Female obesity increases the risk of miscarriage of euploid embryos
Male and Female obesity have both been linked to decreased rates of pregnancy and live birth in natural and assisted cycles. Studies show that high BMI (body mass index) has a harmful effect on gametes, embryos and endometrial receptivity which eventually leads to decreased IVF/ICSI pregnancy rates. Once pregnant though, obese women are at higher risk of adverse maternal and foetal complications that could end in miscarriage.
According to statistics, the leading cause of first trimester miscarriage is embryo aneuploidy and therefore it was assumed that obesity could potentially be a cause of chromosomally abnormal embryos. However, the very latest research has quashed this assumption. Experts now believe that the cause of miscarriage in women with high BMI is not linked to chromosomes but instead due to a disrupted endometrium or an unconducive uterine environment.
Unfortunately, the risk of miscarriage in women suffering from obesity after the transfer of euploid embryos has not been explicitly investigated to date.
To evaluate whether women with high BMI had an increased risk of miscarriage after IVF using euploid embryos.
A multicenter retrospective analysis of all IVF cycles with PGT-A (Preimplantation genetic testing for aneuploidy), from January 2016 to April 2019, performed at the Instituto Valenciano de Infertilidad (IVI) was carried out. It included all women, with documented BMI at the time of ovarian stimulation, who transferred at least one euploid embryo. There was no restrictions on age or PGT-A indication, meaning the need for PGT-A. However, data from oocytes donation cycles was excluded from this study to minimise potential bias.
Next patients were then grouped according to BMI, as defined by WHO;
- Underweight < 18.5 kg/m2
- Normal weight 18.5–24.9 kg/m2
- Overweight 25.0–29.9 kg/m2
- Obese ≥ 30.0 kg/m2
Ovarian stimulation was generally carried out using the Gonadotropin-releasing hormone (GnRH) antagonist protocol, except in a few patients where the long GnRH agonist protocol was administered or no luteinizing hormone surge suppression was carried out.
Initial transvaginal ultrasound was done on stimulation day 5, and repeated every 2 days, along with serum estradiol (E2) and progesterone (P) measurements. Patients were then given a GnRH antagonist (0.25mg) to administer daily once 1 or more follicles reached a mean diameter of 14µm. Final oocyte maturation was triggered, using a GnRH antagonist and or HCG, once 3 or more follicles reached a mean diameter of 17-18µm followed by oocyte retrieval 36 hours later.
From January 2016 to June 2018, chromosome screening of embryos was done primarily through comparative genomic hybridization arrays (CGHa), with next-generation sequencing (NGS) slowly introduced from January 2017 and onwards.
As soon as one euploid blastocyst was available, transfer of embryo was scheduled following a modified natural or hormonally prepared cycle. Luteal support using micronized vaginal progesterone (and estradiol in hormonally prepared cycles) was continued until week 12 of gestation.
Implantation rate, pregnancy rate (PR), biochemical and clinical miscarriage rate (MR), and live birth rate (LBR) of each group was then compared.
A total of 3480 cycles of women undergoing IVF with PGT-A and one euploid embryo was identified. In the obese group (BMI ≥ 30 kg/m2), 130 women specifically had class I obesity (30–34.9 kg/m2; 70.3%), 45 had class II obesity (35– 39.9 kg/m2; 24.3%), and 10 had class III obesity (≥ 40 kg/m2; 5.4%).
Initial baseline patient and IVF cycle characteristic analysis revealed no significant difference in the number of PGT-A cycles done per patient across the 4 groups.
Although the age of women in the overweight group was significantly higher than the 3 other groups, it was not deemed to be (clinically) relevant after performing a linear regression analysis and finding no effect on LBR.
Advanced maternal age (≥ 38 years) was found to be the main cause of infertility and indication for PGT-A among the 4 groups.
Following oocyte retrieval, no significant difference in the fertilization rate, number of euploid embryos and number of embryos transferred per patient was found between the 4 groups.
|No. of women||155||2549||591||185|
|PGT-A cycles (n)||1.33||1.28||1.34||1.35|
|Fertilization rate (%)||82.3||81.9||80.7||80.0|
|Euploid embryos (n)||2.54||2.26||2.26||2.29|
|Transferred embryos (n)||1.04||1.09||1.10||1.05|
Next, analysis of post euploid embryo transfer results revealed no significant differences in implantation rate, pregnancy rate and clinical PR across the 4 groups.
However, women in the obese group had worse outcomes with significantly higher miscarriage rates, leading to significantly lower live birth rates, compared to the other 3 groups.
|Pregnancy Rate (PR)||64.5%||62.4%||63.1%||60.5%||NS|
|– Biochemical Miscarriage||7.7%||8.3%||8.5%||9.2%||NS|
|– Clinical Miscarriage||6.5%||6.8%||8.1%||13.5%||0.007|
|Live Birth rate||48.7%||44.5%||44.8%||34.3%||0.034|
SUMMARY: DOES OBESITY INCREASE THE CHANCE OF MISCARRIAGE
In this study, the chance of miscarriage among obese women (BMI ≥ 30) was significantly higher, with increased rates of miscarriage (13.5% vs. 8.1-6.5%) post ultrasound confirmation of pregnancy, and decreased rates of live birth (34.3% vs. 44.5-48.7%), following the transfer of euploid embryos.
- Retrospective study.
- Small sample size among the extreme and very high BMI sub-groups limiting further analysis.
- No data pertaining to male BMI, lifestyle habits and pregnancy development.
No external funding was declared for this study.
A substance (drug) that causes the same action as the normal substance.
A cell that has a chromosomal anomaly.
A substance (drug) that stops the action or effect of another substance.
A fertilised embryo that has developed an inner cell mass and outer layer (trophoblast) some time from day 4 onwards.
A cell that has the normal number of chromosomes.
Second half of the menstrual cycle, from ovulation to the start of menstruation.
Unfertilised immature / mature egg.
The probability that a result occurred by random chance.
Tremellen K, et al. (2017). Increased miscarriage of euploid pregnancies in obese women undergoing cryopreserved embryo transfer. https://doi.org/10.1016/j.rbmo.2016.09.011
Sundaram R, et al. (2017). Couples’ body composition and time-to-pregnancy. https://doi.org/10.1093/humrep/dex001
Bellver J, et al. (2013). Obesity reduces uterine receptivity: clinical experience from 9,587 first cycles of ovum donation with normal weight donors. https://doi.org/10.1016/j.fertnstert.2013.06.001
Ramlau-Hansen C H, et al. (2007). Subfecundity in overweight and obese couples. https://doi.org/10.1093/humrep/dem035
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