The Influence of Female Body Mass Index on Ovarian Stimulation Efficiency, Embryo Quality, and Reproductive Outcomes: A Retrospective Cohort Study from a Tertiary Care Center

Obesity is one of the most significant public health concerns and a growing global epidemic [1]. It is widely recognized that obesity plays a crucial role in female reproductive health, and the association between excess weight and impaired fertility has been extensively studied in the literature. The mechanisms by which excess weight affects reproduction are complex and multifactorial [2]. Anovulation is one of the most widely accepted causes of obesity, which is associated with hyperinsulinemia and increased insulin resistance [3]. However, additional factors are thought to play a role, as obese women with regular menstrual cycles experience longer time to conception than their normal-weight counterparts [4], suggesting that overweight and obesity contribute to subfertility even in the absence of ovulatory dysfunction. 

The increasing incidence of obesity, along with its effect on fertility and the trend towards delaying motherhood, has led to an increasing number of women with a Body Mass Index (BMI) above the recommended range seeking for Assisted Reproductive Treatments (ART) [5]. These techniques include specific procedures such as In Vitro Fertilization (IVF) and Intracytoplasmic Sperm Injection (ICSI). The negative impact of excess weight has been linked to poorer reproductive outcomes following these techniques, including significantly lower clinical pregnancy and live birth rates, compared with women with a normal BMI [6-8]. This finding supports the idea that the reproductive effect of obesity extends beyond ovulatory dysfunction, indicating a potential effect on embryo quality and/ or endometrial receptivity. 

Overweight and obese mothers are at an increased risk of adverse maternal and fetal/neonatal outcomes such as gestational diabetes, gestational hypertension, postpartum hemorrhage, pre-eclampsia, preterm premature rupture of membranes, and admission of the newborn to the intensive care unit [9]. This study aimed to assess the impact of overweight and obesity on reproductive outcomes in women undergoing IVF/ICSI within an infertile Portuguese population, with clinical pregnancy rates as the primary outcome.

This retrospective study was conducted using the database of the Reproductive Medicine Unit of a tertiary university hospital. Couples who underwent IVF/ICSI cycles with fresh embryo transfer between January 2012 and January 2022 were included in the study. A total of 2,941 couples were included in this study. The exclusion criteria were cycles with donated embryos or gametes. Embryos were categorized according to ASEBIR morphological classification into A/B (good embryo quality) and C/D (poor embryo quality). BMI was calculated by dividing the individual's weight (in kilograms) by the square of their height (in meters). The World Health Organization (WHO) classification was used to stratify the sample into three distinct groups: normal weight (BMI between 18.5 and 24.9 kg/m^²), overweight (BMI between 25 and 29.9 kg/m^²), and obesity (BMI ≥ 30 kg/m^²). The reference group consisted of women with normal weight. 

The primary outcome was to compare the rate of ongoing clinical pregnancy, defined by ultrasound detection of a gestational sac with an embryo showing fetal heart activity at 7 weeks of gestation, between women with overweight/obesity and those with normal BMI. Secondary outcomes included live birth rate and response to ovarian stimulation during ART, measured by the number of oocytes retrieved and the Follicle-to-Oocyte Index (FOI). FOI is the ratio between the number of oocytes retrieved during oocyte retrieval and the number of antral follicles before stimulation. The FOI was also analyzed categorically and stratified into two groups: < 0.5 vs ≥ 0.5. FOI ≥ 50% was considered as normal ovarian response. Live birth rate was defined as the birth of a live newborn at > 22 weeks of gestation. The gestational age was determined based on the date of oocyte retrieval. In Portugal's public healthcare system, current regulations limit IVF/ICSI cycles to women under 40 years of age. All women in the study fulfilled these criteria. 

Comparisons were adjusted for potential confounders such as age, ovarian reserve markers (anti-Müllerian hormone and antral follicle count), infertility type, cause, duration, and smoking status. All women underwent controlled ovarian hyperstimulation with gonadotropins at doses ranging from 150 IU to 300 IU, based on ovarian reserve markers or previous cycle results. As our data included cycles from 2012, both the long agonist protocol, the first-line treatment between 2012 and 2019, and the fixed GnRH antagonist protocol, were included. To account for this bias, comparisons were adjusted according to the stimulation protocol used. 

Statistical analyses were performed using STATA version 14.1. The Shapiro-Wilk test was used to assess whether continuous variables followed a normal or non-normal distribution. For normally distributed continuous variables, the results were presented as means and standard deviations, and comparisons were made using the student’s t-test. Non-normally distributed variables were described as medians and Interquartile Ranges (IQR), with comparisons made using the Mann-Whitney test. Categorical variables were characterized by absolute numbers and relative frequencies, and comparisons between them were performed using the chi-square test or Fisher’s exact test, when appropriate. An association was considered statistically significant if the p-value was < 0.05. Multiple variable logistic regression analysis was used to adjust for the potential confounding factors.

In the total sample of 2,941 patients, the median BMI was 24 kg/m^² (interquartile range: 21-27). Regarding the distribution across the different BMI categories, 79 women (2.7%) were underweight, 1,624 (55.2%) were normal weight, 822 (28%) were overweight, and 416 (14.1%) were obese. The median age of the patients was 35 years (interquartile range: 33-38). Regarding the etiology of infertility, 37.3% of the cases were attributed to male factors, 15% to tubal factors, and 10.4% to endometriosis. Anovulation was present in 0.7% of patients and all these patients had a previous diagnosis of polycystic ovarian syndrome, while 0.1% had uterine factors. A mixed etiology was observed in 9.1% of couples and 2.2% of women had a combination of female factors. Finally, 25.2% of the cases were classified as idiopathic infertility. The characteristics of the study population according to the BMI groups (normal, overweight, and obese) are shown in table 1.

Table 1: Characterization of the population according to BMI group.

BMI: Body Mass Index; AFC: Antral Follicle Count; AMH: Anti-Müllerian Hormone; IQR: Interquartile Range; IVF: In Vitro Fertilization; ICSI: Intracytoplasmic Sperm Injection

As shown in table 1, comparing the obese women group with the normal weight reference group, we found that obese women had a higher Antral Follicle Count (AFC) and higher levels of Anti-Müllerian hormone (AMH) (10 vs. 9, p < 0.001; 2.48 ng/mL vs 1.84 ng/mL, p=0.001, respectively). The obese group also had a lower prevalence of primary infertility (64.4% vs. 71%, p=0.009), a lower proportion of smokers (15.9% vs. 21.9%, p=0.006), and a longer median duration of infertility (7 vs. 5 years, p < 0.001). The obese women also required a higher total dose of gonadotropins (2550 IU vs. 2337 IU, p=0.001), and in a higher proportion, fertilization was performed using the ICSI technique (52.4% vs. 43.8%, p= 0.002). Regarding the protocol used, obese women had a higher proportion of antagonist protocols than did non-obese women (31.7% vs. 23.5%, p=0.001). The distribution of infertility causes was statistically different between obese women and both normal-weight and overweight women. When comparing the groups based on each individual cause of infertility, obese women had a lower proportion of endometriosis than the overweight and normal-weight groups (6% vs. 11%, p=0.004 and 6% vs. 11%, p=0.003, respectively). The proportion of couples with unexplained infertility was lower among obese women than that among overweight and normal-weight women (18.3% vs. 23.8%, p=0.025 and 18.3% vs. 27.2%, p < 0.001, respectively). No statistically significant differences were observed in the remaining comparisons. 

Comparing the overweight and reference groups, we found that overweight women had a lower proportion of cases of primary infertility compared to the normal group (60.6% vs. 71%, p < 0.001). In addition, the duration of infertility was longer in the overweight group (6 vs. 5 years, p < 0.001), as was the total dose of gonadotropins used (2550 vs. 2440 IU, p=0.003). Comparing the overweight and the obese women groups, we found that the obese group had higher levels of AFC and AMH than the overweight group (10 vs 9, p=0.002 and 2.48 ng/mL vs 1.83 ng/mL p=0.001 respectively). In addition, the duration of infertility was longer in the obese group (7 vs. 6 years, p < 0.001). Regarding the technique and protocol used, obese women had a higher proportion of fertilization with the ICSI technique (52.4% vs. 45.1%, p=0.016) and a higher proportion of antagonist protocols for ovarian stimulation (31.7% vs. 25.4%, p=0.019). The results of the analysis of the ovarian stimulation response and the comparison between the BMI groups are detailed in table 2.

Table 2: Parameters related to the efficiency of ovarian stimulation response.

Based on the data in table 2, we found that the median number of oocytes collected was similar among the three groups of BMI. The only statistically significant difference between the overweight and reference groups was the lower proportion of good-quality embryos in the overweight group (54.7% vs. 60%, p=0.01). Comparing obese and normal-weight women, the former had a lower median FOI (0.70 vs 0.83, p=0.003) and a higher proportion of FOI < 0.5 (30.2% vs. 19.7%, p < 0.001). Obese women also showed a lower fertilization rate (p=0.04), a lower percentage of embryo transfers at the blastocyst stage (p=0.01), and a higher proportion of embryo transfers subjectively classified by clinicians as difficult (p=0.01). 

Comparing the overweight women group with the obese women group, a statistically significant difference was observed in the FOI, with a lower median value in the obese group (0.70 vs 0.77, p=0.03). Additionally, the proportion of FOI < 0.5 was significantly higher among obese women (p=0.001). Furthermore, the obese group had a lower percentage of embryo transfers performed at the blastocyst stage (p=0.02). When comparing the clinical pregnancy rates across different BMI classes, the percentage of pregnant women was very similar among the groups: 39.8% in the normal-weight group, 40% in the overweight group, and 39.4% in the obese group, with no statistically significant differences between the groups (p > 0.05). 

When comparing the miscarriage rates across different BMI classes, the percentage of pregnant women was very similar among the groups: 16% in the normal-weight group, 17% in the overweight group, and 21% in the obese group, with no statistically significant differences between the groups (p > 0.05). In addition to assessing clinical pregnancy outcomes according to BMI class, this variable was also assessed as an absolute value (continuous variable). Table 3 provides an overview of the characteristics of the study population according to clinical pregnancy outcomes, including the entire sample of 2,941 women. Regarding our primary outcome, we did not observe a statistically significant difference in the median BMI between the pregnant and nonpregnant women.

Table 3: Characterization of the population according to pregnancy outcome. 

Based on the data presented in table 3, we found that the median age of the pregnant women was lower than that of the nonpregnant group (p < 0.001). Pregnant women had higher AMH levels and AFC (p < 0.001). In the clinical pregnancy group, the proportion of women using a long agonist protocol for ovarian stimulation was higher, and the median total dose of gonadotropins used was lower than that in the nonpregnant group (p < 0.001). The pregnant group also had a higher number of oocytes retrieved, a lower proportion of FOI < 0.5 (p = 0.02), a higher percentage of good-quality embryos (p < 0.001), and embryo transfer at the blastocyst stage (p = 0.005). The live birth rate was slightly lower in the obese women group (28.8%) and the overweight group (30.2%) than in the normal-weight group (32.3%). However, we did not observe any statistically significant differences between the groups (p>0.05). To adjust for potential confounding factors, logistic regression was performed considering the variables that were statistically significantly associated with clinical pregnancy and the BMI, which is the main variable in this study. The results are shown in table 4.

 Table 4: Results of the multiple variable logistic regression model.

BMI: Body Mass Index; AFC: Antral Follicle Count; AMH: Anti-Müllerian Hormone; CI: Confidence Interval; AFC: Antral Follicle Count; AMH: Anti-Müllerian Hormone; IQR: Interquartile Range; IVF: In Vitro Fertilization; ICSI: Intracytoplasmic Sperm Injection.

After adjusting for all potential confounders, good embryo quality and blastocyst stage remained the only parameters that were significantly associated with a higher clinical pregnancy rate.

In our sample, the BMI group stratification was not associated with different clinical pregnancy or live birth rates. A systematic review of 33 studies including 47,967 treatment cycles showed that women with a BMI ≥25 kg/m^² had lower clinical pregnancy rates, lower live-birth rates, and higher miscarriage rates after IVF than those with a BMI < 25 kg/m^² [10]. Recently, these results were reinforced by a meta-analysis of 21 studies comparing obese women with those with a normal BMI [8]. A recent retrospective study by Rafael et al., [11] included 14 213 IVF/ICSI cycles and categorized the participants into four groups: underweight, normal weight, overweight, and obesity. The main outcome was the Cumulative Live Birth Rate (CLBR), and the secondary outcome was the Time To Pregnancy (TTP). The study showed that overweight and obese women had significantly lower rates of CLBR than did normal-weight women. This study also described a detailed analysis of the combined impact of age and BMI on reproductive outcomes, reporting that weight loss with a decrease in BMI can be beneficial, especially in women under the age of 35 years. The group of women aged 36-38 years faces a sharp decline in fertility due to age, so that only substantial weight loss (such as transitioning from obesity to normal weight) showed significant benefits in terms of CLBR. In women over 38 years of age, the effect of older age was determinant and probably irreversible; therefore, a reduction in BMI at 12 months was not sufficient to compensate for the negative impact of age. A central point of this study and reinforced by a recent article from the group is the importance of an individualized approach to weight loss prior to PMA treatment according to female age [12]. In our sample, after adjusting for potential confounders, logistic regression did not find a statistically significant association between female age and pregnancy rate. The median age was 35 years old and IQR 33-38, so most of the women included were < 38 years old, a group when age is not so determinant and irreversible.

Future studies should prospectively assess whether women undergoing weight loss strategies successfully achieve changes in BMI categories, thereby enabling the development of the most effective clinical approach to optimize reproductive treatment for overweight or obese women. While the health benefits of weight loss and achieving a normal BMI for women and pregnant individuals are well documented [9], the results of this study suggest that there may be no evidence-based justification for delaying IVF/ICSI for weight loss, given the potentially detrimental effects of female aging.

In agreement with our results, Ozekinci et al., found that overweight/obese women required substantially higher doses of gonadotropins without any difference in pregnancy rates after IVF/ICSI [13]. The underlying reasons why women with a high BMI require higher doses are not yet fully understood; however, they may be associated with a larger body surface area, resulting in significant pharmacokinetic alterations, inadequate estradiol metabolism, and reduced SHBG levels [14]. Consistent with the literature, our study found that obese and overweight women experienced a longer duration of infertility than those with a normal weight. Hassan and Killick found that women with a pre-pregnancy BMI above 25 kg/m^² took twice as long to conceive as those with a normal BMI) [15]. Our data also indicated a higher fertilization rate among women with a BMI between 18.5 and 24.9 kg/m^². However, the difference was only statistically significant when compared to the obese women group, suggesting that only BMI above 30 kg/m^² appears to have a significant impact on fertilization rates. Other studies have not found a significant difference in fertilization rates between obese or overweight women and those with normal weight [13]. Notably, in the obese group, there was no statistically significant increase in male factor infertility, suggesting that the lower fertilization rate observed in obese women may be indicative of poorer oocyte quality.

The results of our study showed that obese women had higher AFC and AMH levels than normal-weight and overweight women, suggesting a greater ovarian reserve. The relationship between BMI and ovarian reserve markers is complex and remains a matter of controversy. Some authors have not found a significant association between BMI and AMH levels [16] in infertile women, suggesting that the mechanisms responsible for reduced fertility in women with higher BMI are not related to diminished ovarian reserve but rather to anovulation and/or impaired endometrial receptivity [17]. Other authors have reported significantly lower AMH levels in obese women [18]. It is important to note that most studies investigating the relationship between serum AMH concentration and BMI have included women with PCOS, whose AMH levels are often higher [19]. There is a well-established association between PCOS and obesity that may account for the elevated ovarian reserve marker levels observed in this group. However, it is important to note that only 1% of obese women in our study had anovulation and PCOS as the cause of infertility in IVF/ ICSI. 

Regarding the ovarian response to stimulation, we found that the number of oocytes retrieved was similar across all BMI groups; however, there was a significantly lower FOI in overweight and obese women than in women with normal weight. In addition, both groups had higher rates of FOI<50%, reflecting the reduced efficiency of ovarian stimulation. FOI is increasingly recognized as a novel parameter for assessing ovarian response to stimulation [20]. However, current evidence regarding the relationship between FOI and pregnancy rates following IVF/ICSI remains limited and sometimes contradictory. In a study involving 4,323 women, Li and Chen found that higher FOI values were associated with increased clinical pregnancy rates, higher number of oocytes retrieved, and improved embryo quality [21]. Conversely, the conclusions of Carosso et al., differ, as their study on older women (≥39 years) with unexplained infertility found no association between FOI and higher live birth rates [22]. 

In our sample, obese women had a lower percentage of blastocyst-stage embryo transfers than did normal-weight and overweight women, which could be an indicator of poorer embryo quality in obese women. Regarding embryo quality, our study found that women with a BMI within the reference range had a slightly higher proportion of high-quality embryos. This difference was statistically significant only when compared with overweight women, whereas no significant difference was observed between obese and normal-weight women. Although the latter difference may lack statistical significance, it remains to be clinically relevant. The literature has presented inconsistent findings on this topic. Bellver et al., reported no changes in oocyte and embryo quality based on morphological criteria in obese women but observed a progressive decline in implantation, pregnancy, and live birth rates as BMI increased [23]. 

When logistic regression was performed adjusting for variables with a statistically significant association with clinical pregnancy outcomes, embryo quality was the only parameter that maintained a statistically significant association. Embryo quality plays a crucial role in the success of IVF/ICSI. Maternal age and BMI can have an indirect impact on embryo quality, highlighting the importance of promoting healthy lifestyles to improve reproductive outcomes after ART. The main strength of this study was the large sample size of 2941 IVF/ICSI cycles with fresh embryo transfer. An innovative component of this study was the use of the FOI as an indicator of the response to ovarian stimulation, with lower values in women with high BMI, suggesting that obese women tend to have a lower response to ovarian stimulation. Future prospective studies should focus on the potential effects of BMI on oocyte quality, which may explain the lower index. 

We acknowledge some limitations, such as the retrospective design of the study, which prevented us from collecting additional data, particularly on other markers of ovarian response to stimulation, such as the Follicular Output Rate (FORT).

In conclusion, our data suggest that overweight and obesity negatively affect the response to ovarian stimulation, without significantly affecting clinical pregnancy and live birth rates. Overweight and obese women required higher doses of gonadotropins to achieve a similar number of oocytes, despite having a higher proportion of FOI<50%. This suggests that the number of oocytes retrieved was lower than expected, based on the initial antral follicle count. Embryo quality has emerged as a key factor in determining ART success. Female age and Body Mass Index (BMI) are associated with lower embryo quality, and there is a clear benefit of promoting healthy lifestyles. Nonetheless, the decision to immediately start IVF/ICSI versus postponing it to achieve weight reduction must be weighed because of the potential deleterious effect of aging on female fertility.

Catarina Policiano: Conceptualization, Data curation, formal analysis, investigation, methodology, writing-original draft, writing-review, and editing. Margarida Gouveia: conceptualization, Data curation, formal analysis, investigation, methodology, writing of the original draft. Rafaela Fonseca: Data curation, formal analysis, investigation, and methodology. Ana Aguiar: Conceptualisation, investigation, methodology, supervision, writing, review, and editing.

• Ethical compliance 

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Ethical approval for this study was granted by the local ethics committee board (registration number 314/22). All patients gave prospective consent for their records to be accessed for investigational purposes such as this study. The data was collected retrospectively by reviewing the electronic and physical medical records and de-identified data was recorded and stored in a standardized computer spreadsheet. 

• Conflict of interest declaration 

The authors declare that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript.

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