Discussion
Main findings and Interpretations
In the current study, elevated BMI was associated with fewer mature oocytes and available embryos in younger women, but we did not observe a statistically significant decline in blastocyst formation rate, HQE rate, and TQE rate in overweight and obese individuals versus normal-weight controls, which is inconsistent with the research results of Ioanna et al. 9. Despite previous studies reporting that elevated BMI can be associated with poor pregnancy outcomes of fresh IVF cycles, no significant effects of maternal BMI on implantation rate, CPR, OPR, and LBR in all groups and subgroups were observed in fresh cycles. This finding may be related to the lack of differences in the number of HQE and TQE, which could also explain the absence of statistical differences in the abortion rates of fresh cycles. Unlike the recent study demonstrated that obesity was associated with spontaneous abortion19, compared to women with normal weight, the odds of early miscarriage were 1.45 times higher among obese women20.
CLBR was significantly lower among younger women with high BMI relative to the normal BMI group; this may be due to a reduced number of available embryos at cleavage and blastocyst stages in the high BMI group. Nevertheless, the decrease in the number of embryos was triggered by a reduction in the number of retrieved oocytes and mature oocytes, which was statistically different for younger women among different BMI groups. Thus, we speculated that the obesity microenvironment has a greater adverse effect on oocyte maturation and development in younger women than in older women.
Previous animal studies have indicated that obesity adversely affects oocyte maturation and embryonic development 21-25. This could be due to direct damage of the oocytes and indirect effects of dysfunctional systemic maternal endocrinology and metabolism. Murine models fed a high-fat diet (HFD-mice) were used to mimic the effects of obesity and metabolic dysfunction observed in obese humans. In addition to the body weight gain of the HFD-mice, hypercholesterolemia, elevations in glucose, insulin, or free fatty acids, and changes in adipokines may affect oocyte quality21. The adverse effects of maternal obesity have been observed as early as the oocyte and two-cell embryo stages, and there are more apoptotic follicles and smaller and fewer mature oocytes in obese mice compared with control mice26. Oocytes from HFD-mice tend to have meiotic aneuploidy, spindle and chromosome alignment defects, and mitochondrial abnormalities, which are a major cause of early embryonic loss23, 24. In addition, bidirectional communication of the oocyte with the surrounding cells is critical for oocyte development, and several studies have attempted to evaluate the impact of obesity on these ovarian cells. HFD-mice exhibited increased anovulation and decreased fertilization rates in vivo, which is accompanied by remarkably increased apoptosis, endoplasmic reticulum stress, lipid accumulation, and mitochondrial dysfunction in granulose and cumulus cells27. Increased apoptosis of granulose cells might explain the low peak estradiol levels among obese women of any age, despite the increased Gn dose for younger women. But research evidence from human studies is limited, Jungheim et al. demonstrated that obesity does not affect IVF outcomes in women using donor oocytes28. Recent study using the Time-Lapse system indicated that human oocytes from overweight and obese women were smaller and less likely to complete fertilization; the resulting embryos were more likely to reach the morula stage, and the trophectoderm of blastocysts had fewer cells29. Thus, the adverse effect of elevated BMI on oocyte quality rather than endometrial receptivity may be the major factor impairing IVF/ICSI outcomes. However, further research is needed to confirm and consolidate the above ideas.
Moreover, the long-term adverse effects of obesity are mainly reflected in the birth safety and health of the offspring. In the present study, maternal HDP and fetal macrosomia were more likely to occur among younger women with high BMI. Liu et al.30 also reported that obesity might raise the risk of some poor prenatal outcomes through the development of GDM and HDP. Therefore, the fetus is more likely to be exposed to an adverse intrauterine environment, resulting in an increased incidence of fetal macrosomia and cesarean delivery, which, in turn, increases the risk of childhood and adult obesity. In addition, no significant difference in congenital defects between different BMI groups except for cleft lip and cleft palate in younger women was observed in our study.
Interestingly, our findings indicate no significant differences in pregnancy outcomes, obstetric and neonatal complications, and congenital defects between different BMI groups among older women (≥ 38y), whether undergoing fresh cycles or subsequent FET cycles. Therefore, we believe that age is still a major factor affecting IVF/ICSI outcomes. Obesity has a greater adverse impact on younger women (< 38y) compared to older women (≥ 38y). Kort et al.31 showed that 10% weight loss could enhance LBR in overweight/obese women. Liu et al.30 also suggested a 10%–15% reduction in pre-pregnancy maternal BMI for obese women and a 5% reduction for overweight women to lower the incidence of prenatal outcomes. Based on the above evidence, younger women with elevated BMI should consider losing weight before pregnancy, but older women do not have to delay pregnancy to achieve weight loss as they need to balance against the risk of age-related fertility decline. Notably, our weight loss recommendations are based on age boundaries. However, it remains to be tested whether weight management interventions could improve the short- and long-term outcomes of IVF/ICSI treatment.