better. Patients were divided into groups based on exogenous gonadotropin dose and duration.

Group 1 included patients with a dosage of 1500 IU or under and duration under 10 days, group 2 1500 IU or under and 10 or more days, group 3 over 1500 IU and under 10 days, and group 4 over 1500 IU and 10 or more days. Group 1 was considered the control group.

There were 3 protocols used to perform COH: a gonadotropin-releasing hormone (GnRH) agonist long protocol, a GnRH short protocol, and a GnRH antagonist protocol. Patients’ age, body mass index, and ovarian reserve were considered when deciding the protocol.

In the long protocol, a GnRH agonist was employed from the midluteal phase of the last menstrual cycle. In the short protocol, the agonist was employed on days 2 to 3 of the menstrual period. Finally, GnRH antagonists were employed during the antagonist protocol when the diameter of the largest follicle was above 12 mm.

Embryo aneuploidy, mosaicism, and cumulative live birth rates were measured as the primary outcomes of the analysis. Live birth was defined as birth of a viable infant after 28 weeks’ gestation.

There were 603 couples included in the analysis, and prospective mothers were aged a mean 29.13 years. Group 1 included 211 couples with 633 embryos, group 2 113 couples with 339 embryos, group 3 62 couples with 186 embryos, and group 4 216 couples with 651 embryos.

Mean endometrial thickness was significantly higher in groups 2 and 4 vs group 1. However, similar endometrial preparation protocols were conducted across groups.

In groups 2, 3, and 4, 13%, 14.5%, and 12.6% of embryos, respectively, were mosaic embryos. This indicates adjusted odds ratios (aORs) of 1.69, 1.98, and 1.60, respectively, when compared to group 1, which had a rate of 8.8%.

Increased gonadotropin dosage had an aOR of 1.848 for mosaicism incidence with a treatment duration under 10 days. However, this association was not found when the treatment duration was 10 or more days, with an aOR of 0.96.

Live birth rates were significantly lower in groups 2, 3, and 4 compared to group 1, with aORs of 0.49, 0.41, and 0.53, respectively. The proportion of patients with ongoing pregnancy was also decreased in these groups vs group 1.

In group 3, biochemical pregnancy and clinical pregnancy were reported in 79% and 71% of patients, respectively. In group 1, these rates were 91% and 89.6%, respectively. Additionally, the proportion of infants with a low birth weight was significantly greater in group 2 than group 1, at 9.6% vs 2.2%, respectively.

These results indicated an association between excessive exogenous gonadotropins with increased embryonic mosaicism incidence and decreased live birth rate. Investigators concluded consideration should be given for reducing exogenous gonadotropin dosage and duration.


Ni T, Zhou W, Liu Y, et al. Excessive exogenous gonadotropins and genetic and pregnancy outcomes after euploidy embryo transfer: A secondary analysis of a randomized clinical trial. JAMA Netw Open. 2024;7(4):e244438. doi:10.1001/jamanetworkopen.2024.4438

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