Abstract
Objective
Assess the effect of class III (body mass index [BMI, kg/m2] 40–49.9) and class IV obesity (≥ 50) on clinical pregnancy and live birth outcomes after first oocyte retrieval and fresh embryo transfer cycle.
Design
Cohort study
Setting
Academic center
Patients
Patients undergoing their first oocyte retrieval with planned fresh embryo transfer in our clinic between 01/01/2012 and 12/31/2018. Patients were stratified by BMI: 18.5–24.9 (n = 4913), 25–29.9 (n = 1566) 30–34.9 (n = 559), 35–39.9 (n = 218), and ≥ 40 (n = 114).
Intervention
None
Main outcome measure
Live birth rate
Results
Following embryo transfer, there were no differences in pregnancy rates across all BMI groups (p value, linear trend = 0.86). However among pregnant patients, as BMI increased, a significant trend of a decreased live birth rate was observed (p value, test for linear trend = 0.004). Additionally, as BMI increased, a significant trend of an increased miscarriage rate was observed (p value, linear trend = < 0.001). Compared to the normal-weight cohort, women with a BMI ≥ 40 had a significantly higher rate of cancelled fresh transfers after retrieval (18.4% vs. 8.2%, OR 2.51; 95%CI 1.55–4.08). Among singleton deliveries, a significant trend of an increased c-section rate was identified as the BMI increased (p value, linear trend = <0.001).
Conclusion
Overall, patients with a BMI > 40 have worse IVF treatment outcomes compared to normal-weight patients. After embryo transfer, their pregnancy rate is comparable to normal-weight women; however, their miscarriage rate is higher, leading to a lower live birth rate for pregnant women in this population. Patients with a BMI > 40 have a c-section rate that is 50% higher than normal-weight patients.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10815-020-02011-1.
Keywords: Obese, Class III obesity, Class IV obesity, Overweight, Infertility
Introduction
Obesity and its impact on disease morbidity is a serious concern that has been growing worldwide for the last few decades [1]. In the USA alone, an estimated $190 billion US dollars are spent each year on obesity-related healthcare costs [2]. The negative effects of obesity on health outcomes are likely to only increase in prevalence, with recent projections showing that by the year 2030, half of adults in the USA will have a body mass index (BMI; kg/m2) > 30 [3]. Furthermore, it is projected that in the next ten years, almost one-third of females will have a BMI > 35, which will make it the most common BMI category among women.
In reproductive medicine, the impact of obesity on fertility is of great interest and importance as the obesity epidemic becomes greater over time and an increasing number of infertility patients are affected. The adverse effect of obesity on pregnancy outcomes is gradual and the magnitude of the effect becomes more pronounced as BMI increases; therefore, studies with either small sample sizes or a limited number of patients above the overweight (BMI 25–29.9) and class I obesity (BMI 30–34.9) categories do not consistently observe a statistically significant association between BMI and pregnancy outcomes [4, 5]. Large single-center studies and meta-analyses have reported that there is a gradual but significant decline in fecundity as BMI increases above normal [6–8]. However, previous studies have mostly focused on patients who are overweight (BMI 25–29.9) or have class I (BMI 30–34.9) or class II (BMI 35–39.9) obesity [9–11]. Each of these previous studies included a cohort that received all or nearly all cleavage-stage embryo transfers (ET). A study by Russo et al. reported that even when only evaluating single blastocyst embryo transfers, a linear decline in live birth rates persists as BMI increases [12].
As the obesity epidemic continues to worsen with each passing decade, there is an increasing need to understand how the more severe categories of obesity, class III (BMI 40–49.9) and class IV (BMI ≥ 50), affect infertility treatment outcomes. Furthermore, it is important to evaluate whether updates in IVF treatment protocols and the now more common use of blastocyst transfer improve embryo transfer and pregnancy outcomes in obese patients. Therefore, the objective of this study was to evaluate the live birth rates in women with class III and IV obesity following IVF treatment. Secondarily, we aimed to evaluate the difference in outcomes following cleavage-stage and blastocyst-stage embryo transfers among the obesity categories.
Methods
Study population and design
Approval for this study was obtained from the institutional review board at our institution (Protocol number: 19-06020283). This was a retrospective cohort study performed in an academic hospital setting. Patients in our IVF clinic who underwent their first oocyte retrieval with a planned autologous fresh embryo transfer between 01/01/2012 and 12/31/2018 were included. Overweight and obese patients were stratified into their respective BMI classification as designated by the World Health Organization: overweight (BMI 25–29.9), class I obesity (BMI 30–34.9), class II obesity (BMI 35–39.9), and class III and class IV obesity (BMI ≥ 40) [13]. Normal-weight patients (BMI 18.5–24.9) were included as the referent group. Patients with an underweight BMI classification (BMI < 18.5) were excluded. Gestational carrier and donor oocyte cycles were also excluded. Data were collected from our prospectively maintained IVF electronic medical record system. Missing data and key variables were verified in the electronic medical record.
Demographics and outcomes
Patient demographic variables were collected and are shown in Table 1. The mature oocyte rate was defined as the number of mature oocytes retrieved divided by the number of total oocytes retrieved. The fertilization rate was defined as the number of fertilized oocytes at the fertilization evaluation divided by the number of mature oocytes for each patient. Pregnancy was defined as at least a human chorionic gonadotropin (hCG) level > 5 mIU/mL. Spontaneous abortion was defined as a failed pregnancy after the observation of at least a gestational sac on ultrasound. Obstetric data was collected by nurses and physicians via patient self-report. Live birth was defined as delivery at ≥ 24 weeks of gestational age. Preterm delivery was defined as a delivery before 37 weeks of gestation.
Table 1.
Demographic characteristics
| BMI category (kg/m2) | |||||
|---|---|---|---|---|---|
| Normal-weight (18.5–24.9) n = 4913 | Overweight (25–29.9) n = 1566 | Class I obesity (30–34.9) n = 559 | Class II obesity (35–39.9) n = 218 | Class III/IV obesity (≥ 40) n = 114 | |
| Age at oocyte retrieval | 37.1 ± 4.7 | 37.6 ± 4.7 | 37.6 ± 5.1 | 37.8 ± 4.9 | 38.1 ± 4.7 |
| Age | |||||
| <35 | 1633 (33.2%) | 435 (27.8%) | 168 (30.1%) | 60 (27.5%) | 27 (23.7%) |
| 35–37 | 1086 (22.1%) | 325 (20.8%) | 99 (17.7%) | 40 (18.4%) | 22 (19.3%) |
| 38–40 | 1045 (21.3%) | 399 (25.5%) | 126 (22.5%) | 56 (25.7%) | 26 (22.8%) |
| 41–42 | 602 (12.3%) | 223 (14.2%) | 87 (15.6%) | 38 (17.4%) | 24 (21.1%) |
| > 42 | 547 (11.1%) | 184 (11.8%) | 79 (14.1%) | 24 (11.0%) | 15 (13.2%) |
| Race | |||||
| Caucasian | 2584 (52.6%) | 723 (46.2%) | 260 (46.5%) | 101 (46.3%) | 66 (57.9%) |
| Asian | 924 (18.8%) | 233 (14.9%) | 44 (7.9%) | 15 (6.9%) | 2 (1.8%) |
| Black | 96 (2.0%) | 86 (5.5%) | 54 (9.7%) | 24 (11.0%) | 14 (12.3%) |
| Other/unknown | 1309 (26.6%) | 524 (33.5%) | 201 (36.0%) | 78 (35.8%) | 32 (28.1%) |
| Day 3 FSH | 5.2 ± 3.6 | 5.2 ± 3.5 | 5.3 ± 3.4 | 4.9 ± 3.0 | 4.6 ± 2.3 |
| AMH | 2.6 ± 3.5 | 2.6 ± 3.5 | 2.6 ± 3.5 | 2.3 ± 2.8 | 1.7 ± 1.8 |
| AFC | |||||
| 0 to 4 | 266 (5.4%) | 102 (6.5%) | 37 (6.6%) | 18 (8.3%) | 13 (11.4%) |
| 5 to 9 | 1770 (36.0%) | 575 (36.7%) | 230 (41.1%) | 96 (44.0%) | 57 (50.0%) |
| 10 to 14 | 1930 (39.3%) | 570 (36.4%) | 176 (31.5%) | 59 (27.1%) | 28 (24.6%) |
| ≥ 15 | 947 (19.3%) | 319 (20.4%) | 116 (20.8%) | 45 (20.6%) | 16 (14.0%) |
| Infertility diagnosis | |||||
| Anovulatory/PCOS | 302 (6.2%) | 95 (6.1%) | 60 (10.7%) | 30 (13.8%) | 12 (10.5%) |
| DOR | 2734 (55.7%) | 927 (59.2%) | 310 (55.5%) | 117 (53.7%) | 64 (56.1%) |
| Other | 1877 (38.2%) | 544 (34.7%) | 189 (33.8%) | 71 (32.6%) | 38 (33.3%) |
| ICSI | 3855 (78.8%) | 1269 (81.4%) | 442 (79.6%) | 176 (82.3%) | 88 (77.9%) |
| Stimulation protocol | |||||
| Antagonist | 4188 (85.2%) | 1319 (84.2%) | 478 (85.5%) | 182 (83.5%) | 96 (84.2%) |
| Agonist flare | 375 (7.6%) | 120 (7.7%) | 42 (7.5%) | 16 (7.3%) | 8 (7.0%) |
| Clomid/Letrozole | 281 (5.7%) | 105 (6.7%) | 35 (6.3%) | 16 (7.3%) | 8 (7.0%) |
| Other | 69 (1.4%) | 22 (1.4%) | 4 (0.7%) | 4 (1.8%) | 2 (1.8%) |
| Total gonadotropin dose | 3511.5 ± 1866.5 | 3703.5 ± 1817.1 | 3969.1 ± 1821.9 | 4204.7 ± 1965.5 | 4723.9 ± 1988.9 |
| Day of embryo transfer | |||||
| None | 401 (8.2%) | 142 (9.1%) | 48 (8.6%) | 18 (8.26%) | 21 (18.4%) |
| Day 3 | 3287 (66.9%) | 1086 (69.4%) | 389 (69.6%) | 162 (74.3%) | 76 (66.7%) |
| Day 5 | 1225 (24.9%) | 338 (21.6%) | 122 (21.8%) | 38 (17.4%) | 17 (14.9%) |
| Endometrial thickness (mm) | 10.5 ± 2.3 | 10.7 ± 2.3 | 10.8 ± 2.3 | 10.8 ± 2.6 | 11.1 ± 2.4 |
| Number of embryos transferred | 1.9 ± 1.2 | 2.0 ± 1.2 | 2.1 ± 1.2 | 2.1 ± 1.2 | 1.8 ± 1.2 |
BMI, body mass index; kg, kilograms; m, meter; FSH, follicle-stimulating hormone; AMH, antimullerian hormone; AFC, antral follicle count; DOR, diminished ovarian reserve; ICSI, intracytoplasmic sperm injection; PGT-A, preimplantation genetic testing for aneuploidy; hMG, human menopausal gonadotropin; mm, millimeters
Data are mean ± standard deviation or n (%)
Clinical protocols
The ovarian stimulation protocol, timing and dose of the ovulatory trigger, and embryo culture process were performed per the standard protocols at our institution. The ovarian stimulation protocols involved either gonadotropin-releasing hormone (GnRH) antagonists (Ganirelix acetate injection [Merck, Whitehouse Station, NJ, USA] or cetrorelix acetate injection [EMD Serono Inc., Rockland, MA, USA]) for pituitary downregulation or a GnRH agonist flare (leuprolide acetate injection [Sandoz Inc., Princeton, NJ, USA]) [14, 15]. In poor-responder patients, clomiphene citrate (Par Pharmaceutical Inc., Chestnut Ridge, NY, USA) or letrozole (Breckenridge Pharmaceutical Inc., Berlin, CT, USA) was added to some GnRH antagonist protocols at the discretion of the treating physician [16, 17]. In patients with diminished ovarian reserve, estrogen priming was initiated in the mid-luteal phase of the cycle prior to the ovarian stimulation cycle with 0.1-mg estradiol patches (Climara 0.1 mg, Bayer HealthCare) [18]. The ovulatory trigger was administered once there were two leading follicles that had reached 17 mm in size (20 mm for clomiphene and 22–24 mm for letrozole-based protocols). Either an hCG-only trigger (Novarel [Ferring Pharmaceuticals Inc., Parsippany, NJ, USA] or Pregnyl [Merck, Whitehouse Station, NJ, USA]) or a dual trigger with hCG and GnRH agonist (leuprolide acetate) was administered, with hCG dosing based on a previously published sliding-scale protocol [19]. Oocyte retrieval was performed transvaginally under ultrasound guidance approximately 35–37 h after the ovulatory trigger was administered.
Oocyte insemination was performed by standard insemination or by intracytoplasmic sperm injection (ICSI) as clinically indicated. When ICSI was performed, the oocytes were mechanically denuded to assess nuclear maturity, and mature oocytes were then injected with a single sperm. Embryos were cultured in sequential media using the EmbryoScope (Vitrolife, Göteburg, Sweden) time-lapse system. Embryos were evaluated for fertilization on day 1 and graded morphologically on days 3 and 5 [20]. The embryo stage at transfer and the number of embryos selected to transfer were determined by the reproductive endocrinologist in consultation with the embryologist and the patient, and were based on the morphology and the number of developing embryos. Planned fresh embryo transfers were cancelled if there was a lack of oocytes, sperm, fertilization, or embryo development; if there was a moderate risk of ovarian hyperstimulation syndrome; or if requested by the patient. Embryo transfers were performed under ultrasound guidance at the discretion of the reproductive endocrinologist.
The day after oocyte retrieval, patients began administering daily intramuscular progesterone (50 mg) and, once pregnant, continued until 7–8 weeks of gestation. Patients who received a dual trigger were also supplemented with estradiol transdermal patches (Climara 0.1 mg, Bayer HealthCare) every other day until 7–8 weeks of gestation. Serum hCG levels were measured 10 days after embryo transfer. If positive, hCG was measured again 48 h later. If rising appropriately, a viability ultrasound was performed between 5.5 and 7 weeks of gestation. Follow-up ultrasounds were performed to monitor fetal growth and development as indicated. Patient care was transferred to an obstetrician between 8 and 10 weeks of gestation.
Statistical analysis
The primary outcome of this study was live birth rate. Secondary outcomes included oocyte retrieval and embryo development outcomes as well as additional pregnancy outcomes. A Poisson regression model was used to estimate the relative risk (RR) with a 95% confidence interval (CI) to compare each BMI category to the referent BMI category (normal-weight) for oocyte retrieval and embryo development outcomes. This analysis was adjusted a priori for patient age, AMH, and diagnosis of diminished ovarian reserve. A logistic regression model was used to estimate the odds ratio (OR) with a 95% confidence interval (CI) among the study groups for pregnancy and delivery outcomes. This analysis was adjusted a priori for patient age and number of embryos transferred. Normal-weight patients were used as the referent group. Patients with class III and class IV obesity were combined into one group for statistical comparisons due to a relatively low number of patients with class IV obesity. A nonparametric test for trend was performed across BMI groups, in the analyses, to evaluate for a linear trend with increasing BMI category. A statistical significance was denoted by a p value < 0.05. Statistical analyses were performed using StataSE 16 (StataCorp LLC, College Station, TX, USA).
Results
This study consisted of 7370 normal-weight, overweight, and obese patients, including 114 patients with class III and IV obesity. In total, there were 4913 patients in the normal-weight group, 1566 in the overweight group, 559 in the class I obesity group, 218 in the class II obesity group, 106 in the class III obesity group, and 8 in the class IV obesity group. The mean total gonadotropin dose administered during the stimulation increased with each increasing BMI classification. The mean age for each group was between 37.1 and 38.1 years for all of the BMI groups. Additional demographic characteristics are displayed in Table 1.
Table 2 displays the embryo transfer and pregnancy outcomes among the study cohort. Patients with a BMI ≥ 40 had a significantly higher likelihood of having a cancelled fresh embryo transfer (18.4%) compared to normal-weight patients (8.2%; OR 2.51 (1.55–4.08)). Among the 21 patients with a BMI ≥ 40 who had their fresh embryo transfer cancelled, 13 had failed fertilization or embryo development, 3 did not have oocytes recovered at retrieval, 3 did not have mature oocytes to fertilize, and 2 were cancelled due to risk of ovarian hyperstimulation syndrome (Supplemental Table 1). Among all patients who had an embryo transfer, all BMI groups had a similar pregnancy rate compared to normal-weight patients. Among all pregnant patients, the proportion of biochemical pregnancies was similar in all BMI groups when compared to normal-weight patients. The proportion of pregnancies that resulted in a spontaneous abortion trended up significantly as the BMI group increased (test for linear trend, p value < 0.001). When compared to normal-weight patients, spontaneous abortion occurred at a significantly higher proportion in patients with a BMI of 25–29.9 (17.1%; OR 1.35 (1.09–1.68)), a BMI of 30–34.9 (19.9%; OR 1.71 (1.27–2.31)), and a BMI of 35–39.9 (21.8%; OR 1.69 (1.07–2.67)). Spontaneous abortion occurred in 10 (22.2%) patients with a BMI ≥ 40; however, this was not statistically significant (12.6%; OR 1.67 (0.85–4.25)). Live birth was not statistically significantly different in any of the BMI groups when compared to normal-weight patients. However, a significant trend of decreasing live birth rate was observed as BMI increased from 67.7% in normal-weight patients to 53.3% in patients with a BMI ≥ 40 (test for linear trend, p value = 0.004). When singleton live birth outcomes were evaluated, there were no differences in preterm delivery rate in any of the BMI groups when compared to normal-weight patients (test for linear trend, p value = 0.87). When the mode of delivery was evaluated, a significant increasing trend in the cesarean section rate was observed as the BMI increased from 39.0% in normal-weight patients to 61.5% in patients with a BMI ≥ 40 (test for linear trend, p value < 0.001).
Table 2.
The association between BMI and IVF treatment outcomes
| Outcome | BMI (kg/m2) | |||||
|---|---|---|---|---|---|---|
| 18.5–24.9 (n = 4913) | 25–29.9 (n = 1566) | 30–34.9 (n = 559) | 35–39.9 (n = 218) | ≥ 40 (n = 114) | Test for linear trend | |
| No transfer* | 401 (8.2%) | 142 (9.1%) | 48 (8.6%) | 18 (8.3%) | 21 (18.4%) | 0.007 |
| 1.00 (Ref) | 1.12 (0.91, 1.36) | 1.05 (0.77, 1.44) | 1.01 (0.61, 1.65) | 2.51 (1.55, 4.08) | ||
| Pregnancy (for all patients who had retrieval) | 2395 (48.8%) | 747 (47.7%) | 287 (51.3%) | 101 (46.3%) | 45 (39.5%) | 0.34 |
| 1.00 (Ref) | 0.98 (0.87, 1.10) | 1.10 (0.92, 1.32) | 0.92 (0.69, 1.23) | 0.80 (0.54, 1.19) | ||
| Pregnancy (for patients who had embryo transfer) | 2395 (53.1%) | 747 (52.5%) | 287 (56.2%) | 101 (50.5%) | 45 (48.4%) | 0.86 |
| 1.00 (Ref) | 1.01 (0.89, 1.14) | 1.15 (0.98, 1.40) | 0.93 (0.69, 1.24) | 0.87 (0.57, 1.33) | ||
| If pregnant: | (n = 2395) | (n = 747) | (n = 287) | (n = 101) | (n = 45) | |
| Biochemical | 406 (17.0%) | 121 (16.2%) | 51 (17.8%) | 18 (17.8%) | 10 (22.2%) | 0.40 |
| 1.00 (Ref) | 0.92 (0.74, 1.14) | 1.09 (0.80, 1.48) | 0.97 (0.59, 1.60) | 1.20 (0.62, 2.34) | ||
| SAB† | 301 (12.6%) | 128 (17.1%) | 57 (19.9%) | 22 (21.8%) | 10 (22.2%) | < 0.001 |
| 1.00 (Ref) | 1.35 (1.09, 1.68) | 1.71 (1.27, 2.31) | 1.69 (1.07, 2.67) | 1.67 (0.85, 4.25) | ||
| Live birth‡ | 1621 (67.7%) | 477 (63.9%) | 173 (60.3%) | 59 (58.4%) | 24 (53.3%) | 0.004 |
| 1.00 (Ref) | 0.94 (0.82, 1.07) | 0.93 (0.76, 1.14) | 0.76 (0.55, 1.05) | 0.65 (0.40, 1.05) | ||
| Singleton delivery outcomes: | (n = 1279) | (n = 368) | (n = 132) | (n = 44) | (n = 14) | |
|
Preterm delivery* (< 37 weeks) |
102 (8.0%) | 28 (7.6%) | 11 (8.3%) | 4 (9.1%) | 2 (14.3%) | 0.87 |
| 1.00 (Ref) | 0.97 (0.63, 1.50) | 1.07 (0.56, 2.04) | 1.19 (0.41, 3.38) | 2.13 (0.47, 9.69) | ||
| C-section* | 471 (39.0%) | 180 (51.9%) | 73 (57.9%) | 30 (69.8%) | 8 (61.5%) | < 0.001 |
| 1.00 (Ref) (n = 1207) | 1.62 (1.27, 2.07) (n = 347) | 2.11 (1.44, 3.08) (n = 126) | 3.59 (1.83, 7.05) (n = 43) | 2.04 (0.65, 6.34) (n = 13) | ||
BMI, body mass index; kg, kilograms; m, meter
Data are n (%) with odds ratio (95% confidence interval). Logistic regression models adjusted a priori for age and number of embryos transferred to estimate the OR of pregnancy outcomes
*Adjusted for age only
†Spontaneous abortion was defined as a failed pregnancy after the observation of at least a gestational sac on ultrasound
‡Live birth was defined as delivery at ≥ 24 weeks of gestational age
Pregnancy outcomes were stratified by day-3 or day-5 embryo transfer and are shown in Table 3. As expected, the overall pregnancy and live birth rates were higher in patients who were able to have a day-5 embryo transfer than they were in patients who had a day-3 embryo transfer. In both embryo transfer day groups, there were no differences in pregnancy, biochemical pregnancy, or live birth rates among any of the BMI groups when compared to the normal-weight group. In both the day-3 and day-5 embryo transfer groups, the spontaneous abortion rate significantly trended higher as the BMI group increased (day 3 ET: test for linear trend, p value = 0.004; day 5 ET: test for linear trend, p value < 0.001).
Table 3.
The association between BMI classification and embryo transfer outcomes in patients stratified by day of embryo transfer
| Outcome for day 3 embryo transfers | BMI (kg/m2) | |||||
| 18.5–24.9 (n = 3287) | 25–29.9 (n = 1086) | 30–34.9 (n = 389) | 35–39.9 (n = 162) | ≥ 40 (n = 76) | Test for linear trend | |
| Pregnancy | 1562 (47.5%) | 513 (47.2%) | 202 (51.9%) | 74 (45.7%) | 31 (40.8%) | 0.97 |
| 1.00 (Ref) | 1.01 (0.88–1.16) | 1.20 (0.97–1.50) | 0.92 (0.66–1.28) | 0.79 (0.49–1.27) | ||
| Biochemical | 289 (8.8%) | 95 (8.8%) | 41 (10.5%) | 13 (8.0%) | 9 (11.8%) | 0.41 |
| 1.00 (Ref) | 0.97 (0.76–1.24) | 1.17 (0.83–1.66) | 0.89 (0.50–1.60) | 1.44 (0.71–2.92) | ||
| SAB* | 229 (7.0%) | 92 (8.5%) | 43 (11.1%) | 17 (10.5%) | 6 (7.9%) | 0.004 |
| 1.00 (Ref) | 1.21 (0.94–1.56) | 1.59 (1.13–2.25) | 1.55 (0.92–2.61) | 1.18 (0.51–2.75) | ||
| Live birth† | 998 (30.4%) | 312 (28.7%) | 115 (29.6%) | 43 (26.5%) | 16 (21.1%) | 0.065 |
| 1.00 (Ref) | 0.96 (0.82–1.12) | 0.99 (0.78–1.25) | 0.81 (0.56–1.17) | 0.62 (0.35–1.10) | ||
| Outcome for day 5 embryo transfers | BMI (kg/m2) | |||||
| 18.5-24.99 (n = 1,225) | 25-29.99 (n = 338) | 30-34.99 (n = 122) | 35-39.99 (n = 38) | ≥40 (n = 17) | Test for linear trend | |
| Pregnancy | 833 (68.0%) | 234 (69.2%) | 85 (69.7%) | 27 (71.1%) | 14 (82.4%) | 0.27 |
| 1.00 (Ref) | 1.06 (0.81–1.38) | 1.05 (0.70–1.57) | 1.15 (0.56–2.34) | 2.09 (0.60–7.37) | ||
| Biochemical | 117 (9.6%) | 26 (7.7%) | 10 (8.2%) | 5 (13.2%) | 1 (5.9%) | 0.62 |
| 1.00 (Ref) | 0.78 (0.50–1.21) | 0.86 (0.44–1.68) | 1.40 (0.54–3.66) | 0.54 (0.07–4.09) | ||
| SAB* | 72 (5.9%) | 36 (10.7%) | 14 (11.5%) | 5 (13.2%) | 4 (23.5%) | < 0.001 |
| 1.00 (Ref) | 1.91 (1.25–2.91) | 2.15 (1.17–3.94) | 2.46 (0.93–6.50) | 5.16 (1.62–16.43) | ||
| Live birth† | 623 (50.9%) | 165 (48.8%) | 58 (47.5%) | 16 (42.1%) | 8 (47.1%) | 0.21 |
| 1.00 (Ref) | 0.92 (0.72–1.18) | 0.83 (0.57–1.21) | 0.70 (0.36–1.35) | 0.85 (0.32–2.23) | ||
BMI, body mass index; kg, kilograms; m, meter
Data are n (%) with odds ratio (95% confidence interval). Logistic regression models adjusted a priori for age and number of embryos transferred to estimate the OR of pregnancy outcomes
*Spontaneous abortion was defined as a failed pregnancy after the observation of at least a gestational sac on ultrasound
†Live birth was defined as delivery at ≥ 24 weeks of gestational age
Table 4 shows the total oocyte yield and the embryo development results. The mean number of total oocytes retrieved was significantly lower in patients with a BMI ≥ 40 (8.2 ± 5.4) compared to normal-weight patients (11.1 ± 7.4; RR 0.79 (0.74–0.84)). Patients with a BMI of 35–39.9 also had significantly fewer total oocytes retrieved (10.1 ± 6.8; RR 0.93 (0.89–0.97)) compared to normal-weight patients. The total number of oocytes retrieved trended down significantly as BMI increased (test for linear trend, p value < 0.001). The mean number of mature oocytes retrieved was significantly lower in patients with a BMI ≥ 40 (6.5 ± 4.6) compared to normal-weight patients (8.9 ± 6.2; RR 0.78 (0.72–0.84)). There were also significantly fewer mature oocytes retrieved for patients with a BMI of 35–39.9 (8.0 ± 5.6; RR 0.92 (0.87–0.96)) compared to normal-weight patients. The number of mature oocytes retrieved significantly trended down as BMI increased (test for linear trend, p value < 0.001). The mean number of zygotes was significantly lower in patients with a BMI ≥ 40 (4.4 ± 4.0) compared to normal-weight patients (6.6 ± 5.2; RR 0.72 (0.66–0.79)). There were also significantly less zygotes observed for patients with a BMI of 35–39.9 (5.5 ± 4.7; RR 0.86 (0.82–0.91)), patients with a BMI of 30–34.9 (6.2 ± 4.9; RR 0.95 (0.91–0.98)), and patients with a BMI of 25–29.9 (6.2 ± 5.1; RR 0.97 (0.95–0.99)) compared to normal-weight patients. The mean number of zygotes per patient trended down as BMI increased (test for linear trend, p value < 0.001) and the fertilization rate significantly trended down as BMI increased (test for linear trend, p value < 0.001). The mean number of cryopreserved blastocysts was significantly lower in patients with a BMI ≥ 40 (0.8 ± 1.7) compared to normal-weight patients (1.6 ± 2.8; RR 0.51 (0.42–0.64)). There were also significantly fewer cryopreserved blastocysts observed for patients with a BMI of 35–39.9 (1.1 ± 2.2; RR 0.74 (0.65–0.84)), patients with a BMI of 30–34.9 (1.3 ± 2.5; RR 0.82 (0.76–0.88)), and patients with a BMI of 25–29.9 (1.4 ± 2.6; RR 0.92 (0.88–0.97)) compared to normal-weight patients. The mean number of cryopreserved blastocysts per patient trended down as BMI increased (test for linear trend, p value < 0.001).
Table 4.
The association between BMI and embryo development
| Outcome | BMI (kg/m2) | |||||
|---|---|---|---|---|---|---|
| 18.5–24.9 (n = 4913) | 25–29.9 (n = 1566) | 30–34.9 (n = 559) | 35–39.9 (n = 218) | ≥ 40 (n = 114) | Test for linear trend | |
| Oocytes retrieved | 11.1 ± 7.4 | 10.9 ± 7.4 | 11.0 ± 7.8 | 10.1 ± 6.8 | 8.2 ± 5.4 | < 0.001 |
| 1.00 (Ref) | 1.00 (0.99, 1.02) | 0.99 (0.97, 1.02) | 0.93 (0.89, 0.97) | 0.79 (0.74, 0.84) | ||
| Mature oocytes | 8.9 ± 6.2 | 8.7 ± 6.2 | 8.6 ± 6.1 | 8.0 ± 5.6 | 6.5 ± 4.6 | < 0.001 |
| 1.00 (Ref) | 1.01 (0.99, 1.03) | 0.97 (0.94, 1.00) | 0.92 (0.87, 0.96) | 0.78 (0.72, 0.84) | ||
| Mature oocyte rate* | 80.4 ± 19.0 | 80.2 ± 19.5 | 79.1 ± 19.8 | 79.4 ± 20.8 | 78.2 ± 23.4 | 0.24 |
| 2pn | 6.6 ± 5.2 | 6.2 ± 5.1 | 6.2 ± 4.9 | 5.5 ± 4.7 | 4.4 ± 4.0 | < 0.001 |
| 1.00 (Ref) | 0.97 (0.95, 0.99) | 0.95 (0.91, 0.98) | 0.86 (0.82, 0.91) | 0.72 (0.66, 0.79) | ||
| Fertilization rate† | 72.5 ± 25.4 | 70.2 ± 27.3 | 72.2 ± 26.0 | 67.9 ± 27.4 | 60.8 ± 33.2 | < 0.001 |
| Frozen blastocysts‡ | 1.6 ± 2.8 | 1.4 ± 2.6 | 1.3 ± 2.5 | 1.1 ± 2.2 | 0.8 ± 1.7 | < 0.001 |
| 1.00 (Ref) | 0.92 (0.88, 0.97) | 0.82 (0.76, 0.88) | 0.74 (0.65, 0.84) | 0.51 (0.42, 0.64) | ||
BMI, body mass index; kg, kilograms; m, meter; ICSI, intracytoplasmic sperm injection
Data are mean ± standard deviation with relative risk (95% confidence interval)
Poisson regression models adjusted a priori for age, AMH, and diagnosis of DOR to estimate the relative risk (95% confidence interval)
Logistic regression models adjusted a priori for age, AMH, and diagnosis of DOR to estimate the odds ratio (95% confidence interval)
*Mature oocyte rate: number of mature oocytes divided by number of oocytes retrieved
†Fertilization rate: number of fertilized oocytes divided by number of mature oocytes
‡Additionally adjusted for number of embryos transferred
Discussion
The aim of this study was to explore how obesity, specifically class III and IV obesity, impacts IVF treatment and pregnancy outcomes in an updated cohort of patients who have received modern treatment protocols. In our cohort of patients at a single center undergoing their first fresh embryo transfer cycle, we observed that patients with a BMI ≥ 40 have fewer total oocytes retrieved, fewer fertilized oocytes, and ultimately fewer cryopreserved blastocysts compared to normal-weight patients. Additionally, patients with a BMI ≥ 40 have similar pregnancy rates after an embryo transfer compared to normal-weight patients, but are more likely to have a spontaneous abortion. The live birth rate was not statistically significantly lower in patients with a BMI ≥ 40 compared to normal-weight patients, but it was 14.4% lower, which is clinically meaningful.
While it has long been recognized that obesity can negatively affect infertility treatment outcomes, whether this impact is due to a uterine or an oocyte factor is not clearly understood [6–11]. Multiple large retrospective studies have reported evidence for obesity as a cause of altered endometrial receptivity in cohorts of donor oocyte recipients in whom the implantation rate declined as the recipient BMI group increased [8, 21]. These findings are supported by endometrial biopsies performed during the window of implantation which identified alterations in endometrial gene expression in a small sample of obese women [22].
However, others have reported contradictory findings, including a meta-analysis of the obese donor oocyte recipient model which concluded that there is no association between obesity and IVF outcomes in patients using donor oocytes [23]. A recent study by our group (Setton et al.) provided further data to support this conclusion. We compared 71 pairs of donor oocyte recipients, in which one recipient was normal-weight and the other was obese, who received “sibling oocytes” (oocytes from a donor that were retrieved from a single controlled ovarian hyperstimulation cycle and split between the two patients). We observed similar implantation rates and live birth rates between the patient pairs suggesting that obesity does not adversely affect endometrial receptivity [24].
One potential explanation for discrepancies between BMI studies is confounding pathology which may be associated with BMI and live birth, but not completely recognized and accounted for in the analysis. PCOS is one example of a syndrome which is associated with obesity and some studies associated with lower live birth rates compared to normal ovulatory women in a non-obese population [25]. Though, this observation is not consistently reported in the literature and some studies even demonstrate an increased live birth rate in infertile patients with PCOS, thus we chose not to include this variable in our statistical model [26]. It may be prudent for future studies evaluating obesity to aim to identify comorbidities which may be associated with adverse pregnancy outcomes in this population.
In the present study, we observed that women with a BMI ≥ 40 have a lower total number of oocytes retrieved. This could be due to fewer developing follicles to retrieve in these patients or due to technical limitations in accessing all of the available follicles due to additional adipose tissue. The mean total gonadotropin dose for each group increased linearly with BMI and is less likely to be an explanation for the differences in retrieved oocytes. Among the retrieved oocytes, there was a similar mature oocyte rate in each BMI group, suggesting that obesity does not affect oocyte development up to the metaphase II stage. Yet, the fertilization rate of the mature oocytes was observed to decline with increasing BMI and was lowest in the BMI ≥ 40 group. Ultimately, increasing BMI resulted in an inverse relationship with the number of supernumerary embryos cryopreserved. Together, these findings indicate that obesity affects oocyte quality and developmental potential, consistent with prior studies demonstrating its negative impact on oocyte quality and chromosome alignment [27–29].
These observed effects of obesity on embryo development are also reflected in the increased proportion of fresh embryo transfers that were cancelled in patients with a BMI ≥ 40. The most common reason for a cancelled embryo transfer in all groups was due to failure of oocyte fertilization (Supplemental Table 1). Obese patients were also observed to have a higher proportion of cancelled embryo transfers due to no oocytes recovered at retrieval or no mature oocytes to fertilize. Together, this resulted in a pregnancy rate among all patients who had an oocyte retrieval that was almost 10% lower in patients with a BMI ≥ 40 (39.5%) compared to normal-weight patients (48.8%). While this was not a statistically significant finding, it is a clinically important outcome that should be used when counseling patients with class III and IV obesity. When specifically evaluating patients who were able to have a fresh embryo transfer, we found that the pregnancy rate was comparable in each BMI group. However, the increasing rate of spontaneous abortion in each increasing BMI group led to a lower proportion of pregnancies that resulted in a live birth with each increasing BMI group. The live birth rate decreased from 67.7% in normal-weight patients to 53.3% in patients with a BMI ≥ 40. The cause for this increasing spontaneous abortion rate, as discussed previously, is not completely understood. Yet, it does not appear to be explained by aneuploidy, as miscarriage karyotype analysis and preimplantation genetic testing results do not show an increased risk for aneuploidy in obese patients [30–32]. It is possible that the increased risk of miscarriage and the decreased rate of live birth which is observed with increasing BMI are influenced by the embryo stage at transfer, as is shown in Table 3. Nevertheless, this study was not designed to compare cleavage and blastocyst stage embryo transfer outcomes and the size and distribution of patients in each stratified group is not large enough to make any definitive conclusions regarding this point.
While it is clear that obesity affects infertility treatment outcomes, a recent analysis by Goldman et al. determined that maternal age has a greater negative impact on fertility than obesity [33]. Furthermore, oocyte retrieval procedures can be safely performed in patient with class III and IV obesity [34]. The acceptable pregnancy and live birth rates in our cohort of patients with class III and IV obesity provide further evidence that BMI alone should not be used as criteria to deny IVF treatment to a patient when it is medically indicated [35]. Therefore, while weight loss counseling is an important component of infertility management, the age of the patient and their perceived motivation and ability to lose weight should be considered when determining when to proceed with ovarian stimulation and IVF treatment. As a rising number of patients are predicted to have a BMI > 35 and ≥ 40 over the next decade, we will continue to see an increased proportion of infertility patients in these BMI categories; thus, we can use our oocyte and embryo development as well as our pregnancy outcome results to accurately counsel patients regarding their anticipated IVF treatment outcomes.
We acknowledge several limitations of this study. Our study only included patients who were stimulated with a plan for a fresh embryo transfer. Therefore, we were unable to separately analyze patients who underwent preimplantation genetic testing prior to transfer in order to determine whether our pregnancy outcome results persisted when only embryos that tested as euploid were transferred. Importantly, the proportion of fresh and cryopreservation upfront cycles at our center remained consistent throughout the study period with no major changes in clinical practice during this time. Additionally, our study has the usual limitations associated with retrospective studies, including an inability to standardize patient management decisions throughout the IVF cycle, such as the stimulation protocol used or the decision to use IVF or ICSI. However, we included all patients who met the inclusion criteria during the study period in order to accurately represent an updated infertility treatment population. Finally, we were unable to adjust for potential confounders of delivery outcomes, such as neonatal weight or antepartum comorbidities such as gestational diabetes, which are likely to contribute to increased cesarean delivery rates observed in higher BMI classes.
Conclusion
Among patients with a BMI ≥ 40 who have an embryo transfer, the pregnancy rate is comparable to normal-weight patients. However, the rate of spontaneous abortion is higher with increasing BMI, resulting in a trend of a decreasing live birth rate with each subsequent BMI group. Additionally, patients with a BMI ≥ 40 have worse IVF treatment outcomes compared to normal-weight patients. This is attributable to both a lower total number of oocytes retrieved and an increased rate of fertilization failure and poor embryo development. This leads to a greater likelihood that a planned fresh embryo transfer will be cancelled in this population. These results are useful for counseling infertile patients with class III and IV obesity about their predicted outcomes with IVF treatment.
Supplementary Information
(DOCX 15 kb).
Acknowledgments
We would like to thank Alexandra MacWade for her help in proofreading the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
IRB approval
This study was approved by the institutional review board at Weill Cornell Medical College.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Chooi YC, Ding C, Magkos F. The epidemiology of obesity. Metabolism. 2019;92:6–10. doi: 10.1016/j.metabol.2018.09.005. [DOI] [PubMed] [Google Scholar]
- 2.Hruby A, Hu FB. The epidemiology of obesity: a big picture. Pharmacoeconomics. 2015;33(7):673–689. doi: 10.1007/s40273-014-0243-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ward ZJ, Bleich SN, Cradock AL, Barrett JL, Giles CM, Flax C, Long MW, Gortmaker SL. Projected U.S. State-Level Prevalence of adult obesity and severe obesity. N Engl J Med. 2019;381(25):2440–2450. doi: 10.1056/NEJMsa1909301. [DOI] [PubMed] [Google Scholar]
- 4.Ben-Haroush A, Sirota I, Salman L, Son W-Y, Tulandi T, Holzer H, Oron G. The influence of body mass index on pregnancy outcome following single-embryo transfer. J Assist Reprod Genet. 2018;35(7):1295–1300. doi: 10.1007/s10815-018-1186-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Dechaud H, Anahory T, Reyftmann L, Loup V, Hamamah S, Hedon B. Obesity does not adversely affect results in patients who are undergoing in vitro fertilization and embryo transfer. Eur J Obstet Gynecol Reprod Biol. 2006;127(1):88–93. doi: 10.1016/j.ejogrb.2005.12.009. [DOI] [PubMed] [Google Scholar]
- 6.Provost MP, Acharya KS, Acharya CR, Yeh JS, Steward RG, Eaton JL, et al. Pregnancy outcomes decline with increasing body mass index: analysis of 239,127 fresh autologous in vitro fertilization cycles from the 2008-2010 Society for Assisted Reproductive Technology registry. Fertil Steril. 2016;105(3):663–669. doi: 10.1016/j.fertnstert.2015.11.008. [DOI] [PubMed] [Google Scholar]
- 7.Shah DK, Missmer SA, Berry KF, Racowsky C, Ginsburg ES. Effect of obesity on oocyte and embryo quality in women undergoing in vitro fertilization. Obstet Gynecol. 2011;118(1):63–70. doi: 10.1097/AOG.0b013e31821fd360. [DOI] [PubMed] [Google Scholar]
- 8.Provost MP, Acharya KS, Acharya CR, Yeh JS, Steward RG, Eaton JL, et al. Pregnancy outcomes decline with increasing recipient body mass index: an analysis of 22,317 fresh donor/recipient cycles from the 2008-2010 Society for Assisted Reproductive Technology Clinic Outcome Reporting System registry. Fertil Steril. 2016;105(2):364–368. doi: 10.1016/j.fertnstert.2015.10.015. [DOI] [PubMed] [Google Scholar]
- 9.Rittenberg V, Seshadri S, Sunkara SK, Sobaleva S, Oteng-Ntim E, El-Toukhy T. Effect of body mass index on IVF treatment outcome: an updated systematic review and meta-analysis. Reprod BioMed Online. 2011;23(4):421–439. doi: 10.1016/j.rbmo.2011.06.018. [DOI] [PubMed] [Google Scholar]
- 10.Metwally M, Ong KJ, Ledger WL, Li TC. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta-analysis of the evidence. Fertil Steril. 2008;90(3):714–726. doi: 10.1016/j.fertnstert.2007.07.1290. [DOI] [PubMed] [Google Scholar]
- 11.Maheshwari A, Stofberg L, Bhattacharya S. Effect of overweight and obesity on assisted reproductive technology--a systematic review. Hum Reprod Update. 2007;13(5):433–444. doi: 10.1093/humupd/dmm017. [DOI] [PubMed] [Google Scholar]
- 12.Russo M, Ates S, Shaulov T, Dahan MH. Morbid obesity and pregnancy outcomes after single blastocyst transfer: a retrospective, North American study. J Assist Reprod Genet. 2017;34(4):451–457. doi: 10.1007/s10815-017-0883-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser. 2000;894(Journal Article):i–xii, 1–253. [PubMed]
- 14.Surrey ES, Bower J, Hill DM, Ramsey J, Surrey MW. Clinical and endocrine effects of a microdose GnRH agonist flare regimen administered to poor responders who are undergoing in vitro fertilization. Fertil Steril. 1998;69(3):419–424. doi: 10.1016/S0015-0282(97)00575-X. [DOI] [PubMed] [Google Scholar]
- 15.Cheung LP, Lam PM, Lok IH, Chiu TT, Yeung SY, Tjer CC, et al. GnRH antagonist versus long GnRH agonist protocol in poor responders undergoing IVF: a randomized controlled trial. Hum Reprod. 2005;20(3):616–621. doi: 10.1093/humrep/deh668. [DOI] [PubMed] [Google Scholar]
- 16.Tummon IS, Daniel SA, Kaplan BR, Nisker JA, Yuzpe AA. Randomized, prospective comparison of luteal leuprolide acetate and gonadotropins versus clomiphene citrate and gonadotropins in 408 first cycles of in vitro fertilization. Fertil Steril. 1992;58(3):563–568. doi: 10.1016/S0015-0282(16)55264-9. [DOI] [PubMed] [Google Scholar]
- 17.Yarali H, Esinler İ, Polat M, Bozdag G, Tiras B. Antagonist/letrozole protocol in poor ovarian responders for intracytoplasmic sperm injection: a comparative study with the microdose flare-up protocol. Fertil Steril. 2009;92(1):231–235. doi: 10.1016/j.fertnstert.2008.04.057. [DOI] [PubMed] [Google Scholar]
- 18.Dragisic KG, Davis OK, Fasouliotis SJ, Rosenwaks Z. Use of a luteal estradiol patch and a gonadotropin-releasing hormone antagonist suppression protocol before gonadotropin stimulation for in vitro fertilization in poor responders. Fertil Steril. 2005;84(4):1023–1026. doi: 10.1016/j.fertnstert.2005.04.031. [DOI] [PubMed] [Google Scholar]
- 19.Gunnala V, Melnick A, Irani M, Reichman D, Schattman G, Davis O, Rosenwaks Z. Sliding scale HCG trigger yields equivalent pregnancy outcomes and reduces ovarian hyperstimulation syndrome: analysis of 10,427 IVF-ICSI cycles. PLoS One. 2017;12(4):e0176019. doi: 10.1371/journal.pone.0176019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Veeck LL, Zaninovic N. An Atlas of Human Blastocysts. 1. New York: CRC Press; 2003. [Google Scholar]
- 21.Bellver J, Pellicer A, Garcia-Velasco JA, Ballesteros A, Remohi J, Meseguer M. Obesity reduces uterine receptivity: clinical experience from 9,587 first cycles of ovum donation with normal weight donors. Fertil Steril. 2013;100(4):1050–1058. doi: 10.1016/j.fertnstert.2013.06.001. [DOI] [PubMed] [Google Scholar]
- 22.Bellver J, Martínez-Conejero JA, Labarta E, Alamá P, Melo MAB, Remohí J, et al. Endometrial gene expression in the window of implantation is altered in obese women especially in association with polycystic ovary syndrome. Fertil Steril. 2011;95(7):2335–2341.e8. doi: 10.1016/j.fertnstert.2011.03.021. [DOI] [PubMed] [Google Scholar]
- 23.Jungheim ES, Schon SB, Schulte MB, DeUgarte DA, Fowler SA, Tuuli MG. IVF outcomes in obese donor oocyte recipients: a systematic review and meta-analysis. Hum Reprod. 2013;28(10):2720–2727. doi: 10.1093/humrep/det292. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Setton R, Chung A, Zimmerman L, Melnick A, Rosenwaks Z, Spandorfer SD. Body mass index is not associated with donor oocyte recipient success: an ideal study using a paired analysis of sibling-oocytes. F&S Reports. 2020;1(1):25–29. doi: 10.1016/j.xfre.2020.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Steiner N, Ates S, Shaulov T, Shrem G, Volodarsky-Perel A, Dahan SY, Tannus S, Son WY, Dahan MH. A comparison of IVF outcomes transferring a single ideal blastocyst in women with polycystic ovary syndrome and normal ovulatory controls. Arch Gynecol Obstet. 2020;302(6):1479–1486. doi: 10.1007/s00404-020-05699-9. [DOI] [PubMed] [Google Scholar]
- 26.Sha T, Wang X, Cheng W, Yan Y. A meta-analysis of pregnancy-related outcomes and complications in women with polycystic ovary syndrome undergoing IVF. Reprod BioMed Online. 2019;39(2):281–293. doi: 10.1016/j.rbmo.2019.03.203. [DOI] [PubMed] [Google Scholar]
- 27.Machtinger R, Combelles CM, Missmer SA, Correia KF, Fox JH, Racowsky C. The association between severe obesity and characteristics of failed fertilized oocytes. Hum Reprod. 2012;27(11):3198–3207. doi: 10.1093/humrep/des308. [DOI] [PubMed] [Google Scholar]
- 28.Robker RL. Evidence that obesity alters the quality of oocytes and embryos. Pathophysiology. 2008;15(2):115–121. doi: 10.1016/j.pathophys.2008.04.004. [DOI] [PubMed] [Google Scholar]
- 29.Hou Y-J, Zhu C-C, Duan X, Liu H-L, Wang Q, Sun S-C. Both diet and gene mutation induced obesity affect oocyte quality in mice. Sci Rep. 2016;6(1):18858. doi: 10.1038/srep18858. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Goldman KN, Hodes-Wertz B, McCulloh DH, Flom JD, Grifo JA. Association of body mass index with embryonic aneuploidy. Fertil Steril. 2015;103(3):744–748. doi: 10.1016/j.fertnstert.2014.11.029. [DOI] [PubMed] [Google Scholar]
- 31.Kroon B, Harrison K, Martin N, Wong B, Yazdani A. Miscarriage karyotype and its relationship with maternal body mass index, age, and mode of conception. Fertil Steril. 2011;95(5):1827–1829. doi: 10.1016/j.fertnstert.2010.11.065. [DOI] [PubMed] [Google Scholar]
- 32.Landres IV, Milki AA, Lathi RB. Karyotype of miscarriages in relation to maternal weight. Hum Reprod. 2010;25(5):1123–1126. doi: 10.1093/humrep/deq025. [DOI] [PubMed] [Google Scholar]
- 33.Goldman RH, Farland LV, Thomas AM, Zera CA, Ginsburg ES. The combined impact of maternal age and body mass index on cumulative live birth following in vitro fertilization. Am J Obstet Gynecol. 2019;221(6):617.e1–617.e13. doi: 10.1016/j.ajog.2019.05.043. [DOI] [PubMed] [Google Scholar]
- 34.Romanski PA, Farland LV, Tsen LC, Ginsburg ES, Lewis EI. Effect of class III and class IV obesity on oocyte retrieval complications and outcomes. Fertil Steril. 2019;111(2):294–301.e1. doi: 10.1016/j.fertnstert.2018.10.015. [DOI] [PubMed] [Google Scholar]
- 35.Friedler S, Cohen O, Liberty G, Saar-Ryss B, Meltzer S, Lazer T. Should high BMI be a reason for IVF treatment denial? Gynecol Endocrinol. 2017;33(11):853–856. doi: 10.1080/09513590.2017.1327042. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
(DOCX 15 kb).