Enhancing ART success in overweight and obese women: Current strategies and novel evidence-based approaches

TABLE OF ABBREVIATIONS

AFC, antral follicle count

AEs, adverse effects

ALA, alpha-lipoic acid

AMH, anti-Müllerian hormone

ApoB, apolipoprotein B

aRR, adjusted risk ratio

ART, assisted reproductive technologies

ASRM, American Society for Reproductive Medicine

BID, twice daily

BMI, body mass index

CC, clomiphene citrate

CFAS, Canadian Fertility and Andrology Society

CI, confidence interval

CLBR, cumulative live birth rate

COH, controlled ovarian hyperstimulation

COS, controlled ovarian stimulation

COMBI, combination treatment group

CPR, clinical pregnancy rate

DCI, d-chiro-inositol

DHR, dihydrorhodamine

DOR, diminished ovarian reserve

E2, estradiol

ET, embryo transfer

FET, frozen embryo transfer

FF, follicular fluid

FF-HDL, follicular fluid high-density lipoprotein

FSH, follicle-stimulating hormone

FSI, follicular sensitivity index

GC, granulosa cell

GDM, gestational diabetes mellitus

GnRH, gonadotropin-releasing hormone

hCG, human chorionic gonadotropin

HCY, homocysteine

HDL, high-density lipoprotein HMG, human menopausal gonadotropin

HOMA-IR, homeostatic model assessment for insulin resistance

HRT, hormone replacement therapy

ICSI, intracytoplasmic sperm injection

IL-8, interleukin-8

IL-18, interleukin-18

IL-18BP, interleukin-18 binding protein

IU, international units

IVF, in vitro fertilization

kg/m², kilogram per meter square

LA, linoleic acid

LBR, live birth rate

LDL, low-density lipoprotein

LDL-C, low-density lipoprotein cholesterol

LGI, low glycemic index

LH, luteinizing hormone

MET, metformin

MetS, metabolic syndrome

MII, metaphase II

MPA, medroxyprogesterone acetate

MPV, mean platelet volume

mSTC, mildly stimulated cycles

mtDNA, mitochondrial DNA

N, number of patients

NLR, neutrophil to lymphocyte ratio

NRF-2, nuclear factor erythroid 2–related factor 2

NS, not significant

NW, normal weight

OHSS, ovarian hyperstimulation syndrome

OR, odds ratio

PCOS, polycystic ovarian syndrome

PLR, platelet to lymphocyte ratio

PON1, paraoxonase 1

PUFA, polyunsaturated fatty acid

QD, once daily

qPCR, quantitative polymerase chain reaction

RCT, randomized controlled trial

r-hFSH-alfa, recombinant human follicle stimulating hormone alfa

rFSH, recombinant follicle-stimulating hormone

rLH, recombinant luteinizing hormone

RR, risk ratio

s.c., subcutaneous

SD, standard deviation

SDHA, succinate dehydrogenase complex flavoprotein subunit A

SGA, small for gestational age

SHBG, sex hormone binding globulin

SLR, systematic literature review

SoC, standard of care

TC, total cholesterol

TG, triglycerides

WCC, white cell count

ZYP, Zishen Yutai Pill

BACKGROUND

The prevalence of obesity has increased exponentially over the past 4 decades, and it is now widely considered a global health crisis.¹ According to the World Health Organization (WHO), as of 2022, 2.5 billion adults were overweight (body mass index [BMI] ≥25 kg/m²), of whom 890 million were living with obesity (BMI ≥30 kg/m²) worldwide. Among adults, obesity is more prevalent in women (504 million vs. 374 million men in 2022),² and its increasing incidence has been observed among women of reproductive age (18–40 years).^3,4 While obesity negatively impacts reproductive health in both sexes, in women, it can affect menstruation and fertility, and maternal obesity may influence pregnancy and the long-term health of both the mother and the child.^5,6

Assisted reproductive technologies (ART) are strategies involving the manipulation of eggs or embryos to manage female infertility, among which in vitro fertilization (IVF) is the most frequently utilized.⁷ Elevated BMI in women has been commonly linked to adverse reproductive function and ART outcomes.^6,8,9 The mechanisms by which obesity affects fertility and ART outcomes are complex and multifaceted.^5,6,10 These include hormonal dysregulation (e.g., insulin resistance, increased leptin, and altered adipokine levels), dyslipidemia, dysregulation of biogenic amines (e.g., serotonin, dopamine), chronic inflammation and oxidative stress, mitochondrial dysfunction, and epigenetic alterations. Taken together, these cellular, molecular, and physiological mechanisms result in menstrual disturbances, reduced ovarian reserve, impaired ovulation, reduced follicular quality, endometrial dysfunction, impaired embryo implantation, as well as an increased risk of pregnancy-related complications.^5,6,8,10 Additionally, the presence of comorbidities such as metabolic syndrome or polycystic ovary syndrome (PCOS) is also associated with suboptimal reproductive and IVF outcomes.^11–14

Given the significant burden associated with female obesity, reproduction, and infertility, clinical societies and health funding organizations across countries have published policies, guidelines, and recommendations for achieving successful pregnancies among obese women.^6,15–17 To avoid potential complications associated with ART in overweight/obese women, in some countries, women with obesity may face restrictions in accessing government-funded IVF services, with eligibility often contingent on meeting specific BMI thresholds, as outlined in local health authority guidelines.^18–20 In the United Kingdom (UK), specific boards recommend that a woman’s BMI must be between 19–30 kg/m², and sometimes even more restrictive (18–25 kg/m²), to be able to access government-funded IVF treatments.¹⁹ Similarly, in the US, most fertility programs set a BMI threshold of 35–45 kg/m², above which women must delay their IVF treatment until weight loss is achieved.²⁰ While some guidelines recommend prioritizing weight loss or reduction in BMI through lifestyle modifications, medication, or surgery before starting fertility treatments,^16,17 others, such as the American Society for Reproductive Medicine, mention that the evidence is unclear with regard to pre-pregnancy weight loss interventions and successful IVF outcomes, such as live birth rate; however, it may improve the chances of pregnancy following natural conception.¹⁵ In addition to varying BMI thresholds across countries, there appears to be a lack of uniform guidelines for treatment or protocol modifications for successful IVF outcomes in overweight and obese patients.

This scoping review examines traditional and emerging strategies as well as modifications to IVF protocols to enhance reproductive success in this population. In addition, the review aims to identify preconception and periconception biomarkers in overweight and obese women to aid in identifying those at risk of adverse IVF outcomes.

METHODS

A comprehensive literature search was conducted utilizing the keywords and medical subject headings (MeSH), including “Fertilization in Vitro”[MeSH], “Sperm Injections, Intracytoplasmic”[MeSH], “Reproductive Techniques, Assisted”[MeSH]), “IVF”, “in vitro fertil*”, “intracytoplasmic morphologically selected sperm injection”, “obesity”, “overweight”, “adiposity”, “dyslipidemia”, “body mass index”[MeSH], “pregnancy in obesity”, “anti-obesity agents”, “weight loss”, “bariatric surgery”[MeSH]. The search was performed in the PubMed database and retrieved studies published over the last decade, from January 1, 2015, to April 23, 2025. Additionally, relevant articles identified through cross-referencing were included.

The search was focused on overweight or obese women undergoing ART, including IVF and intracytoplasmic sperm injection (ICSI). PubMed indexing filters were utilized to identify primary studies (i.e., observational studies and controlled trials) conducted in humans and published in English. Studies focusing on low BMI (<18.5 kg/m²) in women or the impact of paternal obesity on IVF outcomes were not in the scope of this review.

Titles and abstracts were screened based on the above criteria. If they met the requirements, full-text articles were retrieved for further analysis. Finally, the following information was extracted for each study: first author, year of publication, study type and population, interventions, IVF-related outcomes (e.g., oocyte retrieval, fertilization rate, clinical pregnancy rate, live birth rate, maternal complications, and neonatal outcomes), modifications to IVF treatment protocols, and study results.

RESULTS

We screened 282 studies and included 50 studies (N=33 observational studies and N=17 randomized controlled trials [RCTs]) relevant to the objectives of this review.

Experimental interventions aiming to improve IVF outcomes

Weight loss interventions

Fourteen studies (6 observational studies and 8 RCTs) assessed whether traditional strategies, such as weight loss interventions, influence IVF outcomes (Table 1).^21–34

Three studies conducted in overweight/obese infertile women (BMI ranging from >25 to >45 kg/m²) suggest that short-term lifestyle modifications (8 to 12 weeks), including dietary changes and physical exercise, may positively affect fertility and lead to better IVF outcomes.^28,33,34 Twelve weeks of a hypocaloric diet with a low glycemic index and glycemic load (N=14) was associated with significant weight loss and reduction in the percentage of body fat (P<0.05 each), which may have led to better reproductive outcomes, including more oocytes retrieved (P=0.039) and higher pregnancy rates vs. the control group.³⁴ Espinós et al.²⁸ demonstrated that a 12-week structured diet and exercise program resulted in significant weight loss (P<0.001), reduction in waist circumference (P=0.032), and significantly higher cumulative live birth rate (61.9% vs. 30.0% in the control group; P=0.045). Similarly, in comparison with the group receiving counseling on lifestyle modifications, an approximately 8-week intervention with physical activity combined with a reduced energy diet led to improved pregnancy rates in those with a higher intake of polyunsaturated fatty acid, particularly omega-6 and linoleic acid.³³ Moreover, an RCT showed that health-promoting lifestyle education alone significantly reduced the total number of risk factors 3 months post-intervention and improved clinical pregnancy rates in women with unexplained infertility with mean BMI 25.5 kg/m² (46.15% vs. 19.24% in the control group; P=0.02).³¹ Among women who underwent a lifestyle intervention consisting of a hypocaloric diet with a low glycemic index and physical activity of moderate intensity, combining low-dose liraglutide with metformin significantly improved pregnancy rates (85.7% vs. 28.6% with metformin alone; P=0.03) despite a significant weight loss in both groups (P<0.001).²⁷

Three studies assessed the effect of bariatric surgery on ART outcomes.^22,25,30 In the study by Nilsson-Condori et al.,²² despite a lower number of oocytes retrieved, frozen embryos, and mean birth weight in the surgery group (N=153), the cumulative live birth rate was comparable to the age-, parity-, and BMI-matched controls (N=744) at the time of IVF treatment. This is consistent with the findings of Grzegorczyk-Martin et al.²⁵ where the success of IVF outcomes was similar for BMI-matched overweight women (mean BMI: 28.8–28.9 kg/m²) who had previously undergone bariatric surgery and those that were non-operated; however, the live birth rate was the worst in severely obese non-operated women (mean BMI: 37.7 kg/m²). Milone et al.³⁰ assessed the impact of bariatric surgery in obese women who had initially experienced failure with ART. Post-surgery, there was a significant increase in various ART-related outcomes including increased number of follicles >15 mm, number of top-quality and mature oocytes, number of top-quality embryos, as well as clinical pregnancy and live birth rates (P<0.05 for all).

Multiple large RCTs (N=317–877) have shown that short-term weight loss interventions alone, such as physical activity with or without lifestyle modifications, or pharmacotherapies such as orlistat, result in significant weight loss or reduction in BMI but do not always improve IVF outcomes.^24,29,32 Einarsson et al.²⁶ further showed that weight intervention had no impact on other outcomes such as birth weight, preterm birth rate, gestational age, and neonatal complications.

Two studies stratified groups based on the amount of weight loss post-intervention.^21,23 Shen et al.²¹ observed that in the weight management group with a weight loss goal of ≥10% (N=56), there was a significant improvement in clinical pregnancy (P=0.002) and live birth rate (P=0.004) vs. controls (N=141). Similarly, Wu et al.²³ observed that IVF outcomes were significantly improved in those who lost 5–10 kg or >10 kg of body weight vs. those who lost 1–5 kgs.

Adjunct therapies

Five studies (3 observational studies and 2 RCTs) evaluated the impact of adjunct therapies, alone or in combination with weight loss interventions, aimed at improving ART outcomes (Table 2).^35–39

In 3 studies, micronutrient supplementation demonstrated promising results for various IVF outcomes.^36,37,39 In overweight/obese women with PCOS and who had a family history of diabetes, the combined low-dose use of d-chiro-inositol (500 mg) and α-lipoic acid (300 mg) twice daily for at least 1 month before controlled ovarian hyperstimulation improved insulin sensitivity and showed trends toward better oocyte and embryo quality.³⁶ Similarly, when compared with obese women using folic acid supplementation alone (OB-F), the combined supplementation of α-lipoic acid, myo-inositol, and folic acid (OB-S) improved antioxidant capacity in the follicular fluid which may have contributed to a trend towards an increase in pregnancy rates (OB-S: 33.3% vs. OB-F: 11.1%; not significant); however, the levels of mitochondrial DNA was negatively correlated to the number of total and MII oocytes.³⁷ Pre-treatment intake of folate and vitamin B12, resulting in high serum concentrations of both folate and vitamin B12, was positively associated with clinical pregnancy and live birth rates, while high serum vitamin B12 was also associated with improved implantation.³⁹

The Zishen Yutai Pill (ZYP), a traditional Chinese medicine consisting of 15 natural medicines, significantly improved implantation, biochemical and clinical pregnancy, and live birth rates, particularly in women with BMI >24 kg/m².³⁵

Short-term treatment with metformin (1000 mg per day) in overweight/obese women with PCOS significantly reduced the number of retrieved and fertilized oocytes (P<0.01 each) and did not improve fertilization, implantation, clinical pregnancy, and live birth rates (not significant vs. placebo).³⁸

Modifications to ART protocols in overweight/obese women and women with comorbidities

Dose adjustments to gonadotropins (including follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) or supplementation of gonadotropins during ovarian stimulation/ovulation induction were required in obese women and women with comorbidities such as diminished ovarian reserve, PCOS, and metabolic syndrome, as observed in 16 studies (13 observational studies and 3 RCTs) (Table 3).^{21,23,25,28,30,36,40–49}

Mahony et al.⁴² reported that dose adjustments (increased or decreased) of gonadotropins were frequent in younger patients, those with higher ovarian reserve, and women with ovulation disorders or PCOS. Several clinical studies showed that overweight/obese infertile women or those with comorbidities often require higher doses of gonadotropins and longer stimulation durations while undergoing ART.^{21,23,25,36,40,43–45,47,48} Despite these modifications to the ovarian stimulation/ovulation induction protocols, in some of these studies there appeared to be no positive impact on ART outcomes such as oocyte yield, embryo quality, and pregnancy rates.^{40,43–45,47,48}

Of note, while 1 study showed that weight loss did not alter the total rFSH dose used,²⁸ several other studies have shown that reduced weight can lower gonadotropin consumption.^{21,23,25,30,46} The gonadotropin dose and stimulation duration required was significantly lower post-bariatric surgery.³⁰ In the study by Akpinar et al.⁴⁶ among women with PCOS, those resistant to clomiphene citrate (CC) received CC at a dose of 150 mg/d, while those responsive to CC received 50 mg/d. Of the parameters examined, BMI (P<0.001), LH (P<0.001), and LH/FSH ratio (P=0.01) were significantly higher in the CC-resistant group than that in the CC-responsive group, suggesting that losing weight before treatment may reduce the need for more intensive gonadotropin-based protocols as well as reduce the risk of OHSS. Consistent with these findings, Grzegorczyk-Martin et al.²⁵ observed that gonadotropin dose and stimulation duration was lower while the cumulative live birth rate was significantly higher (P=0.042) in the overweight vs. severely obese women. Similarly, 2 observational studies found that patients who lost more weight (≥10% or >5 kg) required lower doses of gonadotropin and shorter duration of stimulation and also had improved IVF outcomes including clinical pregnancy and live birth rates compared to those who lost less weight (<10% or <5 kg).^21,23 Additionally, co-treatment with letrozole while using the GnRH antagonist protocol in overweight infertile women was associated with significantly reduced gonadotropin consumption and stimulation duration when compared with GnRH antagonist alone (P<0.001).⁴¹

Gizzo et al.⁴⁹ evaluated rLH supplementation with 2 doses (75 and 150 IU/day) at 2 separate timings (starting from GnRH antagonist or rFSH administration). It was found that rather than the total dose of LH, the timing of administration affects the ovarian responses, with the optimal window being the mid-to-late follicular phase.

Studies comparing ART protocols

A head-to-head comparison of ART protocols, particularly protocols used for ovarian stimulation and ovulation induction, was conducted in 8 studies (7 observational studies and 1 RCT) (Table 4).^41,50–56

Four studies demonstrated that the use of letrozole alone or as an adjuvant appeared to be beneficial in improving ART outcomes in overweight or obese women when compared with other stimulation protocols.^41,51,52,54 Letrozole users had more live births vs. CC users across all BMI subgroups; however, among letrozole users, pregnancy complications were higher in those with metabolic syndrome vs. those without metabolic syndrome.⁵² While combining letrozole with CC significantly increased ovulation rates (77% vs. 43% with letrozole alone; P=0.0068), no significant differences were found in clinical pregnancy or live birth outcomes in women with PCOS (mean BMI ~33–34 kg/m²).⁵⁴ Liu et al.⁵¹ observed that the addition of letrozole to medroxyprogesterone acetate (MPA) + hMG increased the number of follicles >16 mm and the follicular output rate vs. MPA + hMG alone; however, the number of mature oocytes, viable embryos, cycle cancellation rate, and implantation rate were comparable between groups. In another study, letrozole co-treatment with the GnRH antagonist protocol significantly improved several ART outcomes including the number of follicles >16 mm, oocyte retrieval rate, usable embryo rate, and live birth rate.⁴¹

Jiang et al.⁵⁵ assessed the addition of CC to MPA + human menopausal gonadotropin (hMG) in IVF cycles among obese women with PCOS. Compared with MPA + hMG alone, the combination with CC reduced the total hMG dose required but resulted in fewer oocytes and top-quality embryos. Zhang et al.⁵⁶ compared conventional IVF (long GnRH antagonist protocol + 150–300 IU/d gonadotropin injections) to minimal stimulation IVF (mini-IVF; 50 mg/d of CC orally + 75–150 IU/d gonadotropin injections) in 439 women and observed that while BMI negatively impacted the number of oocytes retrieved and MII oocytes in conventional IVF, this effect was not seen with mini-IVF.

Endometrial preparation with a letrozole mild cycle (2.5 mg/d of letrozole, before using hMG) or natural cycle (no medication until trigger day) reduced the risk of late miscarriages vs. hormone replacement (25 µg twice per day of oral ethinyl estradiol) or hMG late stimulation cycles (i.e., hMG at small doses).⁵⁰ Similarly, mildly stimulated cycles with letrozole plus hMG resulted in a significantly thicker endometrium, higher live birth rate, and lower miscarriage rates when compared with artificial cycles (estradiol + progesterone).⁵³

Differential levels of biomarkers in normal weight vs. overweight/obese women undergoing IVF treatments

In total, 15 studies (10 observational studies and 5 RCTs) assessed the multifactorial influences of preconception or periconception hormonal, metabolic, and inflammatory factors on ART success and their utility in predicting ART outcomes in overweight and obese women (Table 5).^34,57–70

The differential levels of lipid parameters were assessed for their impact on reproductive success and ART outcomes. Some studies noted that increased BMI and elevated serum lipids, particularly low-density lipoprotein (LDL), total cholesterol (TC), triglycerides (TG), and apolipoprotein-B, negatively impacted various ART outcomes, including ovulation, fertilization, embryo quality, pregnancy, and live birth rates, and increased miscarriage risk.^62–64 In contrast, Bollig et al.⁵⁷ found no link between dyslipidemia and live birth unless both partners who are planning IVF had elevated LDL or TC. High-density lipoprotein (HDL) levels were positively associated with the number of oocytes, normal fertilized oocytes, and cleavage embryos (P<0.05),⁶⁴ and Bacchetti et al.⁶⁶ further highlighted that follicular fluid HDL function reflects oocyte quality more than HDL concentration. Becker et al.³⁴ suggested that dietary interventions promoted a decrease in BMI, percentage of body fat, and leptin concentrations, which in turn improved the oocyte yield (85.4% more oocytes retrieved vs. control; P=0.039) and spontaneous pregnancy rate (21.4% vs. 0% in the control group) in the intervention group. Consistent with this finding, compared with women of normal weight, overweight/obese women have high levels of leptin in the follicular fluid, which were negatively correlated with embryo quality.⁶⁹ Liu et al.⁶⁰ showed that pre-pregnancy LDL/HDL and TC/HDL ratios predicted GDM occurrence in women undergoing their first IVF/ICSI treatment, and those who developed GDM had higher BMI (21.91 vs. 21.23 kg/m² in the non-GDM group, P=0.005).

Some studies evaluated the levels of fertility- and reproduction-related hormones and their impact on ART outcomes. Hokmabadi et al.⁵⁸ identified that elevated serum progesterone (>1.54 ng/ml; initial cutoff considered was 1.2 ng/ml) on the human chorionic gonadotropin (hCG) trigger day was associated with reduced mature (M1) oocyte yield and that BMI further influenced embryo quality, particularly of 8-cell quality B embryos. However, Mizrachi et al.⁶⁸ showed that although hCG levels on the day after trigger were inversely correlated with BMI, they did not influence any laboratory or clinical outcomes, and thus testing hCG levels after ovulation induction was not recommended. The association between anti-Müllerian hormone (AMH) levels on reproductive outcomes was assessed in 2 studies.^59,61 Komorowski et al.⁵⁹ observed that in women with infertility and PCOS, higher AMH levels were associated with reduced ovulation, and this was further influenced by higher BMI; however, AMH levels were not associated with pregnancy and live birth rates. Similarly, Melado Vilades et al.⁶¹ found no differences in pregnancy or live birth rates across different AMH categories (<0.5 ng/ml, 0.5 to <1.3 ng/ml, 1.3–6.25 ng/ml, >6.25 ng/ml). However, obese patients had higher miscarriage risks and lower live birth rates, irrespective of AMH levels, suggesting BMI plays a more decisive role than AMH alone.

Two studies investigated the effect of inflammatory factors on ART outcomes in obese women, especially in those with PCOS. Zhang et al.⁶⁵ reported elevated levels of interleukin-18 (IL-18) in both follicular fluid and serum of obese and PCOS women, with positive correlations to oocyte count and negatively correlated to oocyte quality. Çakıroğlu et al.⁷⁰ observed that in women with PCOS, BMI was positively correlated with neutrophil and lymphocyte count, and mean platelet volume (MPV) while it was negatively correlated with platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR). Additionally, PLR correlated positively with miscarriage rate and MPV was negatively correlated with implantation and clinical pregnancy rates.

Chang et al.⁶⁷ reported that in maternal hyperhomocysteinemia, a metabolic disorder characterized by abnormally high homocysteine levels, the ovulation rate decreased, and the pregnancy loss rate in the second or third trimester increased, helping early prediction of adverse pregnancy outcomes.

DISCUSSION

To the best of our knowledge, this is the first comprehensive scoping review to consolidate findings published over the last decade regarding traditional and emerging treatment strategies and interventions for optimizing ART outcomes in overweight and obese women with fertility disorders and with or without comorbidities, including metabolic syndrome, PCOS, and GDM. This review of 50 studies evaluated various traditional weight loss strategies, adjunct therapies, and ART protocol modifications and assessed their impact on ART outcomes in overweight and obese women. In brief, bariatric surgery, weight management interventions with weight loss ≥10% or >5 kg, micronutrient supplementation, especially in women with PCOS, and ovarian stimulation/ovulation induction and endometrial preparation with letrozole were associated with improved ART outcomes. During ovulation induction, obese women often required increased gonadotropin dosages and longer stimulation periods. Although these modifications did not necessarily lead to better outcomes, weight loss interventions reduced gonadotropin consumption and were associated with better ART outcomes. In addition, the review identified preconception and periconception biomarkers, such as differential levels of lipid parameters, reproductive hormones, and inflammatory markers in overweight and obese women versus women of normal weight, which may help predict the success of IVF treatment.

Based on recent systematic literature reviews and meta-analyses the impact of elevated BMI on ART outcomes in overweight/obese women remains unclear.^8,9,71,72 Recent evidence analyzed in this review demonstrates that short-term lifestyle interventions of 8 to 12 weeks improve ART outcomes, including the number of oocytes retrieved and clinical pregnancy and live birth rates.^28,33,34 Larger clinical studies (N=317–877) showed that weight-loss interventions resulted in significant weight loss, but did not necessarily improve ART outcomes.^24,29,32 However, it is important to highlight that 2 studies reported that a greater degree of weight loss (≥10% or >5 kg) was associated with improved ART outcomes.^21,23 The study by Wu et al.²³ further demonstrated that a greater degree of weight loss (>5 kg vs. 0–5 kg) in obese women with PCOS was associated with significant changes in neuronal-reproductive-metabolic hormones, improved insulin sensitivity, and altered gene expression of follicular granulosa cells, thus providing mechanistic insights into the pathways through which greater weight loss improves fertility. Among women who underwent lifestyle intervention, pregnancy rates were significantly higher when patients were co-treated with a low-dose of liraglutide and metformin than in those treated with metformin alone.²⁷ Newer injectable glucagon-like peptide-1 receptor agonists (e.g., liraglutide and exenatide) show greater weight loss efficacy than older pharmacotherapies (e.g., orlistat), and also improve fertility outcomes in women⁷³; however, these drugs must be used prior to IVF treatment initiation as they are contraindicated during pregnancy.⁷⁴ Consistent with the above findings, several clinical guidelines recommend weight loss before initiating IVF treatment^16,17 and guidelines and fertility programs in some countries state IVF treatment must be deferred until weight loss is achieved in patients whose BMI exceeds a certain threshold.^16,17,20 While long-term weight loss interventions involving bariatric surgery may improve pregnancy outcomes,^22,25,30,75 given the age-related decline in fertility and its impact on successful ART outcomes,⁷⁶ clinicians must weigh the benefits of a long-term weight loss intervention prior to IVF treatment versus immediate IVF treatment at an individual level, especially in older women.

Women who have undergone bariatric surgery may have long-term vitamin and mineral deficiencies and require additional preconception nutritional supplementation.^15,77 The current review demonstrated that in obese women, adjunct therapies such as micronutrient supplementation (e.g., vitamin B12, folate) helped improve insulin sensitivity and various IVF outcomes, including better oocyte and embryo quality, and higher pregnancy and live birth rates.^36,37,39 In fact, per the best practice statement of the Royal Australian and New Zealand College of Obstetricians and Gynecologists, high-dose folate (5 mg) supplementation is recommended in obese women to decrease the risk of neural tube defects, while calcium and aspirin supplementation is recommended during early pregnancy through gestation to reduce the risk of pre-eclampsia.⁷⁷ These findings underscore the potential benefit of supplements in optimizing reproductive outcomes independent of weight loss.

Obesity in women is associated with lower ovarian responsiveness and technical difficulties during oocyte retrieval, including anesthesia- and procedure-related complications.^15,78 It is well known that during ovulation induction, obese women require a higher dose of gonadotropins and longer days of stimulation,¹⁵ which was consistently observed across several studies^{21,23,25,36,40,43–45,47,48}; however, these protocol modifications did not improve outcomes with respect to oocyte yield, embryo quality, and clinical pregnancy in some of these studies.^{40,43–45,47,48} Furthermore, it must be noted that increasing gonadotropin dose and stimulation duration may increase the risk of OHSS in obese women and women with PCOS.^44,78 To minimize the risk of OHSS, Zeng et al.⁷⁸ recommended individualizing initial gonadotropin doses based on body weight. In addition, it was noted that weight lossamong overweight and obese women was associated with reduced gonadotropin consumption^{21,23,25,30,46} and improved ART outcomes.^21,23,25 Furthermore, in a study evaluating rLH supplementation, it was observed that ovarian response was impacted more by the timing of rLH administration rather than the total dose, with the mid-to-late follicular phase considered the optimal window for administration.⁴⁹

Among studies comparing ovarian stimulation and ovulation induction protocols, when compared with the conventional IVF stimulation protocol, findings by Zhang et al.⁵⁶ suggested that the mini-IVF protocol may result in more oocytes and MII oocytes in obese women. In addition, ovarian stimulation/ovulation induction or endometrial preparations with letrozole, alone or in combination with other stimulation protocols, appeared to be especially beneficial for improving several ART outcomes, including increasing follicular output, ovulation, and live birth rates, and reducing the risk of miscarriages.^41,50–54 Based on an abstract presentation at the 2005 Annual Meeting of the American Society for Reproductive Medicine, there were initial concerns regarding letrozole having an increased risk of congenital anomalies^79,80; however, 2 large RCTs^81,82 and several observational studies^83–85 have since shown that there is no increased risk when compared with clomiphene or natural cycles. Letrozole, an aromatase inhibitor, is approved for the treatment of hormone receptor–positive breast cancer in postmenopausal women⁸⁶; however, its use for ovulation induction in infertility treatment, remains off-label in many countries. Despite its increasing clinical application in ART, letrozole is not approved for infertility treatment and is contraindicated in premenopausal and pregnant women.⁸⁶ Therefore, its use in this context warrants careful ethical consideration, including informed patient consent and adherence to applicable regulatory and institutional guidelines. Any potential regulatory approval of letrozole for infertility indications would require robust clinical evidence demonstrating its safety, efficacy, and benefit–risk profile in this specific population.

Obese women and women with comorbidities, such as PCOS and metabolic syndrome, have dysregulated lipid parameters and reproductive hormones, and increased levels of inflammatory markers, which can influence IVF outcomes and the risk of GDM.^{34,59–66,69,70} These findings not only provide mechanistic insights involved in obesity and reproduction but also act as preconception and periconception biomarkers that can help identify obese women at risk of adverse IVF outcomes.⁸⁷ In addition, Bollig et al.⁵⁷ observed that among couples planning to undergo IVF treatments, elevated LDL and TC levels in both partners and elevated LDL levels among males were associated with lower live birth rates. Although this review focuses on female obesity, emerging evidence highlights the need for couple-based approaches, as high male BMI can independently affect semen quality and IVF outcomes.^88–90 In addition, male obesity and diet can influence offspring health through transgenerational, molecular, and potential epigenetic mechanisms.⁹¹ However, these adverse effects on sperm quality and ART success may improve with weight loss.⁸⁹ Therefore, it is recommended that clinicians consider assessing both partners when evaluating the risk of adverse IVF outcomes. Furthermore, future studies should evaluate and identify a panel of key biomarkers with clinical utility in aiding screening the likelihood of overweight/obese individuals having successful ART outcomes, as well as the predictive value of such biomarkers.

Strengths and Limitations

This scoping review synthesizes evidence from 50 studies published over the past decade, providing a comprehensive overview of current and emerging strategies aimed at achieving successful ART outcomes in overweight and obese women. Notably, the inclusion of a substantial number of observational studies (N=33) enhances the relevance of the findings to real-world clinical settings. However, several limitations should be acknowledged. The review was restricted to a single database, which may have limited the scope of the included literature. Additionally, some studies had small sample sizes, which may affect the robustness and generalizability of their findings. Considerable heterogeneity was observed across studies with respect to study populations, BMI classifications, ovarian stimulation or ovulation induction protocols utilized, and reported outcomes. Therefore, these aspects must be carefully considered when interpreting and comparing results across studies.

CONCLUSION

In conclusion, this review highlights the complex and multifaceted impact of obesity on ART outcomes, emphasizing that weight loss alone may not improve reproductive success. Adjunct therapies, including nutritional supplements, modifications to IVF protocols based on female BMI, and preconception and periconception biomarker-led approaches for early identification of at-risk women, show promise in optimizing IVF outcomes in overweight and obese women, particularly in those with comorbidities. Furthermore, the review underscores that given the lack of standardized guidelines, personalized medicine approaches during ART procedures are becoming increasingly important in this high-risk population.

Competing interests

GVD is the Chairman of Aksigen IVF Pvt. Ltd., India. SNP is a Consulting Clinical Director at Aksigen IVF Pvt. Ltd., India. All other authors declare no competing interests related to this article.

Funding

This work received no external funding. It was carried out as part of the academic and clinical activities of Aksigen IVF Pvt. Ltd., India.

Ethics approval and consent to participate

Not applicable

AI statement

We would like to confirm that we have not used any AI tools in preparing the manuscript. The literature search, screening, analyzing, writing, and formatting were all done manually.

Consent for publication

Not applicable

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Authors’ contributions

Conceptualization: GVD, GSD

Methodology/Search Strategy: GVD, NNP, AOM

Literature Review & Evidence Analysis: SNP, NNP

Writing – Original Draft Preparation: GVD, SNP, NNP

Writing – Review & Editing: GVD, SNP, GSD, NNP, AOM

Supervision & Strategic Direction: GSD, GVD, AOM

Final Approval of Manuscript: All authors

Acknowledgments

The authors thank Shefali Harankhedkar and Shalini Murali Krishan of SciVoc Healthcare Consulting for providing medical writing assistance.