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Cochrane Database of Systematic Reviews Review - Intervention

Pharmacological and non‐pharmacological strategies for obese women with subfertility

Authors' declarations of interest

Version published: 25 March 2021 Version history

https://doi.org/10.1002/14651858.CD012650.pub2
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Background

Clinicians primarily recommend weight loss for obese women seeking pregnancy. The effectiveness of interventions aimed at weight loss in obese women with subfertility is unclear.

Objectives

To assess the effectiveness and safety of pharmacological and non‐pharmacological strategies compared with each other, placebo, or no treatment for achieving weight loss in obese women with subfertility.

Search methods

We searched the CGF Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and AMED from inception to 18 August 2020. We also checked reference lists and contacted experts in the field for additional relevant papers.

Selection criteria

We included published and unpublished randomised controlled trials in which weight loss was the main goal of the intervention. Our primary effectiveness outcomes were live birth or ongoing pregnancy and primary safety outcomes were miscarriage and adverse events. Secondary outcomes included clinical pregnancy, weight change, quality of life, and mental health outcome.

Data collection and analysis

Review authors followed standard Cochrane methodology.

Main results

This review includes 10 trials. Evidence was of very low to low quality: the main limitations were due to lack of studies and poor reporting of study methods. The main reasons for downgrading evidence were lack of details by which to judge risk of bias (randomisation and allocation concealment), lack of blinding, and imprecision.

Non‐pharmacological intervention versus no intervention or placebo

Evidence is insufficient to determine whether a diet or lifestyle intervention compared to no intervention affects live birth (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.65 to 1.11; 918 women, 3 studies; I² = 78%; low‐quality evidence). This suggests that if the chance of live birth following no intervention is assumed to be 43%, the chance following diet or lifestyle changes would be 33% to 46%. We are uncertain if lifestyle change compared with no intervention affects miscarriage rate (OR 1.54, 95% CI 0.99 to 2.39; 917 women, 3 studies; I² = 0%; very low‐quality evidence). Evidence is insufficient to determine whether lifestyle change compared with no intervention affects clinical pregnancy (OR 1.06, 95% CI 0.81 to 1.40; 917 women, 3 studies; I² = 73%; low‐quality evidence). Lifestyle intervention resulted in a decrease in body mass index (BMI), but data were not pooled due to heterogeneity in effect (mean difference (MD) ‐3.70, 95% CI ‐4.10 to ‐3.30; 305 women, 1 study; low‐quality evidence; and MD ‐1.80, 95% CI ‐2.67 to ‐0.93; 43 women, 1 study; very low‐quality evidence).

Non‐pharmacological versus non‐pharmacological intervention

We are uncertain whether intensive weight loss interventions compared to standard care nutrition counselling affects live birth (OR 11.00, 95% CI 0.43 to 284; 11 women, 1 study; very low‐quality evidence), clinical pregnancy (OR 11.00, 95% CI 0.43 to 284; 11 women, 1 study; very low‐quality evidence), BMI (MD ‐3.00, 95% CI ‐5.37 to ‐0.63; 11 women, 1 study; very low‐quality evidence), weight change (MD ‐9.00, 95% CI ‐15.50 to ‐2.50; 11 women, 1 study; very low‐quality evidence), quality of life (MD 0.06, 95% CI ‐0.03 to 0.15; 11 women, 1 study; very low‐quality evidence), or mental health (MD ‐7.00, 95% CI ‐13.92 to ‐0.08; 11 women, 1 study; very low‐quality evidence). No study reported on adverse events .

Pharmacological versus pharmacological intervention

For metformin plus liraglutide compared to metformin we are uncertain of an effect on the adverse events nausea (OR 7.22, 95% CI 0.72 to 72.7; 28 women, 1 study; very low‐quality evidence), diarrhoea (OR 0.31, 95% CI 0.01 to 8.3; 28 women, 1 study; very low‐quality evidence), and headache (OR 5.80, 95% CI 0.25 to 133; 28 women, 1 study; very low‐quality evidence). We are uncertain if a combination of metformin plus liraglutide vs metformin affects BMI (MD 2.1, 95% CI ‐0.42 to 2.62; 28 women, 1 study; very low‐quality evidence) and total body fat (MD ‐0.50, 95% CI ‐4.65 to 3.65; 28 women, 1 study; very low‐quality evidence).

For metformin, clomiphene, and L‐carnitine versus metformin, clomiphene, and placebo, we are uncertain of an effect on miscarriage (OR 3.58, 95% CI 0.73 to 17.55; 274 women, 1 study; very low‐quality evidence), clinical pregnancy (OR 5.56, 95% CI 2.57 to 12.02; 274 women, 1 study; very low‐quality evidence) or BMI (MD ‐0.3, 95% CI 1.17 to 0.57, 274 women, 1 study, very low‐quality evidence).

We are uncertain if dexfenfluramine versus placebo affects weight loss in kilograms (MD ‐0.10, 95% CI ‐2.77 to 2.57; 21 women, 1 study; very low‐quality evidence). No study reported on live birth, quality of life, or mental health outcomes.

Pharmacological intervention versus no intervention or placebo

We are uncertain if metformin compared with placebo affects live birth (OR 1.57, 95% CI 0.44 to 5.57; 65 women, 1 study; very low‐quality evidence). This suggests that if the chance of live birth following placebo is assumed to be 15%, the chance following metformin would be 7% to 50%. We are uncertain if metformin compared with placebo affects gastrointestinal adverse events (OR 0.91, 95% CI 0.32 to 2.57; 65 women, 1 study; very low‐quality evidence) or miscarriage (OR 0.50, 95% CI 0.04 to 5.80; 65 women, 1 study; very low‐quality evidence) or clinical pregnancy (OR 2.67, 95% CI 0.90 to 7.93; 96 women, 2 studies; I² = 48%; very low‐quality evidence). We are also uncertain if diet combined with metformin versus diet and placebo affects BMI (MD ‐0.30, 95% CI ‐2.16 to 1.56; 143 women, 1 study; very low‐quality evidence) or waist‐to‐hip ratio (WHR) (MD 2.00, 95% CI ‐2.21 to 6.21; 143 women, 1 study; very low‐quality evidence).

Pharmacological versus non‐pharmacological intervention

No study undertook this comparison.

Authors' conclusions

Evidence is insufficient to support the use of pharmacological and non‐pharmacological strategies for obese women with subfertility. No data are available for the comparison of pharmacological versus non‐pharmacological strategies. We are uncertain whether pharmacological or non‐pharmacological strategies effect live birth, ongoing pregnancy, adverse events, clinical pregnancy, quality of life, or mental health outcomes. However, for obese women with subfertility, a lifestyle intervention may reduce BMI. Future studies should compare a combination of pharmacological and lifestyle interventions for obese women with subfertility.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Do pharmacological and non‐pharmacological strategies reduce weight in obese women with subfertility?

To assess the effectiveness and safety of pharmacological and non‐pharmacological strategies compared with each other, placebo, or no treatment for weight reduction in obese women with subfertility.

Background

To prevent the adverse effects of obesity, weight loss is recommended as the first line of treatment for obese women seeking pregnancy. The effectiveness of pharmacological and non‐pharmacological interventions for obese women with subfertility is unclear.

Study characteristics

We found 10 randomised trials comparing pharmacological and non‐pharmacological strategies in 1490 obese women with subfertility.

Key results

Lack of data is a major concern in interpretation of these data. Only 10 studies were included in the analysis. Three studies compared non‐pharmacological intervention versus no intervention or placebo. We are uncertain whether diet versus no intervention improves live birth, ongoing pregnancy, clinical pregnancy, or adverse events. A diet or lifestyle intervention may result in body mass index (BMI) weight change. Evidence was insufficient to show a difference in waist‐to‐hip ratio (WHR) with diet or lifestyle change compared to no intervention. No study reported on quality of life, or mental health outcomes for this comparison.

One study compared non‐pharmacological interventions ‐ intensive weight loss intervention versus standard of care nutrition counselling; however due to the very low quality of evidence, we are uncertain whether intensive weight loss interventions improve live birth, clinical pregnancy, quality of life, or mental health outcomes. No study reported on adverse events, or weight changes, for this comparison.

Three studies reported on pharmacological versus pharmacological interventions. Evidence was insufficient to show a difference in adverse events between metformin compared to metformin plus liraglutide. Evidence was insufficient to demonstrate a difference between the combination of metformin, clomiphene, and L‐carnitine versus metformin, clomiphene, and placebo for miscarriage. Evidence was insufficient to reveal a difference between the combination of metformin, clomiphene, and L‐carnitine versus metformin, clomiphene, and placebo or metformin plus liraglutide versus metformin in clinical pregnancy. Evidence was insufficient to demonstrate a difference between the combination of metformin, clomiphene, and L‐carnitine versus metformin, clomiphene, and placebo for weight change using BMI. Moreover, evidence was insufficient to reveal a difference between dexfenfluramine versus placebo or metformin plus liraglutide versus metformin for weight loss in kilograms, or per cent of total body fat. No study reported on live birth and change in quality of life or mental health outcomes for this comparison.

In the comparison of pharmacological intervention versus no intervention or placebo, three studies were included. Evidence was insufficient to show a difference between metformin and control groups related to live birth. Evidence was insufficient to reveal a difference between metformin compared to placebo in live birth, clinical pregnancy, or adverse events. Evidence was insufficient to demonstrate a difference between diet combined with metformin versus diet combined with placebo for weight change using BMI or WHR. No study reported on quality of life or mental health outcomes for this comparison.

We found no study comparing non‐pharmacological with pharmacological interventions.

Quality of the evidence

The evidence was of very low to low quality. The main limitations were due to lack of studies and poor reporting of study methods. The main reasons for downgrading of evidence were lack of details by which to judge risk of bias (randomisation and allocation concealment), lack of blinding, and imprecision.

Authors' conclusions

Implications for practice

Evidence is yet insufficient to support the use of pharmacological and non‐pharmacological strategies for weight reduction for obese women with subfertility. No data are available for the comparison of pharmacological versus non‐pharmacological strategies. We are uncertain whether pharmacological or non‐pharmacological strategies improve live birth, ongoing pregnancy, adverse events, clinical pregnancy, quality of life, or mental health outcomes. Our findings were based on very low‐quality evidence from studies that may contribute to these outcomes. Thus, we are not able to draw firm conclusions with regard to the impact of pharmacological and non‐pharmacological strategies for weight reduction. However, limited information suggests that lifestyle intervention for obese women with subfertility may reduce BMI. Although obese women should be counselled about the risk of obesity for fertility and pregnancy outcomes, healthcare providers should caution women that the existing research is of poor quality and of limited quantity.

Implications for research

In view of the high prevalence of obesity‐related subfertility and lack of good evidence, we need well‐designed and well‐conducted RCTs with double‐blinding and adequately powered trials reporting methods such as randomisation and allocation concealment in detail and aiming to share data after the trial. Future studies are advised to focus on lifestyle interventions with or without pharmacological interventions for obese women with subfertility. Follow‐up time needs to be long enough for these clinically relevant outcome data to be obtained. The duration of follow‐up for assessing outcomes should be at least three months, but longer follow‐up is advised to enable reporting of natural pregnancies. Finally, the economic impact of different weight reduction methods should be reported.

Summary of findings

Open in table viewer
Summary of findings 1. Non‐pharmacological intervention compared to no intervention or placebo for obese women with subfertility

Non‐pharmacological intervention compared to no intervention for obese women with subfertility

Patient or population: obese women with subfertility
Setting: hospital
Intervention: non‐pharmacological (diet and/or lifestyle changes)
Comparison: no intervention

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№. of participants
(studies)

Certainty of evidence
(GRADE)

Comments

Risk with non‐pharmacological intervention

Risk with no intervention

Live birth

395 per 1000
(334 to 462)

431 per 1000

OR 0.85
(0.65 to 1.12)

917
(3 RCTs)

⊕⊕⊝⊝
lowa,b

Ongoing pregnancy

536 per 1000
(453 to 617)

588 per 1000

OR 0.81
(0.58 to 1.13)

564
(1 RCT)

⊕⊕⊝⊝
lowc

Miscarriage

122 per 1000
(82 to 177)

83 per 1000

OR 1.54
(0.99 to 2.39)

917
(3 RCTs)

⊕⊝⊝⊝
very lowc,d

Clinical pregnancy

529 per 1000
(458 to 594)

514 per 1000

OR 1.06
(0.81 to 1.40)

917
(3 RCTs)

⊕⊕⊝⊝
lowa,b

Weight change
BMI change (Einarsson 2017)

MD 3.70 kg/m² lower
(4.10 lower to 3.36 lower)

Mean BMI change ranged from 0.04 to 0.7 kg/m²

‐

305
(1 RCT)

⊕⊕⊝⊝
lowc

BMI change (Sim 2014)

MD 1.80 kg/m² lower (2.67 lower to 0.93 lower)

Mean BMI change ranged from ‐1.3 to 0 kg/m²

‐

43

(1 RCT)

⊕⊝⊝⊝ very lowc,e

Quality of life/
Mental health outcome

No study reported this outcome

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial.

GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level for substantial heterogeneity: I² > 70%.

bDowngraded one level for imprecision as reflected by the large confidence interval.

cDowngraded two levels for serious imprecision.

dDowngraded one level for indirectness due to differences in definition.

eDowngraded one level for incomplete outcome data with an uneven dropout between groups.

Open in table viewer
Summary of findings 2. Non‐pharmacological intervention compared to non‐pharmacological intervention for obese women with subfertility

Non‐pharmacological intervention compared to non‐pharmacological intervention for obese women with subfertility

Patient or population: obese women with subfertility
Setting: hospital
Intervention: intensive weight loss intervention
Comparison: standard‐of‐care nutrition counseling

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№. of participants
(studies)

Certainty of evidence
(GRADE)

Comments

Risk with weight loss

Risk with standard of care nutrition

Live birth

500 per 1000

0 per 1000
(0 to 0)

OR 11.00
(0.43 to 284)

11
(1 RCT)

⊕⊝⊝⊝
Very lowa,b

Miscarriage

0 per 1000

0 per 1000

In the trial with 11 women, no pregnancy loss occurred

Clinical pregnancy

500 per 1000

0 per 1000
(0 to 0)

OR 11.00
(0.43 to 284)

11
(1 RCT)

⊕⊝⊝⊝
Very lowa,b

Weight change
Weight change (kg)

Body mass index (BMI)

Mean weight change ranged from 5 to 6 kg

MD 9 kg lower
(15.5 lower to 2.5 lower)

‐

11
(1 RCT)

⊕⊝⊝⊝
Very lowa,b

Mean body mass Index ranged from 2 to 3 kg/m²

MD 3 kg/m² lower
(5.37 lower to 0.63 lower)

‐

11
(1 RCT)

⊕⊝⊝⊝
Very lowa,b

Quality of life/Mental health outcome
Mental health (at 12 weeks)

Quality of life (at 12 weeks)

Mean mental health ranged from 2 to 3

MD 7 lower
(13.92 lower to 0.08 lower)

‐

11
(1 RCT)

⊕⊝⊝⊝
Very lowa,b

Mean quality of life ranged from 0.01 to 0.02

MD 0.06 higher
(0.03 lower to 0.15 higher)

‐

11
(1 RCT)

⊕⊝⊝⊝
Very lowa,b

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial.

GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level for selection bias due to lack of details on random sequence, random allocation, and blinding.

bDowngraded two levels for serious imprecision due to small sample size.

Open in table viewer
Summary of findings 3. Pharmacological intervention compared to pharmacological intervention for obese women with subfertility

Pharmacological intervention compared to pharmacological intervention for obese women with subfertility

Patient or population: obese women with subfertility
Setting: hospital
Intervention: different pharmacological interventions
Comparison: different pharmacological interventions

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№. of participants
(studies)

Certainty of evidence
(GRADE)

Comments

Risk with pharmacological intervention

Risk with pharmacological intervention

Live birth

No study reported this outcome

Adverse events ‐ Metformin plus liraglutide vs metformin

Nausea

Diarrhoea

Headache

71 per 1000

357 per 1000
(52 to 848)

OR 7.22
(0.72 to 73)

28 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

71 per 1000

23 per 1000

OR 0.31 (0.01 to 8.3)

28 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

0 per 1000

0 per 1000

OR 5.80 (0.25 to 133)

28 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Clinical pregnancy
Metformin plus liraglutide vs metformin

Met + CC + L‐carnitine vs Met + CC + placebo

80 per 1000

311 per 1000
(184 to 476)

OR 5.20 (2.59 to 10.4)

28 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

214 per 1000

500 per 1000

(160 to 839)

OR 3.67

(0.70 to 19.1)

274 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Miscarriage
Met + CC + L‐carnitine vs Met + CC + placebo

15 per 1000

51 per 1000

(11 to 208)

OR 3.58 ( 0.73 to 17.6)

274 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Weight ‐ BMI change
Metformin plus liraglutide vs metformin

Met + CC + L‐carnitine vs Met + CC + placebo

Weight change
Dexfenfluramine vs placebo

Weight ‐ body fat
Metformin plus liraglutide vs metformin

Mean BMI change was set at 0

MD 2.1 higher (0.42 lower to 4.52 higher)

‐

28 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Mean BMI change was set at 0

MD 0.3 lower (1.17 lower to 0.57 higher)

‐

274 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Mean weight change was set at 0 kg

MD 0.1 kg lower (2.77 lower to 2.57 higher)

‐

21 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Mean change in % total body fat was set at 0

MD 0.5 lower
(4.65 lower to 3.65 higher)

‐

28 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Quality of life/Mental health outcome

No study reported this outcome

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial.

GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level for selection bias due to lack of details on random sequence, random allocation, and blinding.

bDowngraded two levels for serious imprecision as reflected by the large confidence interval.

Open in table viewer
Summary of findings 4. Pharmacological intervention compared to no intervention or placebo for obese women with subfertility

Pharmacological intervention compared to no intervention/placebo for obese women with subfertility

Patient or population: obese women with subfertility
Setting: hospital
Intervention: metformin
Comparison: no intervention/placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№. of participants
(studies)

Certainty of evidence
(GRADE)

Comments

Risk with pharmacological intervention

Risk with no intervention/placebo

Live birth

219 per 1000
(73 to 499)

152 per 1000

OR 1.57
(0.44 to 5.57)

65 (1 RCT)

⊕⊝⊝⊝
very lowa,b

Ongoing pregnancy

No study reported this outcome

Miscarriage

31 per 1000
(3 to 272)

61 per 1000

OR 0.50
(0.04 to 5.80)

65 (1 RCTs)

⊕⊝⊝⊝
very lowa,b

Adverse events (GI)

313 per 1000

333 per 1000

OR 0.91 (0.32 to 2.57)

65 (1 RCT)

⊕⊝⊝⊝
very lowa,b

Clinical pregnancy

237 per 1000
(95 to 480)

104 per 1000

OR 2.67
(0.90 to 7.93)

96 (2 RCTs)

⊕⊝⊝⊝
very lowa,b

Weight change
BMI

WHR

MD 0.3 kg/m² lower
(2.16 lower to 1.56 higher)

Mean BMI change was set at 0

‐

143
(1 RCTs)

⊕⊝⊝⊝
very lowa,c

MD 2 cm higher
(2.21 lower to 6.21 higher)

Mean WHR change was set at 0

‐

143
(1 RCT)

⊕⊝⊝⊝
very lowa,c

Quality of life/Mental health outcome

No study reported this outcome

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial.

GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded twice for serious imprecision as reflected by the large confidence interval.

bDowngraded once in view of inconsistency in clinical pregnancy, which could not be seen in studies in view of the presence of only a single trial with 65 women for the outcomes live birth and miscarriage.

cDowngraded once for selection bias due to lack of details on random sequence, random allocation, and blinding.

Background

Description of the condition

Obesity rates have been rising worldwide, creating a global health problem. The World Health Organization has defined obesity as body mass index (BMI) > 30 kg/m². According to estimates, in 2015, about 2.3 billion men and women were overweight (BMI 25 to 30 kg/m²), and 700 million were obese (BMI > 30 kg/m²). The prevalence of obesity is estimated to range from 5% in some developing countries to more than 30% in developed countries (Hossain 2007; Ogden 2006).

The obesity epidemic has contributed to fertility problems. Obese women have a lesser chance of conceiving naturally than non‐obese women (Chong 1986; Crosignani 1994; Hamilton‐Fairley 1992), and they are at greater risk of miscarriage (Boots 2011). Obesity can result in anovulation and a reduced chance of conceiving among ovulatory subfertile women (Metwally 2007; van der Steeg 2008). Furthermore, pregnancy and live birth rates following IVF appear to be lower in obese women (Koloszar 2002; Wang 2002; Fedorcsák 2004; Sermonade 2019). Moreover, literature suggests that obesity is related to maternal and neonatal complications such as congenital anomalies, hypertensive disorder, gestational diabetes, prolonged labour, macrosomia, and shoulder dystocia (Edwards 1996; Garbaciak 1985; Waller 1994; Weiss 2004).

To prevent the adverse effects of obesity, weight loss is recommended as the first line of treatment for obese women seeking pregnancy (Thessaloniki 2008).

Description of the intervention

Treatment for obesity can involve both non‐pharmacological and pharmacological strategies.

Non‐pharmacological strategies

Diet

Generally, weight loss occurs when energy intake is lower than energy expenditure. In two small studies, replacing protein for carbohydrate within the context of an energy‐restricted diet using 12‐week and 1‐month dietary intervention among the overweight or obese target population (polycystic ovarian syndrome (PCOS) patients) provided the same improved reproductive outcomes that were achieved in the control group (Moran 2005; Stamets 2004), although postprandial glucose response was 3.5 times lower in the group with a higher‐protein diet. Lifestyle modification through diet and exercise programmes in obese women with PCOS improves reproductive outcomes (Clark 1998; Huber‐Buchholz 1999). An important point is that a minimal amount of weight loss (5% to 10%) over as little as four weeks is sufficient to improve the presentation of PCOS despite patients remaining clinically overweight or obese (Clark 1998; Hamilton‐Fairley 1993; Wahrenberg 1999).

Exercise

Exercise is an important component of any lifestyle modification and weight management programme. The results of two studies that examined effects of exercise on insulin resistance in overweight or obese women with PCOS (who were followed for 16 to 24 weeks and for 6 months) were different. Neither of these studies reported changes in hormone or reproductive parameters (Brown 2009; Randeva 2002). In these studies, the impact of exercise was not evaluated separately from diet, and the result may suffer from reporting bias (Thomson 2010).

Behavioural

Behavioural might contribute to greater weight loss when combined with medical therapy and diet. In one study (Wadden 2005), participants were followed for 52 weeks, during which time counselling was given including regular supportive and motivational personal or group sessions. Behaviour therapy improved weight loss as well as weight maintenance and control.

Complementary and traditional healthcare approaches

The terms 'complementary' and 'alternative' describe practices and products that people choose as adjuncts or alternatives to Western medical approaches (Kaptchuk 2001; Straus 2004). The National Institutes of Health has grouped such interventions into five somewhat overlapping domains as follows (nccam.nih.gov/health/whatiscam).

  • Biologically based practices. These include use of a vast array of vitamins and mineral supplements, natural products such as chondroitin sulphate, which is derived from bovine or shark cartilage, and herbals such as ginkgo biloba and echinacea.

  • Manipulative and body‐based approaches. These types of therapies, which include massage, have been used throughout history. In the 19th century, additional formal manipulative disciplines emerged in the United States: chiropractic medicine and osteopathic medicine, which had a great influence in complementary medicine.

  • Mind‐body medicine. Many ancient cultures assumed that the mind exerts powerful influences on bodily functions and vice versa. Attempts to reassert proper harmony between these bodily systems led to the development of mind‐body medicine, an array of approaches that incorporate spiritual, meditative, and relaxation techniques.

  • Alternative medical systems. Whereas the ancient Greeks postulated that health requires a balance of vital humors, Asian cultures considered that health depends on the balance and flow of vital energies through the body. This latter theory underlies the practice of acupuncture, for example, which asserts that vital energy flow can be restored by placing needles at critical body points.

  • Energy medicine. This approach uses therapies that involve the use of energy ‐ biofield‐based or bioelectromagnetic‐based interventions. An example of the former is Reiki therapy, which aims to realign and strengthen healthful energies through the intervention of energies radiating from the hands of a master healer.

Pharmacological strategies

Numerous anti‐obesity medications are prescribed for weight loss. These drugs may be classified as follows.

  • Drugs acting on the gastrointestinal tract (GIT): lipase inhibitors (orlistat).

  • Centrally acting anti‐obesity agents: catecholaminergic agents (phentermine).

  • Serotonin and noradrenaline reuptake inhibitors such as sibutramine, selective serotonin reuptake inhibitors (SSRIs) (sertraline).

  • Dopamine reuptake antagonists (bupropion), anti‐depressants (fluoxetine).

  • Exercise mimetics ephedrine, caffeine, synephrine, beta 3 adrenergic agonists, uncoupling proteins 2 and 3 (thermogenin).

  • Leptin‐related agents: therapeutic leptin, leptin analogues, leptin receptor agonists.

All of these drugs have side effects, and side effect profiles vary per drug. Sibutramine is associated with modest increases in heart rate and blood pressure; gastrointestinal symptoms predominate with the use of orlistat; phentermine can induce cardiovascular and gastrointestinal side effects; fluoxetine is associated with agitation and nervousness, in addition to gastrointestinal side effects; bupropion with paraesthesia, insomnia, and central nervous system effects; and topiramate with paraesthesia and changes in taste (Li 2005).

How the intervention might work

The aetiology of obesity is believed to be multi‐factorial, with both genetic and environmental contributions. A key determinant of obesity is the balance between ingested calories and the body's basal energy expenditure. Obesity therefore results when small positive energy balances accumulate over a long time (Flegal 2010; Swinburn 2009). Weight loss can be achieved through lifestyle intervention programmes incorporating the combination of a healthy diet, increased physical activity, behavioural modification, and use of complementary and traditional healthcare approaches and medications.

An adverse effect of obesity on female fertility could be mediated by several mechanisms. First, obesity potentially contributes to excess oestrogen as a result of extraglandular aromatisation of androgen precursors. Moreover, sex hormone–binding globulin levels are diminished, resulting in more bioavailable oestrogen and androgen for aromatisation. Second, obesity increases leptin levels. The actions of leptin on the hypothalamus‐pituitary‐ovary (HPO) axis are believed to have differential effects on central and peripheral components of the reproductive system. In the central nervous system, leptin has been shown to modulate gonadotropin‐releasing hormone (GnRH) pulse frequency in vitro (Scott 2009). On the gonadal level, leptin has been found in ovarian follicular fluid, and leptin receptor has been localised to human granulosa and theca cells. In humans, leptin may interrupt normal oocyte maturation (Smith 2002). Weight loss improves the metabolic, endocrine, and reproductive profile of obese women (Falsetti 1992; Hollmann 1996; Kumar 1993). Evidence indicates that a 5% weight loss improves both natural and induced conception, as well as the chance of a healthy live birth (Khaskheli 2013).

Weight loss can be achieved by pharmacological treatments and non‐pharmacological intervention programmes. Pharmacological treatment for obesity is considered an option for infertile women who are overweight or obese because the safety of these treatments has not been fully studied (Johansson 2015; Kominiarek 2017). A systematic review suggested that sibutramine, orlistat, phentermine, probably diethylpropion, probably fluoxetine, bupropion, and topiramate might promote modest weight loss for at least six months when given along with recommendations for diet (and possibly other behavioural and exercise interventions) (Li 2005). Medications act on the mechanisms regulating appetite and satiety and help combat the pathophysiological adaptations that drive weight regain (Garvey 2013). Due to the potential risks associated with surgery or weight loss medications, health organisations have recommended that infertile women who are overweight or obese should follow lifestyle changes (ASRM 2015). Recent international guidelines strongly support the importance of pre‐pregnancy lifestyle interventions in an interdisciplinary situation to encourage healthy lifestyles and maintain weight loss for obese women (Brauer 2015; Kominiarek 2017). In addition, knowledge about the effects of supplements and complementary therapy (herbal medicine and acupuncture) is emerging, but evidence for the overall effects of these interventions is incomplete.

Lifestyle modification, which generally consists of a combination of nutrition, physical activity, and behavioural modification, is an oft‐used strategy to help patients achieve weight loss and maintenance (Berkel 2005; Lang 2006). It has been suggested that complementary and alternative medicine including acupuncture might improve weight loss by (1) regulating obesity‐related neuropeptides (Cabioglu 2006; Gucel 2012); (2) regulating hypothalamus‐pituitary‐adrenal cortex and sympathetic adrenal cortex (Yin 2005); and (3) conferring lipid‐lowering effects (Abdallah 2011). A systematic review and meta‐analysis suggested that acupuncture for obesity might be beneficial compared to placebo or lifestyle control, but results were limited by the clinical heterogeneity and poor methodological quality of the included trials (Cho 2009).

Why it is important to do this review

With the growing incidence of infertility among obese women, it is becoming increasingly common for women to utilise assisted reproductive treatment to become pregnant (Kupta 2014). Overweight and obese women have poor maternity outcomes (Koning 2012; Pandey 2010; Rittenberg 2011), while weight reduction improves reproductive outcomes for these patients (Crosignani 2003; Pandey 2010). The effectiveness of pharmacological and non‐pharmacological interventions for obese women with subfertility is unclear. Moreover, despite the fact that non‐pharmacological interventions are commonly recommended for management of obese subfertile women, their effectiveness in comparison with pharmacological strategies has not been previously examined in a systematic review (Kim 2020).

Objectives

To assess the effectiveness and safety of pharmacological and non‐pharmacological strategies compared with each other, placebo, or no treatment, for achieving weight loss in obese women with subfertility.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and cross‐over randomised trials. For cross‐over trials, only data from the first phase will be included in meta‐analyses, as the cross‐over is not a valid design in this context.

Types of participants

Obese women (BMI ≥ 30 kg/m², or as appropriate for the ethnicity of women in the primary study) of childbearing age (post‐menarche and pre‐menopause) of any ethnic origin who have been unable to conceive for at least 12 months (including primary and secondary subfertility), with or without reasons (anovulatory, unexplained, tubal disease, endometriosis, uterine abnormalities, male factor), and with all types of fertility treatment including intrauterine insemination (IUI), in vitro fertilisation (IVF), and expectant management.

Types of interventions

We included all studies in which weight loss was the main treatment intervention or weight loss interventions were part of a subfertility management programme.

Eligible comparisons are pharmacological, non‐pharmacological, and no intervention or placebo.

We considered the following comparisons.

  • Non‐pharmacological versus pharmacological intervention (e.g. acupuncture versus SSRI).

  • Non‐pharmacological versus non‐pharmacological intervention (e.g. acupuncture versus exercise, one type of exercise versus another).

  • Pharmacological versus pharmacological intervention (e.g. one SSRI versus one type of pharmacological intervention, one SSRI versus another).

  • Pharmacological intervention versus no intervention or placebo.

  • Non‐pharmacological intervention versus no intervention or placebo.

The following interventions will be considered.

Non–pharmacological interventions

  • Behaviour: behaviour modification, behaviour change, brief intervention, brief advice, nurse counselling, physician counselling, psychological counselling, waiting list for treatment with the promise of treatment upon achieving a weight target, behavioural advice, behaviour therapy, Internet‐based support, self‐directed support, social support, group therapy, family therapy, psychotherapy, support group, relaxation, health education, health promotion, motivation, meditation, religious intervention.

  • Diet: diet modification, dietician‐led dietary advice, self‐directed dietary instruction, low‐carbohydrate diet, low‐fat diet, hypocaloric diet.

  • Exercise: walking, jogging, running, swimming, aerobics, structured exercise referral/interventions, weight‐lifting/training, gymnastics, resistance training, fitness training, endurance training, cycling, boxing, kick‐boxing, pedometry, exercise therapy, sports therapy.

  • Complementary and traditional healthcare approaches: acupuncture; electro‐therapy; physical therapy; aromatherapy; auricular stimulation; body therapy; acupuncture ‐ Moxibustion; Tai‐chi; phytooestrogens; soy products; phytovitamins; dietary supplements and herbal products including conjugated linoleic, pyruvate, ephedra sinica (ma huang), chromium, hydroxy citric acid (Garcinia cambogia), and Chitosan.

Pharmacological interventions

  • Drugs acting on the GIT: lipase inhibitors (e.g. orlistat (Xenical), tetrahydrolipstatin), bulking agents (e.g. methylcellulose (Celevac), ispaghula husk, sterculia, bran, guar gum), insulin sensitisers, gastrointestinal peptides, glucagon‐like peptide‐1, enterostatin.

  • Centrally acting anti‐obesity agents: catecholaminergic agents (e.g. phentermine, mazindol, diethylpropion, phenylpropanolamine), serotonergic agents (e.g. fenfluramine, dexfenfluramine, fluoxetine), combined catecholaminergic plus serotoninergic agents (e.g. phentermine plus fenfluramine).

  • Serotonin and noradrenaline reuptake inhibitors (e.g. sibutramine), selective serotonin reuptake inhibitors (SSRIs; e.g. sertraline).

  • Dopamine reuptake antagonists (e.g. bupropion), anti‐depressants (e.g. fluoxetine).

  • Exercise mimetics (e.g. ephedrine, caffeine, synephrine), beta 3 adrenergic agonists, uncoupling proteins 2 and 3 (Thermogenin).

  • Leptin‐related agents (e.g. therapeutic leptin, leptin analogues, leptin receptor agonists).

We excluded surgical interventions.

Types of outcome measures

Primary outcomes

  • Live birth or ongoing pregnancy (when live birth is not available)

    • Live birth is defined as delivery of a live fetus after 20 completed weeks of gestation

    • Ongoing pregnancy is defined as evidence of a gestational sac with fetal heart motion at 12 weeks, confirmed by ultrasound

  • Adverse events: miscarriage (loss of pregnancy during the first 20 weeks of gestation) or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea)

Secondary outcomes

  • Clinical pregnancy: defined as evidence of a gestational sac, confirmed by ultrasound

  • Weight change (e.g. body mass index (BMI), waist to hip ratio (WHR), percentage of body fat or total body fat)

  • Change in endocrine parameters: total and free testosterone (ng/dL or nmol/L), sex hormone‐binding globulin (SHBG; nmol/L), testosterone‐to‐SHBG ratio, diabetic tests such as glucose tolerance test (GTT; mmol/L), glycated haemoglobin (HbA1c; mmol/mol)

  • Quality of life or mental health outcome. If studies reported more than one scale, preference will be given to the SF‐36 (36‐Item Short Form Health Survey), then to other validated generic scales, and finally, to condition‐specific scales

Search methods for identification of studies

In consultation with the Cochrane Gynaecology and Fertility Group (CGF) Information Specialist, we formulated a comprehensive search strategy to identify all RCTs of pharmacological and non‐pharmacological strategies for obese women with subfertility regardless of language or publication status (published, unpublished, in press, or in progress).

Electronic searches

We searched the following electronic databases, trial registers, and websites:

  • Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, ProCite platform, searched on 18 August 2020 (Appendix 1).

  • Cochrane Central Register of Controlled Trials (CENTRAL), via the Cochrane Central Register of Studies Online (CRSO), Web platform, searched on 18 August 2020 (Appendix 2).

  • MEDLINE, Ovid platform, searched from 1946 to 18 August 2020 (Appendix 3).

  • Embase, Ovid platform, searched from 1980 to 18 August 2020 (Appendix 4).

  • PsycINFO, Ovid platform, searched from 1806 to 18 August 2020 (Appendix 5).

  • Allied and Complementary Medicine Database (AMED), Ovid platform, searched from 1985 to 18 August 2020 (Appendix 6).

  • Cumulative Index to Nursing and Allied Health Literature (CINAHL), Ebsco platform, searched from 1961 to 26 September 2019 (Appendix 7). (CINAHL references are now included in CENTRAL; therefore the CENTRAL search on 18 August 2020 included CINAHL references).

The MEDLINE search from inception to 18 August 2020 was combined with the Cochrane highly sensitive search strategy for identifying randomised trials, which appears in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2020, Version 6.1, Chapters 4, 4.4.7; 4S1). Searches of Embase and CINAHL from inception to 18 August 2020 were combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/what-we-do/methodology/search-filters/).

Searching other resources

Other sources of trials below were searched on 18 August 2020:

  • Trial registers for ongoing and registered trials: www.clinicaltrials.gov (a service of the US National Institutes of Health), the World Health Organization International Trials Registry Platform search portal, at www.who.int/trialsearch/Default.aspx.;

  • Database of Abstracts of Reviews of Effects (DARE), part of the Cochrane Library, at onlinelibrary.wiley.com/o/cochrane/cochrane_cldare_articles_fs.html (for reference lists from relevant non‐Cochrane reviews);

  • Relevant non‐Cochrane reviews;

  • Web of Science wokinfo.com/ (another source of trials and conference abstracts);

  • OpenGrey at www.opengrey.eu/ (for unpublished literature from Europe);

  • PubMed (for recent trials not yet indexed in MEDLINE);

  • ProQuest.

We checked the reference lists of relevant trials, reviews, and textbooks. We contacted experts in the field for relevant trials and to obtain additional data. Output of all searches was managed with EndNote, which lists all studies and removes duplicates.

Data collection and analysis

Selection of studies

After an initial screen of titles and abstracts retrieved by the search, conducted by two review authors (FB and ST), we retrieved the full text of all potentially eligible studies. These review authors independently examined these full‐text articles for compliance with the inclusion criteria and selected eligible studies. We corresponded with study investigators, as required, to clarify study eligibility. Any disagreement about whether to include or exclude a study was discussed with a third review author (SJ) until consensus was achieved. We have listed excluded studies and reasons for their exclusion in the Characteristics of excluded studies tables. See Figure 1 (PRISMA flow chart) for details of the screening and selection process.

Figure 1
Study flow diagram.

Study flow diagram.

Data extraction and management

Two review authors (FB and ST) independently extracted data from eligible studies using a data extraction form that had been designed and pilot‐tested by review authors. Any disagreements were resolved by discussion. Data extracted included study characteristics and outcome data. When studies had multiple publications, review authors collated multiple reports of the same under a single study ID with multiple references. We corresponded with study investigators to request further data on methods and/or results, as required. Data extracted included population characteristics (e.g. female age, BMI, waist‐hip ratio, ethnicity), study characteristics, and outcome data.

Assessment of risk of bias in included studies

Two review authors (FB and ST) assessed risk of bias using the Cochrane 'Risk of bias' assessment tool to assess selection bias (random sequence generation, allocation concealment); performance bias (blinding of women and personnel); detection bias (blinding of outcome assessors); attrition bias (incomplete outcome data); reporting bias (selective reporting); and other biases (Higgins 2011). Disagreements were resolved by consensus or by discussion with a third review author (SJ).

Random sequence generation was scored at low risk of bias when an appropriate method of sequence generation was described according to Cochrane methods (Higgins 2011).

Allocation concealment was considered at low risk of bias if opaque and numbered envelopes or a centralised Internet‐based randomisation procedure was used. Lack of blinding is unlikely to affect live birth (scored at low risk of bias) but might affect adverse events (scored at high risk of bias). Attrition bias was scored low when all or most (> 95%) of the women randomised were analysed. Reporting bias was scored low when all relevant outcomes were reported as planned in the protocol, as described in published protocols in journals or in trial registers. To score other forms of bias, we looked at differences in baseline values and treatment details. If these issues were unclear, we scored the risk of bias as unclear.

We corresponded with study authors to identify any within‐trial selective reporting. We sought published protocols and compared outcomes between the protocol and the final published study. The 'Risk of bias' table is presented with the table Characteristics of included studies. All judgements are fully described. Conclusions are presented in the ’Risk of bias’ table and are incorporated into the interpretation of review findings through sensitivity analyses.

With respect to within‐trial selective reporting, when identified studies failed to report the primary outcome of live birth but did report interim outcomes such as pregnancy, we assessed whether the interim values were similar to those reported in studies that also reported live birth.

Measures of treatment effect

We performed a statistical analysis in accordance with statistical guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We used a fixed‐effect model for all analyses.

For dichotomous data (e.g. live birth rates), we used numbers of events in control and intervention groups of each study to calculate odds ratios (ORs). For reporting purposes, we translated primary outcomes to absolute risks.

For continuous data (e.g. weight loss), if all studies reported exactly the same outcomes, we planned to calculate mean differences (MDs) between treatment groups. If similar outcomes were reported on different scales (e.g. change in weight, quality of life), we planned to calculate standardised mean differences (SMDs). We planned to reverse the direction of effect of individual studies, if required, to ensure consistency across trials. We planned to treat ordinal data (e.g. quality of life scores) as continuous data. We planned to present 95% confidence intervals for all outcomes.

When data to calculate RRs or MDs were not available, we planned to utilise the most detailed numerical data available that may facilitate similar analyses of included studies (e.g. test statistics, P values). We planned to assess whether estimates calculated in the review for individual studies were compatible in each case with estimates reported in study publications.

Because cluster‐RCTs are included in the review, we planned to first make an assessment as to whether the trial had been analysed in such a way as to account for clustering, and if not, we planned to make an adjustment to the trial results using one of several available approaches including a generic inverse‐variance method via effect estimates and their standard errors extracted from cluster‐RCTs.

Unit of analysis issues

The primary analysis was planned to be per woman randomised; per pregnancy data may also be included for some outcomes (e.g. miscarriage). Data that do not allow valid analysis (e.g. 'per cycle' data) were planned to be briefly summarised in an additional table and not to be meta‐analysed. Multiple births were planned to count as one live birth event. Only first‐phase data from cross‐over trials were planned to be included.

Dealing with missing data

We planned to analyse data on an intention‐to‐treat basis as far as possible (i.e. including all randomised women in the analysis, in the groups to which they were randomised). We planned to attempt to obtain missing data from the original study authors. When these were unobtainable, we planned to undertake imputation of individual values for live birth only: live birth was planned to be assumed not to have occurred in women without a reported outcome. For other outcomes, we planned to analyse only available data. Any imputation undertaken was planned to be subjected to Sensitivity analysis.

If studies reported sufficient detail to calculate mean differences but no information on associated SD, we planned to assume the outcome to have an SD equal to the highest SD from other studies within the same analysis.

Assessment of heterogeneity

We planned to consider whether the clinical and methodological characteristics of included studies were sufficiently similar for meta‐analysis to provide a clinically meaningful summary. We planned to assess statistical heterogeneity by using the I² value. An I² measurement greater than 50% was planned to be taken to indicate substantial heterogeneity (Higgins 2011).

Assessment of reporting biases

In view of the difficulty of detecting publication bias and other biases, review authors aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies, and by being alert for duplication of data. If 10 or more studies were included in an analysis, we planned to use a funnel plot to assess the potential for publication bias.

Data synthesis

If studies were sufficiently similar, we planned to combine data using a fixed‐effect model for the following comparisons.

  • Non‐pharmacological intervention versus no intervention/placebo.

  • Non‐pharmacological versus non‐pharmacological intervention.

  • Pharmacological versus pharmacological intervention.

  • Pharmacological intervention versus no intervention/placebo.

  • Pharmacological versus non‐pharmacological intervention.

See Types of interventions for the exact study interventions we planned to investigate.

An increase in the risk of all outcomes was planned to be displayed graphically in meta‐analyses to the right of the centre‐line, and a decrease in the risk of an outcome to the left of the centre‐line.

Subgroup analysis and investigation of heterogeneity

When sufficient data were available (at least five RCTs), we planned to perform the following subgroup analyses for primary outcomes only.

  • Duration of intervention (short: 2 to 4 weeks, medium: 4 weeks to 6 months, long: longer than 6 months) (Lim 2019).

  • Cause of infertility: anovulatory versus unexplained versus other causes.

  • Maternal age: ≤ 35 or ≥ 36 years.

  • Severity of obesity (BMI): 30.0 < BMI < 34.9 (class I obesity) versus 35.0 < BMI < 39.9 (class II obesity) versus BMI ≥ 40.0 (class III obesity).

Sensitivity analysis

We planned to conduct the following sensitivity analyses for primary outcomes, to examine stability regarding pooled outcomes.

  • Restriction to studies without high risk of bias.

  • Use of a random‐effects model.

  • Use of risk ratio rather than odds ratio.

Summary of findings and assessment of the certainty of the evidence

We prepared a 'Summary of findings' table using GRADEpro (GRADEpro GDT 2014) and Cochrane methods (Higgins 2011). This table evaluates the overall quality of the body of evidence for the primary review outcomes (live birth or ongoing pregnancy, adverse events, clinical pregnancy, miscarriage) for the main review comparison (pharmacological versus non‐pharmacological strategies). Additional 'Summary of findings' tables were also prepared for the main review outcomes for other important comparisons.

We assessed the quality of the evidence using GRADE criteria: risk of bias, consistency of effect, imprecision, indirectness and publication bias. Judgements about evidence quality (high, moderate, low or very low) were made by two review authors working independently, with disagreements resolved by discussion. Judgements were justified, documented, and incorporated into reporting of results for each outcome.

We extracted study data, formatted our comparisons in data tables and prepared a 'Summary of findings' table using the GRADEpro Guideline Development Tool (GDT) (GRADEpro GDT 2014) before writing the results and conclusions of our review.

Results

Description of studies

We have reported the characteristics of included and excluded studies in the Characteristics of included studies and Characteristics of excluded studies tables. We did not identify any studies from the reference lists.

Results of the search

Our search retrieved 5577 articles (910 duplicates were removed). Of these articles, 4667 studies were screened by title and abstract and 68 studies were assessed at full text for eligibility. Finally, we included 10 studies that met the inclusion criteria for the review (Figure 1). The 10 included trials varied in size from 11 to 564 women (Einarsson 2017; El 2019; Galletly 1996; Johnson 2010; Khorram 2006; Mutsaerts 2016; Rothberg 2016; Salamun 2018; Sim 2014; Tang 2006).

Included studies

Study design

One study was a cross‐over randomised clinical trial (Galletly 1996) for which we tried to extract pre‐cross‐over data, and the others were RCTs (Einarsson 2017; El 2019; Johnson 2010; Khorram 2006; Mutsaerts 2016; Rothberg 2016; Salamun 2018; Sim 2014; Tang 2006). Einarsson 2017, El 2019, and Johnson 2010 used a computerised randomisation programme for the randomisation process, and Tang 2006 used a table of random numbers. Khorram 2006 explained that randomisation was done by picking a card out of a box. A web‐based randomisation program was adopted for Mutsaerts 2016. It is not clear how randomisation was done in Galletly 1996, Sim 2014, Salamun 2018, and Rothberg 2016.

Sample size

The number of women included in the studies ranged from 11 to 564.

Setting

All studies except one were conducted in high‐income countries (Egypt; El 2019). One study was undertaken in the UK (Tang 2006), one in The Netherlands (Mutsaerts 2016), two in the USA (Khorram 2006; Rothberg 2016), one in Sweden (Einarsson 2017), one in New Zealand (Johnson 2010), one in Slovenia (Salamun 2018), and two in Australia (Galletly 1996; Sim 2014). All trials recruited women in hospital settings.

Participants

All women in the included studies met our inclusion criteria. We found 10 randomised trials including 1490 obese women with subfertility. Einarsson 2017 included 305 participants, Sim 2014 48 participants, Mutsaerts 2016 564 participants, Rothberg 2016 11 participants, Salamun 2018 28 participants, El 2019 274 participants, Galletly 1996 21 participants, Tang 2006 143 participants, Khorram 2006 31 participants, and Johnson 2010 65 participants.

The main inclusion criterion was:

The main exclusion criteria were:

There were no significant differences between baseline characteristics in all studies (El 2019Galletly 1996Johnson 2010; Khorram 2006; Mutsaerts 2016; Rothberg 2016; Sim 2014; Tang 2006), except termination of pregnancy in Einarsson 2017 and 120‐minute overload of insulin levels in Salamun 2018.

Interventions
Non‐pharmacological intervention versus no intervention or placebo

One study compared diet versus no intervention (IVF) (Einarsson 2017). In the intervention group, weight reduction was done before IVF, starting with 12 weeks of a low‐calorie liquid formula diet (LCD) of 880 kcal/d and thereafter weight stabilisation for two to five weeks. In the control group, only IVF was done.

One study compared lifestyle versus no intervention (Mutsaerts 2016). In Mutsaerts 2016, the lifestyle intervention consisted of a six‐month structured programme aiming at a weight loss of 5% to 10% of original body weight. It included six structured outpatient visits and four telephone consultations with a pre‐trained intervention coach. Daily dietary energy intake was reduced by 600 kcal and was maintained at a minimum of 1200 kcal/d. Physical activity was stimulated to a level of 10,000 steps a day and at least 30 minutes of exercise two to three times a week. Behavioural changes were facilitated by motivational counselling. After the six‐month programme was completed, or when weight loss of 5% to 10% had been achieved, women started with appropriate infertility treatment if they were not yet pregnant. The control group received appropriate infertility treatment immediately after randomisation.

One study compared diet versus no intervention in a 12‐week intervention consisting of a very low‐energy diet for the first six weeks followed by a hypocaloric diet, combined with a weekly group multi‐disciplinary programme (Sim 2014). The control group received recommendations for weight loss and the same printed material as the intervention group.

Non‐pharmacological versus non‐pharmacological intervention

One study compared two different diet methods (Rothberg 2016): an intensive weight loss intervention (IWL) and standard of care nutrition counselling (SCN). IWL consisted of 12 weeks of a very low‐energy diet (800 kcal/d) and four weeks of a low‐calorie conventional food‐based diet (CFD) to promote 15% weight loss. SCN consisted of 16 weeks of CFD to promote 5% weight loss.

Pharmacological versus pharmacological intervention

One study compared metformin versus metformin combined with liraglutide (Salamun 2018). Metformin (MET) was initiated at a dose of 500 mg once per day and was increased by 500 mg every three days up to 1000 mg twice daily. In the group given metformin 1000 mg twice daily combined with 1.2 mg liraglutide once daily subcutaneously (COMBI), there was a run‐in period of 12 days to titrate metformin up to 1000 mg twice daily before liraglutide was added. Liraglutide was initiated at a dose of 0.6 mg injected subcutaneously once per day and was increased to 1.2 mg after three days. Medical treatment in both groups lasted 12 weeks.

One study compared dexfenfluramine/placebo versus placebo/dexfenfluramine (Galletly 1996). Dexfenfluramine and placebo were given in a cross‐over design. Dexfenfluramine dosage was 15 mg twice daily, and the duration of each treatment condition was 12 weeks.

One study compared L‐carnitine versus placebo (El 2019). Group 1 (clomiphene citrate (CC) plus metformin and L‐carnitine) received 150 mg/d CC from day 3 to day 7 of the menstrual cycle plus oral L‐carnitine (3 g) and metformin 850 mg (1 tablet daily); the dose was doubled after one week to 1700 mg/d (2 tablets daily). Metformin was ingested before a meal once daily during the first week, and thereafter twice daily. L‐carnitine and metformin were stopped only when pregnancy was documented. Group 2 (CC plus metformin and placebo) received 150 mg/d CC plus metformin (as above) and placebo capsules that were designed to look exactly like L‐carnitine capsules.

Pharmacological intervention versus no intervention or placebo

One study compared diet combined with metformin versus diet combined with placebo (Tang 2006). The intervention group took metformin (850 mg) twice daily over six months. The control group received placebo over six months.

One study compared metformin versus no intervention (Khorram 2006). All patients received CC 100 mg per day on cycle days 5 through 9 only. In group 1 (CC + MET), participants received MET 500 mg three times a day, given on cycle days 1 through 14, with cycle day 1 defined as the first day of menstrual flow. Group 2 (CC) received CC 100 mg per day on cycle days 5 through 9 only.

One study compared metformin versus placebo (Johnson 2010). Women with BMI > 32 received no treatment other than advice and encouragement on a lifestyle intervention (which included advice on calorie restriction and on increasing aerobic exercise to 30 minutes at least five times per week combined with an opportunity to see a dietician and an exercise therapist if required (i.e. standard care)). Women were then allocated to placebo or intervention groups. The intervention group (in addition to standard care) received metformin 500 mg three times daily at a gradually increasing dose over two weeks for six months.

Pharmacological versus non‐pharmacological intervention

No study was found for this comparison.

Excluded studies

We excluded 58 studies from the review for the following reasons.

  • 49 of 58 included women not of interest to this review.

  • 4 of 58 reported outcomes not of interest to this review and unlikely to ever be measured, as the objectives were different from the objective of this review.

  • 1 of 58 reported interventions not of interest to this review.

  • 4 of 58 studies are awaiting classification.

Risk of bias in included studies

We have summarised the risk of bias of included studies in Figure 2 and Figure 3.

Figure 2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Random sequence generation

The method of random sequence generation was associated with a low risk of bias in seven trials (Einarsson 2017, El 2019, Johnson 2010, Khorram 2006, Mutsaerts 2016, Tang 2006Sim 2014 ). The three remaining trials were rated as unclear risk of bias as they did not report the methods of randomisation (Rothberg 2016, Galletly 1996, Salamun 2018).

Allocation concealment

Five studies were at low risk of selection bias, for allocation to intervention was Internet‐based or sequentially opaque envelopes were used (El 2019; Einarsson 2017; Johnson 2010; Mutsaerts 2016; Tang 2006). One study was at high risk of selection bias related to allocation concealment through open random allocation (Khorram 2006). Four studies were at unclear risk of selection bias, as they not report adequate details to establish whether an appropriate method of allocation and/or concealment had been used (Galletly 1996; Rothberg 2016; Salamun 2018; Sim 2014).

Blinding

Three studies described blinding of women and were at low risk of performance bias (El 2019; Johnson 2010; Tang 2006). In five studies (Einarsson 2017; Mutsaerts 2016; Rothberg 2016; Salamun 2018; Sim 2014), blinding of treatment assignments was not possible, and the studies were at high risk of performance bias. Two studies did not describe blinding; we judged them to be at unclear risk of bias (Galletly 1996; Khorram 2006).

Related to detection bias (outcome), three studies described blinding of both women and outcome assessors and were at low risk of this bias (El 2019; Johnson 2010; Tang 2006). Three study used no blinding, and we judged this trial to be at high risk (Mutsaerts 2016; Rothberg 2016; Salamun 2018). Four studies were judged to have unclear detection bias (Galletly 1996; Khorram 2006; Sim 2014; Einarsson 2017).

Incomplete outcome data

Eight studies mentioned dropouts or withdrawals, but the numbers were balanced across groups with similar reasons for missing data; therefore, we judged them as having low risk of attrition bias (Einarsson 2017; El 2019; Johnson 2010; Mutsaerts 2016; Rothberg 2016; Salamun 2018; Tang 2006). One study was considered to have high risk of bias for incomplete outcome data in view of the high (20%) drop‐out rate (Sim 2014). We judged two studies to be at unclear risk of attrition bias, as they did not mention dropouts or withdrawals (Galletly 1996; Khorram 2006).

Selective reporting

Seven studies were at low risk of selective bias, as the protocols for these articles were available and their aims were pre‐specified (Einarsson 2017; El 2019; Johnson 2010; Mutsaerts 2016; Rothberg 2016; Salamun 2018; Sim 2014). Three studies were at high risk of selective bias, as the protocols were unavailable (Galletly 1996; Khorram 2006; Tang 2006).

Other potential sources of bias

We did not identify any other potential sources of bias in the included studies, and we judged each of the included studies to be at low risk of other potential sources of bias.

Publication bias

We did not assess potential publication bias using a funnel plot or other corrective analytical methods in view of the small number of studies that could be included in the meta‐analysis (maximally, three RCTs) (Egger 1997).

Effects of interventions

See: Summary of findings 1 Non‐pharmacological intervention compared to no intervention or placebo for obese women with subfertility; Summary of findings 2 Non‐pharmacological intervention compared to non‐pharmacological intervention for obese women with subfertility; Summary of findings 3 Pharmacological intervention compared to pharmacological intervention for obese women with subfertility; Summary of findings 4 Pharmacological intervention compared to no intervention or placebo for obese women with subfertility

Non‐pharmacological intervention versus no intervention or placebo

Three studies compared diet or a lifestyle intervention with no intervention: One study compared diet versus no IVF intervention (Einarsson 2017); another study compared diet versus no intervention (Sim 2014); and another study compared lifestyle versus no intervention (Mutsaerts 2016).

Primary outcomes
Live birth rate or ongoing pregnancy

All three studies that compared diet or a lifestyle intervention alone versus no intervention provided data on live birth rates. We found no conclusive evidence of a difference in live birth (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.65 to 1.11; 3 studies, 917 women; I² = 78%; low‐quality evidence; Analysis 1.1). The corresponding relative risk was 0.91 (95% CI 0.78 to 1.06), and use of a random‐effects model resulted in an OR of 1.17 (95% CI 0.55 to 2.48). This suggests that if the chance of live birth following no intervention is assumed to be 43%, the chance following diet or lifestyle change would be 33% to 46%. This result needs to be interpreted with caution in view of high statistical heterogeneity. Heterogeneity in results was caused mainly by the smallest study of 48 women (Sim 2014); excluding this study resulted in an OR for live birth of 0.87 (95% CI 0.75 to 1.02) and I² of 49%.

In a two‐year follow‐up study of the Einarsson 2017 trial, the cumulative live birth rate was 57% (87/152) and 54% (82/153) for the weight loss/IVF group versus the IVF only group (OR 1.07, 95% CI 0.87 to 1.31).

Adverse events

We are uncertain whether miscarriage may occur more often following diet or lifestyle change compared to no intervention (OR 1.54, 95% CI 0.99 to 2.39; 3 studies, 917 women; I² = 0%; low‐quality evidence; Analysis 1.3).

Secondary outcomes
Clinical pregnancy

For diet alone versus no intervention, we found insufficient evidence of a difference for clinical pregnancy (OR 1.06, 95% CI 0.81 to 1.40, 1.13; 3 studies, 917 women; I² = 73%; low‐quality evidence; Analysis 1.4). This result needs to be interpreted with caution in view of high statistical heterogeneity. Heterogeneity in results was caused mainly by the smallest study of 48 women (Sim 2014); excluding this study resulted in an OR for live birth of 0.98 (95% CI 0.74 to 1.29) and I² of 11%.

Weight change

All three studies found lower BMI in the lifestyle intervention group. One study reported BMI at three months following lifestyle change compared with no intervention (mean difference (MD) ‐1.00, 95% CI ‐1.02 to ‐0.98; 1 study, 574 women) and at six months (MD ‐1.30, 95% CI ‐1.32 to ‐1.28; 1 study, 574 women), but as a large proportion of pregnant women had to be excluded from the analysis, these results are difficult to interpret (Mutsaerts 2016). Diet resulted in a decrease in BMI in two studies (Einarsson 2017; Sim 2014), but data were not pooled due to heterogeneity in effect (MD ‐3.70, 95% CI ‐4.10 to ‐3.36; 305 women, 1 study; low‐quality evidence; and MD ‐1.80, 95% CI ‐2.67 to ‐0.93; 43 women, 1 study; very low‐quality evidence).

In a two‐year follow‐up study of the Einarsson 2017 trial, women in the weight loss group had regained their pre‐trial weight (mean (SD) BMI after 2 years was 32.5 (3.5) and 33.1 (3.0) for the weight loss/IVF versus IVF only arm).

Change in endocrine parameters

This outcome was not reported.

Quality of life or mental health outcome

This outcome was not reported.

Non‐pharmacological versus non‐pharmacological intervention

One study with 11 women compared two different diet methods including intensive weight loss intervention (IWL) versus standard of care nutrition counselling (SCN) (Rothberg 2016).

Primary outcomes
Live birth rate or ongoing pregnancy

There was uncertainty about the effects of IWL versus SCN on live birth (OR 11, 95% CI 0.43 to 284; 1 study, 11 women; very low‐quality evidence; Analysis 2.1). An absolute translation could not be calculated as there were no live births in the SCN group.

Adverse events

In the trial with 11 women, no pregnancy loss occurred.

Secondary outcomes
Clinical pregnancy

Evidence of a difference in clinical pregnancy for IWL versus SCN was insufficient (OR 11, 95% CI 0.43 to 284; 1 study, 11 women; very low‐quality evidence; Analysis 2.2).

Weight change

In the single trial with 11 women, we found greater weight loss and a larger decrease in BMI for IWL versus SCN (MD ‐9.00 kg, 95% CI ‐15.5 to ‐2.5; and MD ‐3.00, 95% CI ‐5.37 to ‐0.63, respectively), but In view of the very low quality of the evidence, we are uncertain whether IWL reduces weight and BMI to a greater extent than SCN.

Change in endocrine parameters

No data on endocrine parameters were available.

Quality of life or mental health outcome

Evidence of a difference between IWL and SCN in quality of life (MD 0.06, 95% CI ‐0.03 to 0.15; 1 study, 11 women; very low‐quality evidence) and in mental health outcome (MD ‐7.00, 95% CI ‐13.92 to ‐0.08; 1 study, 11 women; very low‐quality evidence) was insufficient.

Pharmacological versus pharmacological intervention

One study compared metformin plus liraglutide versus metformin (Salamun 2018); one study compared a combination of metformin, clomiphene, and L‐carnitine versus metformin, clomiphene, and placebo (El 2019); and one study compared dexfenfluramine versus placebo (Galletly 1996); for this last study, only weight loss as an outcome could be retrieved from the pre‐cross‐over data.

Primary outcomes
Live birth rate or ongoing pregnancy

No comparison of live birth rate or ongoing pregnancy was available.

Adverse events

For metformin plus CC plus L‐carnitine versus metformin plus CC plus placebo (El 2019), we found insufficient evidence of a difference in miscarriage (OR 3.58, 95% CI 0.73 to 17.55; 243 women, 1 study; very low‐quality evidence; Analysis 3.1).

For metformin plus liraglutide versus metformin (Salamun 2018), we found insufficient evidence of a difference for nausea (OR 7.22, 95% CI 0.72 to 72.7; 28 women, 1 study; very low‐quality evidence; Analysis 3.2); diarrhoea (OR 0.31, 95% CI 0.01 to 8.29; 28 women, 1 study; very low‐quality evidence; Analysis 3.3) and headache (OR 5.80, 95% CI 0.25 to 133; 28 women, 1 study; very low‐quality evidence; Analysis 3.4).

Secondary outcomes
Clinical pregnancy

For metformin plus liraglutide versus metformin (Salamun 2018), we found insufficient evidence of a difference in clinical pregnancy (OR 3.67, 95% CI 0.70 to 19.12; 28 women, 1 study; very low‐quality evidence; Analysis 3.5).

For metformin plus clomiphene citrate (CC) plus L‐carnitine versus metformin plus CC plus placebo (El 2019), we found evidence of a difference in favour of L‐carnitine for clinical pregnancy but considered this evidence to be of very low quality (OR 5.56, 95% CI 2.57 to 12.02; 274 women, 1 study; very low‐quality evidence; Analysis 3.5).

Weight change

For metformin plus liraglutide versus metformin (Salamun 2018), we found insufficient evidence of a difference in BMI (MD 2.10, 95% CI ‐0.42 to 4.62; 28 women, 1 study; very low‐quality evidence).

For dexfenfluramine versus placebo (Galletly 1996), we are unsure whether the data for weight loss presents pre‐cross‐over data. We found insufficient evidence of a difference in mean weight loss (MD ‐0.10, 95% CI ‐2.77 to 2.57; 21 women, 1 study; very low‐quality evidence). The mean weight loss ranged from 3 to 4 kg in the intervention group .

One study provided no evidence of a difference for metformin plus liraglutide versus metformin in percentage of body fat (MD ‐0.50, 95% CI ‐4.65 to 3.65; 28 women, 1 study; very low‐quality evidence) (Salamun 2018).

Change in endocrine parameters

For metformin plus liraglutide versus metformin (Salamun 2018), we found insufficient evidence of a difference in the oral glucose tolerance test (OGTT) (MD ‐0.30, 95% CI ‐1.92 to 1.3; 28 women, 1 study; very low‐quality evidence), free testosterone (MD 0.80, 95% CI ‐3.0 to 4.60; 28 women, 1 study; very low‐quality evidence), total testosterone (MD 0.20, 95% CI ‐0.21 to 0.61; 28 women, 1 study; very low‐quality evidence), and sex hormone‐binding globulin (SHBG) (MD 0.30, 95% CI ‐12.22 to 12.82; 28 women, 1 study; very low‐quality evidence).

Quality of life or mental health outcome

No comparison of quality of life or mental health outcome was available.

Pharmacological intervention versus no intervention or placebo

We found three studies: one study compared diet combined with metformin versus diet combined with placebo (Tang 2006); one study compared metformin versus no intervention (Khorram 2006); another study compared metformin versus placebo (Johnson 2010).

Primary outcomes
Live birth rate or ongoing pregnancy

Only one study that compared metformin with placebo reported on live birth, resulting in insufficient evidence of a difference (OR 1.57, 95% CI 0.44 to 5.57; 1 study, 65 women; very low‐quality evidence; Analysis 4.1) (Johnson 2010). This suggests that if the chance of live birth following placebo is assumed to be 15%, the chance following metformin would be 7.3% to 50%.

Adverse events

One study compared pharmacological intervention versus no treatment or placebo, with no conclusive evidence of a difference for miscarriage (OR 0.50, 95% CI 0.04 to 5.80; 65 women, 1 study; very low‐quality evidence; Analysis 4.2) (Johnson 2010).

We found insufficient evidence of a difference between metformin and placebo in gastrointestinal adverse events (OR 0.91, 95% CI 0.32 to 2.57; 1 study, 65 women; very low‐quality evidence; Analysis 4.3) (Johnson 2010).

Secondary outcomes
Clinical pregnancy

Two studies compared metformin versus no treatment or placebo, with no conclusive evidence of a difference for pregnancy (OR 2.67, 95% CI 0.90 to 7.93; 96 women, 2 studies; I² = 48%; very low‐quality evidence; Analysis 4.4) (Johnson 2010; Khorram 2006)

Weight change

One study reported on weight change, with no conclusive evidence of a change in BMI (MD ‐0.30, 95% CI ‐2.16 to 1.56; 143 women, 1 study; very low‐quality evidence) or WHR (MD 2.00, 95% CI ‐2.21 to 6.21; 1 study, 143 women; very low‐quality evidence) for metformin versus placebo (Tang 2006).

Change in endocrine parameters

One study reported on endocrine parameters (Khorram 2006). Changes in endocrine parameters were inconclusive for free testosterone (MD 0.7 nmol/L, 95% CI ‐1.01 to 2.42; 31 women, 1 study; very low‐quality evidence). Total testosterone and SHBG were higher following metformin versus placebo, but evidence was of very low quality (total testosterone: MD 6.20 nmol/L, 95% CI 0.46 to 11.94; 1 study, 31 women; very low‐quality evidence; SHBG: 5.50 nmol/L, 95% CI 3.79 to 7.21; 1 study, 31 women; very low‐quality evidence).

Quality of life or mental health outcome

No comparison of quality of life or mental health outcome was available.

Non‐pharmacological versus pharmacological intervention

No study reported this comparison.

For this review, we did not gather enough data to perform subgroup analyses. Moreover, for this version of the review, we identified insufficient studies to perform meaningful sensitivity analyses.

Discussion

Summary of main results

Based on available data, we are uncertain about the effectiveness and safety of pharmaceutical and non‐pharmaceutical interventions for weight reduction in obese women with subfertility due to evidence of very low to low quality. We included 10 trials that varied in size from 11 to 564 women. The best evidence was found for diet/lifestyle interventions (three randomised controlled trials (RCTs)). Compared to no intervention or placebo, the lifestyle intervention did not appear to improve live birth or clinical pregnancy; however, lifestyle intervention may lower body mass index (BMI) among obese women. It is unclear whether intensive weight loss interventions compared to nutrition counselling had a positive or negative effect on any outcomes.

For pharmaceutical interventions, all outcomes were scored to have evidence of very low quality. Whether pharmaceutical interventions such as liraglutide, L‐carnitine as addition to metformin, and clomiphene result in improved fertility or weight outcomes is unclear. Similarly, we found no conclusive evidence for metformin versus placebo or no intervention in terms of live birth, clinical pregnancy, or weight change outcomes.

We found no trials that compared pharmacological versus non‐pharmacological interventions.

Overall completeness and applicability of evidence

There is a serious lack of evidence in the field of weight reduction in obese women with subfertility. The included studies only partially addressed the objectives of this review. Outcome data could not be retrieved for several of the comparisons and outcomes that we sought to investigate. The high heterogeneity of pharmacological and non‐pharmacological strategies in included studies may limit the generalisability of trial results regarding the effectiveness of pharmacological and non‐pharmacological strategies for obese women with subfertility. The included studies were clinically heterogeneous and differed in factors such as duration of treatment, type of intervention, dosage, and length of follow‐up. Given the very low quality of evidence for the pharmaceutical interventions, the applicability of those findings is limited and does not allow us to draw conclusions.

It was our intention to include studies with obese women with a BMI of at least 30. In two trials the minimal BMI was 29 (Khorram 2006, Mutsaerts 2016) with medians or means above 36. The study groups consider the effect of including a few women with a BMI of 29 instead of 30 negligible.

Quality of the evidence

Although evidence generated in this review was based on 10 RCTs, this evidence was of very low to low quality as determined by GRADE methods (see 'Summary of findings' for the main comparison and 'Summary of findings 2'). The main limitations were due to lack of studies and poor reporting of study methods. The quality of individual studies was generally low, with over 40% failing to describe adequate methods of blinding of participants and personnel, outcome assessment, and selective reporting (see Figure 2 and Figure 3).

Potential biases in the review process

To minimise bias and issues related to subjectivity of judgement, any disagreements that occurred during the review process were discussed among all review authors until consensus was reached. Two review authors independently carried out data extraction. The accuracy of data was further checked by a third review author. Potential risk of bias in each study and the overall quality of evidence for each outcome were assessed by two independent review authors. We adopted a highly sensitive search strategy. However, the literature identified was predominantly written in English, and most studies were conducted in high‐income countries.

Agreements and disagreements with other studies or reviews

One systematic review evaluated the effectiveness of non‐pharmacological interventions for overweight or obese infertile women (Kim 2020). On the basis of 21 RCTs, it was suggested that non‐pharmacological interventions could have a positive effect on pregnancy and natural conception rates, whereas it remains unclear whether they improve the live birth rate. Not all women in the included studies were overweight, and most were not obese, which may explain the medium to high heterogeneity of effect sizes for pregnancy rates and live birth rates in all non‐pharmacological interventions.

An earlier systematic review evaluated first whether weight loss interventions for infertile patients achieve their goal in reducing weight, and second whether they result in improved fertility outcomes (Best 2017). A total of 40 studies were included, of which 14 were RCTs. Results suggest that weight loss interventions, particularly diet and exercise, may improve pregnancy rates and ovulatory status.

In a Cochrane Review aiming to assess the effectiveness of lifestyle treatment (diet, exercise, behavioural, or combined treatments) for women with PCOS, lifestyle intervention improved body composition, hyperandrogenism, and insulin resistance, but evidence for an effect of diet on reproductive outcomes was lacking (Lim 2019).

Our review differs from previous reviews in that it is focused on obese women only. We conducted an extensive search until 2020 and could include data from 10 studies. In contrast to previous reviews, we are uncertain whether pharmacological or non‐pharmacological strategies improve live birth, ongoing pregnancy, adverse events, clinical pregnancy, quality of life, or mental health outcomes. However, for obese women with subfertility, a lifestyle intervention may reduce BMI.

Study flow diagram.

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Figure 1

Study flow diagram.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Comparison 1: Non‐pharmacological intervention versus no intervention or placebo, Outcome 1: Live birth

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Analysis 1.1

Comparison 1: Non‐pharmacological intervention versus no intervention or placebo, Outcome 1: Live birth

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Comparison 1: Non‐pharmacological intervention versus no intervention or placebo, Outcome 2: Ongoing pregnancy

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Analysis 1.2

Comparison 1: Non‐pharmacological intervention versus no intervention or placebo, Outcome 2: Ongoing pregnancy

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Comparison 1: Non‐pharmacological intervention versus no intervention or placebo, Outcome 3: Miscarriage

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Analysis 1.3

Comparison 1: Non‐pharmacological intervention versus no intervention or placebo, Outcome 3: Miscarriage

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Comparison 1: Non‐pharmacological intervention versus no intervention or placebo, Outcome 4: Clinical pregnancy

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Analysis 1.4

Comparison 1: Non‐pharmacological intervention versus no intervention or placebo, Outcome 4: Clinical pregnancy

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Comparison 1: Non‐pharmacological intervention versus no intervention or placebo, Outcome 5: BMI change

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Analysis 1.5

Comparison 1: Non‐pharmacological intervention versus no intervention or placebo, Outcome 5: BMI change

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Comparison 2: Non‐pharmacological intervention versus non‐pharmacological intervention, Outcome 1: Live birth

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Analysis 2.1

Comparison 2: Non‐pharmacological intervention versus non‐pharmacological intervention, Outcome 1: Live birth

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Comparison 2: Non‐pharmacological intervention versus non‐pharmacological intervention, Outcome 2: Clinical pregnancy

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Analysis 2.2

Comparison 2: Non‐pharmacological intervention versus non‐pharmacological intervention, Outcome 2: Clinical pregnancy

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Comparison 2: Non‐pharmacological intervention versus non‐pharmacological intervention, Outcome 3: BMI change

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Analysis 2.3

Comparison 2: Non‐pharmacological intervention versus non‐pharmacological intervention, Outcome 3: BMI change

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Comparison 2: Non‐pharmacological intervention versus non‐pharmacological intervention, Outcome 4: Weight change

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Analysis 2.4

Comparison 2: Non‐pharmacological intervention versus non‐pharmacological intervention, Outcome 4: Weight change

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Comparison 2: Non‐pharmacological intervention versus non‐pharmacological intervention, Outcome 5: Mental health

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Analysis 2.5

Comparison 2: Non‐pharmacological intervention versus non‐pharmacological intervention, Outcome 5: Mental health

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Comparison 2: Non‐pharmacological intervention versus non‐pharmacological intervention, Outcome 6: Quality of life

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Analysis 2.6

Comparison 2: Non‐pharmacological intervention versus non‐pharmacological intervention, Outcome 6: Quality of life

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Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 1: Miscarriage

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Analysis 3.1

Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 1: Miscarriage

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Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 2: Adverse event ( nausea)

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Analysis 3.2

Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 2: Adverse event ( nausea)

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Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 3: Adverse event (diarrhoea)

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Analysis 3.3

Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 3: Adverse event (diarrhoea)

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Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 4: Adverse event (headache)

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Analysis 3.4

Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 4: Adverse event (headache)

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Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 5: Clinical pregnancy

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Analysis 3.5

Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 5: Clinical pregnancy

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Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 6: BMI change

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Analysis 3.6

Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 6: BMI change

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Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 7: Weight loss

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Analysis 3.7

Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 7: Weight loss

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Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 8: Percent of total body fat

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Analysis 3.8

Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 8: Percent of total body fat

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Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 9: Glucose test (OGTT)

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Analysis 3.9

Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 9: Glucose test (OGTT)

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Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 10: Free testosterone

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Analysis 3.10

Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 10: Free testosterone

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Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 11: Total testosterone

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Analysis 3.11

Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 11: Total testosterone

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Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 12: SHBG

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Analysis 3.12

Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 12: SHBG

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Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 1: Live birth

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Analysis 4.1

Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 1: Live birth

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Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 2: Miscarriage

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Analysis 4.2

Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 2: Miscarriage

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Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 3: Adverse event (GI)

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Analysis 4.3

Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 3: Adverse event (GI)

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Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 4: Clinical pregnancy

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Analysis 4.4

Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 4: Clinical pregnancy

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Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 5: BMI change

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Analysis 4.5

Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 5: BMI change

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Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 6: WHR

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Analysis 4.6

Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 6: WHR

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Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 7: Total testosterone

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Analysis 4.7

Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 7: Total testosterone

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Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 8: Free testosterone

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Analysis 4.8

Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 8: Free testosterone

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Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 9: SHBG

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Analysis 4.9

Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 9: SHBG

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Summary of findings 1. Non‐pharmacological intervention compared to no intervention or placebo for obese women with subfertility

Non‐pharmacological intervention compared to no intervention for obese women with subfertility

Patient or population: obese women with subfertility
Setting: hospital
Intervention: non‐pharmacological (diet and/or lifestyle changes)
Comparison: no intervention

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№. of participants
(studies)

Certainty of evidence
(GRADE)

Comments

Risk with non‐pharmacological intervention

Risk with no intervention

Live birth

395 per 1000
(334 to 462)

431 per 1000

OR 0.85
(0.65 to 1.12)

917
(3 RCTs)

⊕⊕⊝⊝
lowa,b

Ongoing pregnancy

536 per 1000
(453 to 617)

588 per 1000

OR 0.81
(0.58 to 1.13)

564
(1 RCT)

⊕⊕⊝⊝
lowc

Miscarriage

122 per 1000
(82 to 177)

83 per 1000

OR 1.54
(0.99 to 2.39)

917
(3 RCTs)

⊕⊝⊝⊝
very lowc,d

Clinical pregnancy

529 per 1000
(458 to 594)

514 per 1000

OR 1.06
(0.81 to 1.40)

917
(3 RCTs)

⊕⊕⊝⊝
lowa,b

Weight change
BMI change (Einarsson 2017)

MD 3.70 kg/m² lower
(4.10 lower to 3.36 lower)

Mean BMI change ranged from 0.04 to 0.7 kg/m²

‐

305
(1 RCT)

⊕⊕⊝⊝
lowc

BMI change (Sim 2014)

MD 1.80 kg/m² lower (2.67 lower to 0.93 lower)

Mean BMI change ranged from ‐1.3 to 0 kg/m²

‐

43

(1 RCT)

⊕⊝⊝⊝ very lowc,e

Quality of life/
Mental health outcome

No study reported this outcome

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial.

GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level for substantial heterogeneity: I² > 70%.

bDowngraded one level for imprecision as reflected by the large confidence interval.

cDowngraded two levels for serious imprecision.

dDowngraded one level for indirectness due to differences in definition.

eDowngraded one level for incomplete outcome data with an uneven dropout between groups.

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Summary of findings 1. Non‐pharmacological intervention compared to no intervention or placebo for obese women with subfertility
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Summary of findings 2. Non‐pharmacological intervention compared to non‐pharmacological intervention for obese women with subfertility

Non‐pharmacological intervention compared to non‐pharmacological intervention for obese women with subfertility

Patient or population: obese women with subfertility
Setting: hospital
Intervention: intensive weight loss intervention
Comparison: standard‐of‐care nutrition counseling

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№. of participants
(studies)

Certainty of evidence
(GRADE)

Comments

Risk with weight loss

Risk with standard of care nutrition

Live birth

500 per 1000

0 per 1000
(0 to 0)

OR 11.00
(0.43 to 284)

11
(1 RCT)

⊕⊝⊝⊝
Very lowa,b

Miscarriage

0 per 1000

0 per 1000

In the trial with 11 women, no pregnancy loss occurred

Clinical pregnancy

500 per 1000

0 per 1000
(0 to 0)

OR 11.00
(0.43 to 284)

11
(1 RCT)

⊕⊝⊝⊝
Very lowa,b

Weight change
Weight change (kg)

Body mass index (BMI)

Mean weight change ranged from 5 to 6 kg

MD 9 kg lower
(15.5 lower to 2.5 lower)

‐

11
(1 RCT)

⊕⊝⊝⊝
Very lowa,b

Mean body mass Index ranged from 2 to 3 kg/m²

MD 3 kg/m² lower
(5.37 lower to 0.63 lower)

‐

11
(1 RCT)

⊕⊝⊝⊝
Very lowa,b

Quality of life/Mental health outcome
Mental health (at 12 weeks)

Quality of life (at 12 weeks)

Mean mental health ranged from 2 to 3

MD 7 lower
(13.92 lower to 0.08 lower)

‐

11
(1 RCT)

⊕⊝⊝⊝
Very lowa,b

Mean quality of life ranged from 0.01 to 0.02

MD 0.06 higher
(0.03 lower to 0.15 higher)

‐

11
(1 RCT)

⊕⊝⊝⊝
Very lowa,b

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial.

GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level for selection bias due to lack of details on random sequence, random allocation, and blinding.

bDowngraded two levels for serious imprecision due to small sample size.

Figures and Tables -
Summary of findings 2. Non‐pharmacological intervention compared to non‐pharmacological intervention for obese women with subfertility
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Summary of findings 3. Pharmacological intervention compared to pharmacological intervention for obese women with subfertility

Pharmacological intervention compared to pharmacological intervention for obese women with subfertility

Patient or population: obese women with subfertility
Setting: hospital
Intervention: different pharmacological interventions
Comparison: different pharmacological interventions

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№. of participants
(studies)

Certainty of evidence
(GRADE)

Comments

Risk with pharmacological intervention

Risk with pharmacological intervention

Live birth

No study reported this outcome

Adverse events ‐ Metformin plus liraglutide vs metformin

Nausea

Diarrhoea

Headache

71 per 1000

357 per 1000
(52 to 848)

OR 7.22
(0.72 to 73)

28 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

71 per 1000

23 per 1000

OR 0.31 (0.01 to 8.3)

28 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

0 per 1000

0 per 1000

OR 5.80 (0.25 to 133)

28 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Clinical pregnancy
Metformin plus liraglutide vs metformin

Met + CC + L‐carnitine vs Met + CC + placebo

80 per 1000

311 per 1000
(184 to 476)

OR 5.20 (2.59 to 10.4)

28 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

214 per 1000

500 per 1000

(160 to 839)

OR 3.67

(0.70 to 19.1)

274 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Miscarriage
Met + CC + L‐carnitine vs Met + CC + placebo

15 per 1000

51 per 1000

(11 to 208)

OR 3.58 ( 0.73 to 17.6)

274 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Weight ‐ BMI change
Metformin plus liraglutide vs metformin

Met + CC + L‐carnitine vs Met + CC + placebo

Weight change
Dexfenfluramine vs placebo

Weight ‐ body fat
Metformin plus liraglutide vs metformin

Mean BMI change was set at 0

MD 2.1 higher (0.42 lower to 4.52 higher)

‐

28 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Mean BMI change was set at 0

MD 0.3 lower (1.17 lower to 0.57 higher)

‐

274 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Mean weight change was set at 0 kg

MD 0.1 kg lower (2.77 lower to 2.57 higher)

‐

21 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Mean change in % total body fat was set at 0

MD 0.5 lower
(4.65 lower to 3.65 higher)

‐

28 (1 RCT)

⊕⊝⊝⊝
Very lowa,b

Quality of life/Mental health outcome

No study reported this outcome

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial.

GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level for selection bias due to lack of details on random sequence, random allocation, and blinding.

bDowngraded two levels for serious imprecision as reflected by the large confidence interval.

Figures and Tables -
Summary of findings 3. Pharmacological intervention compared to pharmacological intervention for obese women with subfertility
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Summary of findings 4. Pharmacological intervention compared to no intervention or placebo for obese women with subfertility

Pharmacological intervention compared to no intervention/placebo for obese women with subfertility

Patient or population: obese women with subfertility
Setting: hospital
Intervention: metformin
Comparison: no intervention/placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№. of participants
(studies)

Certainty of evidence
(GRADE)

Comments

Risk with pharmacological intervention

Risk with no intervention/placebo

Live birth

219 per 1000
(73 to 499)

152 per 1000

OR 1.57
(0.44 to 5.57)

65 (1 RCT)

⊕⊝⊝⊝
very lowa,b

Ongoing pregnancy

No study reported this outcome

Miscarriage

31 per 1000
(3 to 272)

61 per 1000

OR 0.50
(0.04 to 5.80)

65 (1 RCTs)

⊕⊝⊝⊝
very lowa,b

Adverse events (GI)

313 per 1000

333 per 1000

OR 0.91 (0.32 to 2.57)

65 (1 RCT)

⊕⊝⊝⊝
very lowa,b

Clinical pregnancy

237 per 1000
(95 to 480)

104 per 1000

OR 2.67
(0.90 to 7.93)

96 (2 RCTs)

⊕⊝⊝⊝
very lowa,b

Weight change
BMI

WHR

MD 0.3 kg/m² lower
(2.16 lower to 1.56 higher)

Mean BMI change was set at 0

‐

143
(1 RCTs)

⊕⊝⊝⊝
very lowa,c

MD 2 cm higher
(2.21 lower to 6.21 higher)

Mean WHR change was set at 0

‐

143
(1 RCT)

⊕⊝⊝⊝
very lowa,c

Quality of life/Mental health outcome

No study reported this outcome

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial.

GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aDowngraded twice for serious imprecision as reflected by the large confidence interval.

bDowngraded once in view of inconsistency in clinical pregnancy, which could not be seen in studies in view of the presence of only a single trial with 65 women for the outcomes live birth and miscarriage.

cDowngraded once for selection bias due to lack of details on random sequence, random allocation, and blinding.

Figures and Tables -
Summary of findings 4. Pharmacological intervention compared to no intervention or placebo for obese women with subfertility
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Comparison 1. Non‐pharmacological intervention versus no intervention or placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Live birth Show forest plot

3

918

Odds Ratio (M‐H, Fixed, 95% CI)

0.85 [0.65, 1.11]

1.2 Ongoing pregnancy Show forest plot

1

564

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.58, 1.13]

1.3 Miscarriage Show forest plot

3

917

Odds Ratio (M‐H, Fixed, 95% CI)

1.54 [0.99, 2.39]

1.4 Clinical pregnancy Show forest plot

3

917

Odds Ratio (M‐H, Fixed, 95% CI)

1.06 [0.81, 1.40]

1.5 BMI change Show forest plot

2

Mean Difference (IV, Fixed, 95% CI)

Subtotals only
Figures and Tables -
Comparison 1. Non‐pharmacological intervention versus no intervention or placebo
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Comparison 2. Non‐pharmacological intervention versus non‐pharmacological intervention

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Live birth Show forest plot

1

11

Odds Ratio (M‐H, Fixed, 95% CI)

11.00 [0.43, 284.30]

2.2 Clinical pregnancy Show forest plot

1

11

Odds Ratio (M‐H, Fixed, 95% CI)

11.00 [0.43, 284.30]

2.3 BMI change Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

2.4 Weight change Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

2.5 Mental health Show forest plot

1

11

Mean Difference (IV, Fixed, 95% CI)

‐7.00 [‐13.92, ‐0.08]

2.6 Quality of life Show forest plot

1

11

Mean Difference (IV, Fixed, 95% CI)

0.06 [‐0.03, 0.15]
Figures and Tables -
Comparison 2. Non‐pharmacological intervention versus non‐pharmacological intervention
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Comparison 3. Pharmacological intervention versus pharmacological intervention

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Miscarriage Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.2 Adverse event ( nausea) Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.3 Adverse event (diarrhoea) Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.4 Adverse event (headache) Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.5 Clinical pregnancy Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.5.1 Metformin plus liraglutide vs metformin

1

28

Odds Ratio (M‐H, Fixed, 95% CI)

3.67 [0.70, 19.12]

3.5.2 Metformin + CC + L‐carnitine vs metformin + CC + placebo

1

274

Odds Ratio (M‐H, Fixed, 95% CI)

5.56 [2.57, 12.02]

3.6 BMI change Show forest plot

2

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

3.6.1 Metformin + CC + L‐carnitine vs metformin + CC + placebo

1

274

Mean Difference (IV, Fixed, 95% CI)

‐0.30 [‐1.17, 0.57]

3.6.2 Metformin plus liraglutide vs metformin

1

28

Mean Difference (IV, Fixed, 95% CI)

2.10 [‐0.42, 4.62]

3.7 Weight loss Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

3.7.1 Dexfenfluramine vs placebo

1

21

Mean Difference (IV, Fixed, 95% CI)

‐0.10 [‐2.77, 2.57]

3.8 Percent of total body fat Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

3.8.1 Metformin plus liraglutide vs metformin

1

28

Mean Difference (IV, Fixed, 95% CI)

‐0.50 [‐4.65, 3.65]

3.9 Glucose test (OGTT) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

3.9.1 Metformin plus liraglutide vs metformin

1

28

Mean Difference (IV, Fixed, 95% CI)

‐0.30 [‐1.90, 1.30]

3.10 Free testosterone Show forest plot

2

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

3.10.1 Metformin plus liraglutide vs metformin

1

28

Mean Difference (IV, Fixed, 95% CI)

0.80 [‐3.00, 4.60]

3.10.2 Metformin + CC + L‐carnitine vs metformin + CC + placebo

1

274

Mean Difference (IV, Fixed, 95% CI)

‐1.76 [‐2.06, ‐1.46]

3.11 Total testosterone Show forest plot

1

28

Mean Difference (IV, Fixed, 95% CI)

0.20 [‐0.21, 0.61]

3.11.1 Metformin plus liraglutide vs metformin

1

28

Mean Difference (IV, Fixed, 95% CI)

0.20 [‐0.21, 0.61]

3.12 SHBG Show forest plot

1

28

Mean Difference (IV, Fixed, 95% CI)

0.30 [‐12.22, 12.82]

3.12.1 Metformin plus liraglutide vs metformin

1

28

Mean Difference (IV, Fixed, 95% CI)

0.30 [‐12.22, 12.82]
Figures and Tables -
Comparison 3. Pharmacological intervention versus pharmacological intervention
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Comparison 4. Pharmacological intervention versus no intervention/placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

4.1 Live birth Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.2 Miscarriage Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.3 Adverse event (GI) Show forest plot

1

65

Odds Ratio (M‐H, Fixed, 95% CI)

0.91 [0.32, 2.57]

4.4 Clinical pregnancy Show forest plot

2

96

Odds Ratio (M‐H, Fixed, 95% CI)

2.67 [0.90, 7.93]

4.5 BMI change Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

4.6 WHR Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

4.7 Total testosterone Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

4.8 Free testosterone Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

4.9 SHBG Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only
Figures and Tables -
Comparison 4. Pharmacological intervention versus no intervention/placebo
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