Combined oral contraceptive use and adiposity in women with polycystic ovary syndrome. A meta-analysis of randomized clinical trials

Combined oral contraceptive use and adiposity in women with polycystic ovary syndrome. 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A meta-analysis of randomized clinical trials Sebastião Freitas de Medeiros, José Maria Soares Junior, Matheus Antônio Souto de Medeiros, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3882087/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Jul, 2024 Read the published version in Archives of Gynecology and Obstetrics → Version 1 posted 4 You are reading this latest preprint version Abstract Background. Combined oral contraceptives (COCs) are of first line treatment of women with polycystic ovary syndrome (PCOS) who do not intend to become pregnant. PCOS is a heterogeneous condition with subphenotypes with different risks for future development of cardiovascular disease. The combination of COC and PCOS may or may not amplify the risks of cardiovascular events. Objective. To investigate whether surrogates for adiposity may be influenced by the use of COCs with different formulations in women with PCOS. Method. A literature search was conduct in Google Scholar and Pubmed databases. Hand search of randomized clinical trials in the references of obtained manuscripts was also performed. The search identified 3820 articles and 13 randomized clinical trials in which was possible to compare the results obtained before and after the use of COCs. Random-effects model was used to estimate the standardized mean differences (SMD) and standard erros (SE). Risk of bias was examined using the Rob2 tool. Result. Thirteen heterogeneous RCTs reported no difference on waist circumference with the use of different COC formulations (p = 0.714). On the contray, body fat mass increased with the use of pill (p = 0.013). Anthropometric-metabolic biomarkers waist triglyceride index and visceral adiposity index did not change but the lipid accumulation product tended to be higher after use of COCs. Conclusion. Combined oral contraceptives with different formulations might increase fat mass accumulation in women with PCOS. Lipids may also be accumulated in the PCOS users. Polycystic ovary syndrome oral contraceptive lipids metabolism adiposity biomarkers Figures Figure 1 Figure 2 Figure 3 Figure 4 What does this study adds to the clinical work? The present meta-analysis of randomized clinical trials indicated that the use of different oral contraceptive formulations increase adiposity in women with polycystic ovary syndrome. Take home messages The study with adequate number of randomized clinical trials comparing biomarkers of adiposity before and after use of different COCs in women with polycystic ovary syndrome Despite the heterogeneity observed among studies the meta-analysis demonstrated that the use of COCs may increase adiposity in women with polycystic ovary syndrome. Implications Polycystic ovary syndrome, particularly the hyperandrogenic phenotype, may be associated with metabolic abnormalities and increased risk for cardiovascular diseases. For clinical practice, the concomitant use of COCs as the first-line treatment of PCOS may amplify the risks. The literature available remains controversial. The current meta-analysis updates the knowledge regarding the association of COCs use with PCOS, and adiposity. Introduction Polycystic ovary syndrome (PCOS) has been reported in 5%-20% of women of reproductive age worldwide [ 1 , 2 ]. In addition to the core phenotypes (menstrual disturbances and hyperandrogenism), dysglycemia, dyslipidemia, metabolic syndrome, and central obesity are also common [ 3 ], and these variables must be considered in the clinical practice of PCOS assistance [ 4 ]. Overall, these data indicated that patients with PCOS could be linked to the future development of cardiovascular disease (CVD) and venous thromboembolism [ 5 – 8 ]. Combined oral contraceptives (COCs) have been considered the first-line therapy for PCOS women with menstrual irregularity and clinical and/or biochemical hyperandrogenism who do not wish to become pregnant [ 9 – 11 ]. However, some deleterious metabolic and inflammatory effects have been demonstrated with the association between PCOS and COC use [ 12 – 15 ]. Because proper PCOS might increase the risk of CVC, the potential additional risk of using COCs in women with PCOS has been already evaluated, particularly in women with a hyperandrogenic phenotype [ 16 – 17 ]. The choice for a determined COC formulation in women with PCOS should be based on estrogen type and dose and progestin type to tailor PCOS phenotypes [ 18 – 20 ]. Nevertheless, it has recently been demonstrated that the use of COCs in women with PCOS may be safe [ 21 , 22 ]. The current knowledge regarding the effect of different COCs on the amount and distribution of adipose tissue in women with PCOS needs to be expanded [ 4 , 23 – 25 ]. This meta-analysis of randomized clinical trials (RCTs) was designed to estimate the potential risk of different formulations of COCs on adiposity biomarkers in women with PCOS as a whole group. Methods Objective and data extraction The main objective of this meta-analysis was to evaluate available data regarding the effect of different COC formulations on surrogate biomarkers of adiposity in women with PCOS as a whole group. The electronic search of randomized clinical trials reporting on this subject was limited to the English language. The combined terms PCOS and COC usage were searched in the Google School and Medline databases. References in reviews or original publications were also hand-searched. A total of 3820 articles were found, and 3756 were excluded after browsing the titles and/or abstracts. A total of 64 full papers were assessed for eligibility. Later, 51 publications were excluded because they were of observational design, did not provide sufficient data of interest or did not provide before and after data for analysis. Ultimately, 13 fully randomized clinical trials providing sufficient data for analysis were selected [ 26 – 38 ]. Study eligibility was verified independently by three authors (S.F. M, M.M.W. Y, AKLWY). The study quality was also independently assessed by two authors (S.F. M and M.A.S.M). Risk of bias The risk of bias of each study was examined using the RoB2 tool [ 39 ], and individual quality items included bias arising from the randomized process, due to deviations from intended intervention, due to missing outcome data, and due to outcome measurement, due to selection of the report results. The biases were summarized as overall bias. Outcome measures The primary outcomes of interest were waist circumference (WC), body mass index (BMI), waist hip ratio (WHR), total fat mass (TFM), triglyceride levels (TG), high density lipoprotein cholesterol (HDL-C), waist circumference triglyceride index (WTI), visceral adiposity index (VAI), and lipid accumulation product (LAP). When expressed in mg/ml, TG and HDL-C were standardized to all units in mass to SI system measurement; therefore, HDL-C and TG results were converted into mmol/l. VAI was calculated from original data using the equation VAI = WC/(36.58+(1.89 x BMI) x (TG x 0.081) x (1.52 x HDL-C), and LAP for females was also calculated from original data using the equation LAP=(WCcm-58.3 x TGmmol/l) [40]. In each RCT in which the mean and standard deviation were not reported, these data were calculated from the sample size, range, median or interquartile range [ 41 – 4 3]. Specifically, standard derivation was calculated using the formula: SD= \(\sqrt{n}\) x upper limit – lower limit divided by 3.92 [44]. The mean was calculated by median, the smallest value (a), the largest value (b) and the sample size using the formula: x = a+2 m + b/4, where a and b are the low and high end of the range, respectively, and m is the median. When the sample size was small, as in most RCTs included in this meta-analysis, the formula x = a + 2 m + b/4 plus a-2 m + b/4n was applied [45] Data Analysis Considering that studies have used different methods to measure the principal variables and that PCOS was diagnosed by different criteria [Nation Institute of Health, and Androgen Excess Society (AES) [ 46 – 48 ]], the effect sizes are presented as the standard mean differences (SMD) and standard errors (SE). Data were pooled by using a random-effects model with 95% confidence intervals. Then, it was assumed that the true effect size may vary from study to study and that the summary effect was the estimate of the mean of the distribution of effect sizes [ 49 ]. Effect sizes were weighted by the inverse of the within-study variance [ 50 ]. Heterogeneity among studies was assessed for each result by using the Cochrane Q statistic, where Q is the weighted sum of squares. The variance of the effect size between studies (Tau 2 ) was estimated using the method of moments [ 51 ]. The ratio of true heterogeneity to total observed variation (I 2 ) was also estimated [ 52 ]. Additionally, the predictive interval of effect size to indicate a true heterogeneity was provided. All analyses were performed using the Compreensive Meta-analysis Software [ 49 ]. Results Study selection A total of 3820 articles were initially identified using a combination of COC and PCOS. After screening by three authors (SFM, MMWY and AKLWY), 64 studies were included, and 3756 articles were excluded because they were reviews, did not compare data before and after COC use or presented data only as figures that did not allow us to compare the results. Furthermore, 51 studies were excluded because of design or incomplete data for comparing before and after results. Finally, 13 full open or blind randomized clinical trials published between 2004 and 2023 were selected (Fig. 1 , Table 1 ). Three of them were double blinded [ 27 , 35 , 28 ], and 10 studies were open trials [ 38 , 30 , 32 , 34 , 29 , 37 , 31 , 36 , 33 , 26 ]. A total of 519 PCOS patients were enrolled. To define PCOS, three studies used NHI criteria [ 30 , 31 , 38 ], one study used AES criteria [ 27 ] and nine trials used the Rotterdam criteria [ 26 , 28 , 29 , 32 – 37 ]. In the included studies, the treatment duration varied between 3 months and 12 months. The majority of trials included only adult patients [ 26 – 29 , 32 – 37 ], two studies included adolescents [ 30 , 31 ], and one study included both adolescents and adults [ 38 ]. Risk of bias In the present meta-analysis, four studies fulfilled the criteria for a low risk of bias RoB2, and nine studies had some concerns and were considered to have a moderate risk of bias RoB2 [ 39 ]. All studies clearly described PCOS diagnostic criteria and inclusion and exclusion criteria. The randomization method was not reported by some studies using RoB2 assessment (Fig. 2 ). Effects of intervention Individual and pooled results of the included RCTs are presented in the following sections. Supplemental Tables 1 to 3 summarize the effect sizes of interventions on body mass index (BMI), triglycerides (TG) and high density lipoprotein cholesterol (HDL-C) levels using different COC formulations. These data were necessary to estimate the WTI, VAI and LAP variables. Association between COCs and waist circumference Nine RCTs reported on the effects of different COC formulations on WC. Regarding progestin type, one study [ 27 ] compared COCs with three different progestins (desogestrel, drospirenone, ciproterone acetate) and did not find anthropometric or metabolic differences among these formulations. Three studies used desogestrel [ 27 , 32 , 33 ], one study used cyproterone acetate [ 27 ], three studies used drospirenone [ 27 , 30 , 36 ], two studies used norgestimate [ 28 , 29 ] and one study used chlormadinone acetate [ 34 ]. A total of 438 women with PCOS had WC measured before and after treatment with different COC formulations, with a pooled SDM of 0.048 (95% CI/-0.200 to 0.292, p = 0.114) (Fig. 3 ). These studies were heterogeneous regarding this variable Tau 2 = 0.127 Q = 36.33, p < 0.001, I 2 = 66,96. The predicting interval of effect size for different populations ranged from − 0.78 to 0.876. Association between COCs and body fat mass (BFM) Only four RCTs reported on the effects of different COC formulations on BFM measurement by dual-energy x-ray absortiometry (DEXA). Drospirenone was used in two studies [ 36 , 38 ], desogestrel was used in one study [ 29 ], and levonorgestrel was used in the other [ 31 ]. A total of 110 women with PCOS had BFM measured before and after treatment with COCs. The pooled SDM was 0.525 (95% CI 0.115 to 0.90, p = 0.013) (Fig. 3 ). The studies presented moderate heterogeneity (Tau 2 = 0.107, Q = 7.15, p = 0.067, I 2= 58.04). The predictive interval of effect size for different populations ranged from − 1.146 to 2.216. Association between COCs and waist triglyceride index A comparison of WTI, measured before and after the use of different COC formulations, was performed in five RCTs. Progestin drospirenone was used in one study [ 30 ], and norgestimate acetate, chlormadinone acetate, levonorgestrel, and desogestrel were also used in one study each [ 28 , 21 , 33 , 34 ]; these studies enrolled 83 women with PCOS. The pooled SDM was 0.636 (95% CI-0.058 to 1.331, p = 0.073) (Fig. 4 ). The studies presented high heterogeneity (Tau 2 = 0.462, Q = 16.95, p = 0.002, I 2= 76.41). The predictive interval for different populations ranged from − 3.076 to 1.804. Association between COCs and visceral adiposity index Five RCTs reported on the effect of different COC formulations on VAI, calculated before and after COC use. This index was calculated using data already provided by each study [ 28 , 30 , 31 , 33 , 34 ]. Progestins used in each study were reported on the WTI topic, and the studies enrolled 83 women with PCOS. The pooled SDM was 0.210 (95% CI – 0.362 to 0.182, p = 0.473) (Fig. 4 ). The studies presented moderate to high heterogeneity in the measurement of this variable (Tau 2 = 0.275, Q = 12.12, p = 0.016, I 2 = 67.01). The predictive interval for different populations ranged from − 2.120 to 1.701. Association between COCs and lipid accumulation products LAP was calculated in five RCTs, totaling 83 patients with PCOS, published between 2008 and 2023 [ 28 , 30 , 31 , 33 , 34 ]. The progestin used in each study was already reported for calculation of WTI and VAI (drospirenone, norgestimate, chlormadinone acetate, levonorgestrel and desogestrel). The pooled SDM was − 0.290 (95% CI-0.597 to 0.016, p = 0.064) (Fig. 4 ). The studies were hormogenous (Tau 2 = 0.000, Q = 2.12, p = 0.713, I 2 = 0.00). The predictive interval for other populations was not provided. Association between COCs and body mass index, triglyceride and high-density lipoprotein cholesterol levels Because these variables were used only for calculation of the variables of interest in the present study, their results are shown in the supplementary material (Supplementary Tables 1, 2, 3). Discussion Several conflicting reports have been published on whether many of the side effects of COC use may determine alterations in the biomarkers of adiposity in women with PCOS. Women with PCOS subphenotypes such as insulin resistance, dysglycemia, dyslipidemia, arterial hypertension, low-grade chronic inflammation, nonalcoholic fatty liver disease, and obesity have no contraindications for the use of COC; eligibility criteria 2 or 3 [ 53 ]. In fact, as stated before, COCs are the first-line therapy for women with PCOS not seeking to become pregnant. This meta-analysis evaluated the effects of thirteen randomized clinical trials, comparing before and after results after the use of different COC formulations on the core clinical biomarker of adiposity in women with polycystic ovary syndrome as a whole group, including both adolescents and adults. The meta-analysis demonstrated that COCS of different compositions, used for a short period of time (3 to 12 months), have little impact on anthropometric-metabolic biomarkers of adiposity, predisposing PCOS users to cardiovascular disease. Moderate to high heterogeneity was found among several randomized trials. The nine RCTs reporting on WC published between 2004 and 2023, including 438 women with PCOS, did not show a significant effect of the different COC combinations on WC measurement. The studies showed moderate to high heterogeneity, and individually, these studies did not discuss the findings in these variables. The current meta-analysis demonstrated that COCs with different progestins do not significantly modify waist circumference in users of pills. This result supports the findings of a previous systematic review including studies of different designs [ 54 ]. Additionally, the predictive interval for other populations may vary around the unit. Another previous review [ 20 ], and one observational study found that COC containing CPA may determine a small increase in WC [ 55 ]. Furthermore, three RCTs showed a nonsignificant small increase in WC with COCs containing drospirenone [ 27 , 35 , 56 ]. Otherwise, COCs with chlormadinone acetate showed a nonsignificant decrease in WC [ 34 ]. Regarding BFM, two RCTs analyzed the influence of COCs on the percentage of body fat mass, but they were not included in the current meta-analysis due to missing data [ 26 , 37 ]. Considering the BFM measure in kilograms, using DEXA, four RCTs were published between 2004 and 2020, including 110 women with PCOS, and demonstrated a significant increase in fat mass. Regarding reliability of the results, the small number of RCTs presenting moderate heterogeneity must be considered. Limited data are available on changes in body fat mass with the use of COCs. Applying bioelectric impedance analyses, one study reported a significant increase in fat percentage and central fat mass deposition with a combination of ethinylestradiol and drospirenone in lean women with PCOS [ 56 ]. A systematic review published more than two decades ago [ 54 ] and a narrative review [ 20 ] had their results confirmed by the current meta-analysis. As explained previously, the effect of the use of COCs in the WTI was estimated using data provided by five RCTs. Despite being not statistically significant, the results showed a tendency to increase these biomarkers during the use of oral contraceptives for a short period of time (p = 0.075). Additionally, the studies were heterogeneous and analyzed a small number of women with PCOS. The results indicate that more studies, including a high number of subjects, are necessary to make a definitive conclusion. As far as we know, no study on this matter has already been published. Excess visceral adipose tissue is considered a major risk factor for metabolic and cardiovascular diseases, independent of general adiposity [ 57 ], in both adolescents and adult women with PCOS [ 58 – 61 ]. We found that only one previous RCT reported on the association of COC use and VAI [ 63 ]. In that study, it was found that users of COC, particularly containing CPA, presented a significant increase in the mean VAI. Unfortunately, this RCT was not included in the current meta-analysis because data allowing us to calculate VAI were not provided, even after tentative contact with the authors. In summary, the current meta-analysis, including only RCTs, found that COCs did not modify the VAI in women with PCOS. It is important to highlight that the included trials were heterogeneous regarding this variable. LAP is an established marker of adiposity in PCOS [ 62 ]. The current meta-analysis including five RCTs published between 2008 and 2021 found a tendency to increase LAP in PCOS users of COC (P = 0.060). Unfortunately, the RCTs included a small sample size, and the studies were heterogeneous. As already affirmed, only one RCT described the effect of oral contraceptives on LAP in women with PCOS; this study found that COCs significantly increase LAP, particularly with COC containing CPA [ 62 ]. Despite this tendency, more studies, including a higher number of patients, might clarify the association of COC and LAP in women with PCOS. The meta-analysis included only studies in the English language. Additionally, the studies included adolescents and adults and used different progestins. Frequently, the studies poorly described the randomization process and most were open trials. The small sample size of several studies may have affected the SMD. Furthermore, the use of cyclic COCs to treat PCOS should be changed to a continuous regime to avoid increases in gonadotropins and testosterone during the pill-free interval. Despite the use of clinical procedures to obtain anthropometric parameters, the variables examined in the present study have shown a high correlation with DEXA, usually with Pearson coefficient correlations over 0.8. Conclusion Collectively, the available RCTs suggested that COCs with different compositions might not present significant adverse effects on adiposity biomarkers in women with PCOS, at least when used for 3–12 months. Because of remarkable heterogeneity among studies, the short duration of COC use, the cyclic use of COCs instead of a continuous protocol, and the small sample size in several studies, it was made clear that further robust trials are urgently needed. Women with PCOS must be separated by phenotypes, allowinal to tailored the best protocol for each user. It is recommended that the use of pill-free regime COCs to treat PCOS should be moved to a continuous protocol. Declarations Authors’ roles Sebastião Freitas de Medeiros: design, data’s description, data analysis, statistical analysis, and writing the manuscript. José Maria Soares Junior: revision of the manuscript. Matheus Antonio Souto de Medeiros: data search, data analysis, revision of the menuscript Ana Karine Lin Winck Yamamoto: data search, revision of the manuscript Cindy Lin Winck de Medeiros: data search, and revision of the manuscript Anna Bethany da Silva Carvalho: data search, revision of the manuscript Márcia Marly Winck Yamamoto: data search, data analysis, revision of the manuscript Edmund Chada Baracat: revision of the manuscript Acknowledgement The authors acknowledge to American Journal Experts for English revision. Conflict of interest The authors declare there are either no financial or other conflicts of interest that could be perceived as prejudicing the impartiality of this study. References Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. 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Boston: Blackwell Scientific Publications, 1992;377-84; The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41-7. Borenstein, M., Hedges, L. V., Higgins, J. P. T., & Rothstein, H. R. (2009). Introduction to meta-analysis. Chichester, UK: Wiley. Hedges LV, Olkin I. Chapters seven and nine in statistical methods for meta analysis. In: Statistical Methods for Meta Analysis. New York: Academic Press, Inc., 1985 DerSimonian R, Laird N. Meta-analysis in clinical trials revisited. Contemp Clin Trials. 2015;45(Pt A):139-45. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003;327:556-7. WHO, Medical Eligibility Criteria for Contraceptive Use. 5th edition. Geneva: World Health Organization; 2015. Pasquali R, Gambineri A, Anconetani B, et al. The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long-term oestrogen-progestagen treatment. Clin Endocrinol (Oxf). 1999;50(4):517-27. Kahraman K, Sükür YE, Atabekoğlu CS, et al. Comparison of two oral contraceptive forms containing cyproterone acetate and drospirenone in the treatment of patients with polycystic ovary syndrome: a randomized clinical trial. Arch Gynecol Obstet. 2014;290(2):321-8. Aydin K, Cinar N, Aksoy DY, Bozdag G, Yildiz BO. Body composition in lean women with polycystic ovary syndrome: effect of ethinyl estradiol and drospirenone combination. Contraception. 2013;87(3):358-62. Lee CM, Huxley RR, Wildman RP, Woodward M. Indices of abdominal obesity are better discriminators of cardiovascular risk factors than BMI: a meta-analysis. J Clin Epidemiol. 2008;61(7):646-53. Ng NYH, Liu KH, Tam CHT, Jiang G, Cheng F, Hou Y, Yau TT, Ozaki R, Chan MH, Lim CK, Sahota DS, Li TC, Cheung LP, Tam WH, Chu WCW, Ma RCW. The relationship between visceral adiposity and cardiometabolic risk in Chinese women with polycystic ovary syndrome. Obes Res Clin Pract. 2021 15(6):593-9. de Medeiros SF, de Medeiros MAS, Barbosa BB, Yamamoto MMW, Maciel GAR. Comparison of metabolic and obesity biomarkers between adolescent and adult women with polycystic ovary syndrome. Arch Gynecol Obstet. 2021a;303(3):739-49. de Medeiros SF, de Medeiros MAS, Barbosa BB, Yamamoto MMW. The Role of Visceral Adiposity Index as Predictor of Metabolic Syndrome in Obese and Nonobese Women with Polycystic Ovary Syndrome. Metab Syndr Relat Disord. 2021b;19(1):18-25. Dong Y, Bai L, Cai R, Zhou J, Ding W. Visceral adiposity index performed better than traditional adiposity indicators in predicting unhealthy metabolic phenotype among Chinese children and adolescents. Scientific Reports. 2021 Dec;11(1):23850. Amiri M, Nahidi F, Yarandi RB, Khalili D, Tohidi M, Tehrani FR. Effects of oral contraceptives on the quality of life of women with polycystic ovary syndrome: a crossover randomized controlled trial. Health Qual Life Outcomes. 2020;31;18(1):293. Bir A, Ghosh A, Chowdhury S. Visceral adiposity index and lipid accumulation product index: The promising role in assessing cardiometabolic risk in non-obese patients of PCOS. J Educ Health Promot. 2023;31(12):148. Table Table 1. Effect of combined oral contraceptive formulations on biomarkers of adiposity in women with polycystic ovary syndrome. Randomized clinical trial Studys year Country Diagnostic criteria Study desing Sample size Age (years) mean ± SD Regime Intervention Follow up (month) Ibañez and de Zegher, 2004 Spain NIH O-RCT 16 14.60±0.30 21/7 EE 30/ DRSP 3 09 Ibañez and de Zegher, 2004 Spain NIH O-RCT 11 18.60±0.30 NR EE 30/ DRSP 3 09 Hoeger et al, 2008 USA NIH O-RCT 10 15.90±1.90 NR EE 30/ DRSP 3 06 Kilic et al, 2011 Turkey ROTTERDAM O-RCT 25 29.00±3.50 NR EE 30/ DSG 0.15 06 Kilic et al, 2011 Turkey ROTTERDAM O-RCT 24 26.70±3.80 NR EE 20/ DSG 0.15 06 Essah et al, 2011 USA ROTTERDAM D-RCT 10 29.20±4.40 NR EE 35/ NGM 0.18-0.25 03 Bhattacharya and Jha, 2012 India AES D-RCT 49 22.40±4.47 21/7 EE 30/ DSG 0.15 12 Bhattacharya and Jha, 2012 India AES D-RCT 51 22.32±4.17 21/7 EE 35/ CPA 2 12 Bhattacharya and Jha, 2012 India AES D-RCT 50 22.32±4.76 21/7 EE 30/ DRSP 3 12 Vieira et al, 2012 Brazil ROTTERDAM O-RCT 21 25.00±3.80 21/7 EE 30/ CMA 2 12 Glintiborg et al, 2014 Denmark ROTTERDAM O-RCT 23 28(23-30) NR EE 30/ DSG 12 Feng et al, 2015 China ROTTERDAM O-RCT 41 28.57±3.04 21/7 EE 35/ CPA 2 03 Bhattacharya et al, 2016 India ROTTERDAM O-RCT 48 22.28±3.91 21/7 EE 20/ DRSP 3 12 Bhattacharya et al, 2016 India ROTTERDAM O-RCT 46 21.47±4.21 21/7 EE 30/ DRSP 3 12 Kumar et al, 2018 India ROTTERDAM O-RCT 28 22.90±5.00 28/28 EE 35/ CPA 2 06 Moretti et al, 2018 Italy ROTTERDAM D-RCT 24 27.4(25.39-30.69) 28/28 EE 30/CMA 2 12 Ibañez z et al, 2020 Spain NIH O-RCT 31 15.90±0.20 21/7 EG 30/ LNG 100 12 Mosorin et al, 2023 Finland ROTTERDAM O-RCT 11 32.40±6.60 NR EE 20/ DSG 150 03 NIH= National Institute of Hearth, USA; AES= Androgen Excess Sociely; O-RCT= Open randomized clinical trial; D-RCT= double blind randomized clinical trial; NR= Not clearly reported; DRSP= drospirenona ; DSG= desogestrel; CPA= ciproterone acetate; CMA= cholrmadinone acetate; LNG= levonorgestral; Supplementary Files SupplementaryTables.doc Cite Share Download PDF Status: Published Journal Publication published 18 Jul, 2024 Read the published version in Archives of Gynecology and Obstetrics → Version 1 posted Reviewers invited by journal 04 Feb, 2024 Editor invited by journal 22 Jan, 2024 Editor assigned by journal 22 Jan, 2024 First submitted to journal 19 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3882087","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":271077019,"identity":"02cb765b-acf0-4436-8d31-906f41ccd897","order_by":0,"name":"Sebastião Freitas de Medeiros","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYDCCAyCCjYEHSDI+QBcnqIXZ4ACaOF4tYFKCKC18xxtYN3wos5Exb29/Vv2h4l4+fwPzw0c3GO7k49IieeYA280Z59J4ZM6cMbtx4Eyx5YwDbMbGOQzPLBtwaDG4kcB2m7ftMI+ERA7bjYNtCQYMB3jYpHMYDhvgssXg/gO223/b/gO1pD8rOPgvwUCeoJYbDGy3GdsOALUkmDEcbEgwMCCkRfJMYtvNnnPJPBI8Z4wlzhxLMDA8DPKLwTOcWviOHz5240eZnb0Ee/vDDxU1CQZyx5sfPs6puINTCzDOG9AEmMEOxq1hFIyCUTAKRgFhAABeqFmCOGRSmwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-1292-2515","institution":"Universidade Federal de Mato Grosso","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Sebastião","middleName":"Freitas","lastName":"de Medeiros","suffix":""},{"id":271077020,"identity":"15e22201-defb-4ed1-b4a4-a3a450477285","order_by":1,"name":"José Maria Soares Junior","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"José","middleName":"Maria Soares","lastName":"Junior","suffix":""},{"id":271077021,"identity":"6bc3c87d-6955-40f7-94bb-c576f5cd8bd7","order_by":2,"name":"Matheus Antônio Souto de Medeiros","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Matheus","middleName":"Antônio Souto","lastName":"de Medeiros","suffix":""},{"id":271077022,"identity":"9f18fb7c-8354-4171-9854-969596c22584","order_by":3,"name":"Ana Karine Lin Winck Yamamoto","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ana","middleName":"Karine Lin Winck","lastName":"Yamamoto","suffix":""},{"id":271077023,"identity":"acfd5570-f792-4924-8160-dcb17e9f1f94","order_by":4,"name":"Cindy Lin Winck de Medeiros","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cindy","middleName":"Lin Winck","lastName":"de Medeiros","suffix":""},{"id":271077024,"identity":"08da3b5f-f230-49b5-9d31-f576b351986e","order_by":5,"name":"Anna Bethany da Silva Carvalho","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anna","middleName":"Bethany da Silva","lastName":"Carvalho","suffix":""},{"id":271077025,"identity":"50410a5b-c8e8-4631-91f1-384e2a51dc07","order_by":6,"name":"Márcia Marly Winck Yamamoto","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Márcia","middleName":"Marly Winck","lastName":"Yamamoto","suffix":""},{"id":271077026,"identity":"4cac1ad9-a4c8-474a-95f1-9d279d1aaaf0","order_by":7,"name":"Edmund Chada Baracat","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Edmund","middleName":"Chada","lastName":"Baracat","suffix":""}],"badges":[],"createdAt":"2024-01-20 17:04:54","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3882087/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3882087/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00404-024-07637-5","type":"published","date":"2024-07-18T16:13:14+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":50821841,"identity":"9f1e433e-041d-4dc8-a4d2-316bb44809b3","added_by":"auto","created_at":"2024-02-07 21:45:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":41735,"visible":true,"origin":"","legend":"\u003cp\u003ePrisma flow diagrama search performed for randomized clinical trials, comparing the effects of combined oral contraceptive formulations before and after 03-12 months duration of use.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3882087/v1/430e8f8cc01c2bb7c2337879.png"},{"id":50821844,"identity":"72a2888f-de46-4bde-aa80-bbe5c71fc7d7","added_by":"auto","created_at":"2024-02-07 21:45:51","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":910309,"visible":true,"origin":"","legend":"\u003cp\u003eA. Risk of bias assessment of individual randomized clinical trials\u003c/p\u003e\n\u003cp\u003eB. Risk of bias graph as percentage (intention-to-treat)\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3882087/v1/c79c04270e678ea7e7667aaa.jpg"},{"id":50821842,"identity":"0da47955-20a3-41ba-9e2d-b0776e4d0d41","added_by":"auto","created_at":"2024-02-07 21:45:51","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":134424,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of the standard difference means between different COC formulations use, waist circumference and body fat mass in women with polycystic ovary syndrome.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3882087/v1/3c762bb50d8ce7ff2b6bfaf1.png"},{"id":50822343,"identity":"8de05281-21e1-4d1b-b6cb-407dcaf2ff77","added_by":"auto","created_at":"2024-02-07 21:53:51","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":128965,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of the standard difference means between different COC formulations use, waist circumference triglyceride index, visceral adiposity index, and lipid accumulation product in women with polycystic ovary syndrome.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-3882087/v1/4a27a58f636d865508dc90f4.png"},{"id":61595217,"identity":"cf3a37d0-450f-4f74-aae3-f0e4cf5e4ed4","added_by":"auto","created_at":"2024-08-01 17:21:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1981654,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3882087/v1/f9c53f12-6920-444a-addb-bf9007683db7.pdf"},{"id":50821840,"identity":"cbd0b73f-e337-472f-b1f3-c6a847cc42e9","added_by":"auto","created_at":"2024-02-07 21:45:51","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":211456,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.doc","url":"https://assets-eu.researchsquare.com/files/rs-3882087/v1/52ed20a8c685f346693986c0.doc"}],"financialInterests":"","formattedTitle":"Combined oral contraceptive use and adiposity in women with polycystic ovary syndrome. A meta-analysis of randomized clinical trials","fulltext":[{"header":"What does this study adds to the clinical work?","content":"\u003cp\u003eThe present meta-analysis of randomized clinical trials indicated that the use of different oral contraceptive formulations increase adiposity in women with polycystic ovary syndrome.\u003c/p\u003e"},{"header":"Take home messages","content":"\u003cp\u003eThe study with adequate number of randomized clinical trials comparing biomarkers of adiposity before and after use of different COCs in women with polycystic ovary syndrome\u003c/p\u003e\n\u003cp\u003eDespite the heterogeneity observed among studies the meta-analysis demonstrated that the use of COCs may increase adiposity in women with polycystic ovary syndrome.\u003c/p\u003e"},{"header":"Implications","content":"\u003cp\u003ePolycystic ovary syndrome, particularly the hyperandrogenic phenotype, may be associated with metabolic abnormalities and increased risk for cardiovascular diseases. For clinical practice, the concomitant use of COCs as the first-line treatment of PCOS may amplify the risks. The literature available remains controversial. The current meta-analysis updates the knowledge regarding the association of COCs use with PCOS, and adiposity.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003ePolycystic ovary syndrome (PCOS) has been reported in 5%-20% of women of reproductive age worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In addition to the core phenotypes (menstrual disturbances and hyperandrogenism), dysglycemia, dyslipidemia, metabolic syndrome, and central obesity are also common [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and these variables must be considered in the clinical practice of PCOS assistance [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Overall, these data indicated that patients with PCOS could be linked to the future development of cardiovascular disease (CVD) and venous thromboembolism [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Combined oral contraceptives (COCs) have been considered the first-line therapy for PCOS women with menstrual irregularity and clinical and/or biochemical hyperandrogenism who do not wish to become pregnant [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, some deleterious metabolic and inflammatory effects have been demonstrated with the association between PCOS and COC use [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Because proper PCOS might increase the risk of CVC, the potential additional risk of using COCs in women with PCOS has been already evaluated, particularly in women with a hyperandrogenic phenotype [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe choice for a determined COC formulation in women with PCOS should be based on estrogen type and dose and progestin type to tailor PCOS phenotypes [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Nevertheless, it has recently been demonstrated that the use of COCs in women with PCOS may be safe [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The current knowledge regarding the effect of different COCs on the amount and distribution of adipose tissue in women with PCOS needs to be expanded [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This meta-analysis of randomized clinical trials (RCTs) was designed to estimate the potential risk of different formulations of COCs on adiposity biomarkers in women with PCOS as a whole group.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eObjective and data extraction\u003c/h2\u003e \u003cp\u003eThe main objective of this meta-analysis was to evaluate available data regarding the effect of different COC formulations on surrogate biomarkers of adiposity in women with PCOS as a whole group. The electronic search of randomized clinical trials reporting on this subject was limited to the English language. The combined terms PCOS and COC usage were searched in the Google School and Medline databases. References in reviews or original publications were also hand-searched. A total of 3820 articles were found, and 3756 were excluded after browsing the titles and/or abstracts. A total of 64 full papers were assessed for eligibility. Later, 51 publications were excluded because they were of observational design, did not provide sufficient data of interest or did not provide before and after data for analysis. Ultimately, 13 fully randomized clinical trials providing sufficient data for analysis were selected [\u003cspan additionalcitationids=\"CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Study eligibility was verified independently by three authors (S.F. M, M.M.W. Y, AKLWY). The study quality was also independently assessed by two authors (S.F. M and M.A.S.M).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eRisk of bias\u003c/h2\u003e \u003cp\u003eThe risk of bias of each study was examined using the RoB2 tool [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], and individual quality items included bias arising from the randomized process, due to deviations from intended intervention, due to missing outcome data, and due to outcome measurement, due to selection of the report results. The biases were summarized as overall bias.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eOutcome measures\u003c/h2\u003e \u003cp\u003e The primary outcomes of interest were waist circumference (WC), body mass index (BMI), waist hip ratio (WHR), total fat mass (TFM), triglyceride levels (TG), high density lipoprotein cholesterol (HDL-C), waist circumference triglyceride index (WTI), visceral adiposity index (VAI), and lipid accumulation product (LAP). When expressed in mg/ml, TG and HDL-C were standardized to all units in mass to SI system measurement; therefore, HDL-C and TG results were converted into mmol/l. VAI was calculated from original data using the equation VAI\u0026thinsp;=\u0026thinsp;WC/(36.58+(1.89 x BMI) x (TG x 0.081) x (1.52 x HDL-C), and LAP for females was also calculated from original data using the equation LAP=(WCcm-58.3 x TGmmol/l) [40]. In each RCT in which the mean and standard deviation were not reported, these data were calculated from the sample size, range, median or interquartile range [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e3]. Specifically, standard derivation was calculated using the formula: SD= \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\sqrt{n}\\)\u003c/span\u003e\u003c/span\u003e x upper limit \u0026ndash; lower limit divided by 3.92 [44]. The mean was calculated by median, the smallest value (a), the largest value (b) and the sample size using the formula: x\u0026thinsp;=\u0026thinsp;a+2 m\u0026thinsp;+\u0026thinsp;b/4, where a and b are the low and high end of the range, respectively, and m is the median. When the sample size was small, as in most RCTs included in this meta-analysis, the formula x\u0026thinsp;=\u0026thinsp;a\u0026thinsp;+\u0026thinsp;2 m\u0026thinsp;+\u0026thinsp;b/4 plus a-2 m\u0026thinsp;+\u0026thinsp;b/4n was applied [45]\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData Analysis\u003c/h2\u003e \u003cp\u003eConsidering that studies have used different methods to measure the principal variables and that PCOS was diagnosed by different criteria [Nation Institute of Health, and Androgen Excess Society (AES) [\u003cspan additionalcitationids=\"CR47\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]], the effect sizes are presented as the standard mean differences (SMD) and standard errors (SE). Data were pooled by using a random-effects model with 95% confidence intervals. Then, it was assumed that the true effect size may vary from study to study and that the summary effect was the estimate of the mean of the distribution of effect sizes [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Effect sizes were weighted by the inverse of the within-study variance [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Heterogeneity among studies was assessed for each result by using the Cochrane Q statistic, where Q is the weighted sum of squares. The variance of the effect size between studies (Tau\u003csup\u003e2\u003c/sup\u003e) was estimated using the method of moments [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. The ratio of true heterogeneity to total observed variation (I\u003csup\u003e2\u003c/sup\u003e) was also estimated [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Additionally, the predictive interval of effect size to indicate a true heterogeneity was provided. All analyses were performed using the Compreensive Meta-analysis Software [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy selection\u003c/h2\u003e\n \u003cp\u003eA total of 3820 articles were initially identified using a combination of COC and PCOS. After screening by three authors (SFM, MMWY and AKLWY), 64 studies were included, and 3756 articles were excluded because they were reviews, did not compare data before and after COC use or presented data only as figures that did not allow us to compare the results. Furthermore, 51 studies were excluded because of design or incomplete data for comparing before and after results. Finally, 13 full open or blind randomized clinical trials published between 2004 and 2023 were selected (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Three of them were double blinded [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e], and 10 studies were open trials [\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. A total of 519 PCOS patients were enrolled. To define PCOS, three studies used NHI criteria [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e], one study used AES criteria [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e] and nine trials used the Rotterdam criteria [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]. In the included studies, the treatment duration varied between 3 months and 12 months.\u003c/p\u003e\n \u003cp\u003eThe majority of trials included only adult patients [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e], two studies included adolescents [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e], and one study included both adolescents and adults [\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003eRisk of bias\u003c/h2\u003e\n \u003cp\u003eIn the present meta-analysis, four studies fulfilled the criteria for a low risk of bias RoB2, and nine studies had some concerns and were considered to have a moderate risk of bias RoB2 [\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e]. All studies clearly described PCOS diagnostic criteria and inclusion and exclusion criteria. The randomization method was not reported by some studies using RoB2 assessment (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003eEffects of intervention\u003c/h2\u003e\n \u003cp\u003eIndividual and pooled results of the included RCTs are presented in the following sections. Supplemental Tables\u0026nbsp;1 to 3 summarize the effect sizes of interventions on body mass index (BMI), triglycerides (TG) and high density lipoprotein cholesterol (HDL-C) levels using different COC formulations. These data were necessary to estimate the WTI, VAI and LAP variables.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eAssociation between COCs and waist circumference\u003c/h2\u003e\n \u003cp\u003eNine RCTs reported on the effects of different COC formulations on WC. Regarding progestin type, one study [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e] compared COCs with three different progestins (desogestrel, drospirenone, ciproterone acetate) and did not find anthropometric or metabolic differences among these formulations. Three studies used desogestrel [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e], one study used cyproterone acetate [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], three studies used drospirenone [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e], two studies used norgestimate [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e] and one study used chlormadinone acetate [\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]. A total of 438 women with PCOS had WC measured before and after treatment with different COC formulations, with a pooled SDM of 0.048 (95% CI/-0.200 to 0.292, p\u0026thinsp;=\u0026thinsp;0.114) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). These studies were heterogeneous regarding this variable Tau\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.127 Q\u0026thinsp;=\u0026thinsp;36.33, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;66,96. The predicting interval of effect size for different populations ranged from \u0026minus;\u0026thinsp;0.78 to 0.876.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eAssociation between COCs and body fat mass (BFM)\u003c/h2\u003e\n \u003cp\u003eOnly four RCTs reported on the effects of different COC formulations on BFM measurement by dual-energy x-ray absortiometry (DEXA). Drospirenone was used in two studies [\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e], desogestrel was used in one study [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e], and levonorgestrel was used in the other [\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]. A total of 110 women with PCOS had BFM measured before and after treatment with COCs. The pooled SDM was 0.525 (95% CI 0.115 to 0.90, p\u0026thinsp;=\u0026thinsp;0.013) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The studies presented moderate heterogeneity (Tau\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.107, Q\u0026thinsp;=\u0026thinsp;7.15, p\u0026thinsp;=\u0026thinsp;0.067, I\u003csup\u003e2=\u003c/sup\u003e 58.04). The predictive interval of effect size for different populations ranged from \u0026minus;\u0026thinsp;1.146 to 2.216.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eAssociation between COCs and waist triglyceride index\u003c/h2\u003e\n \u003cp\u003eA comparison of WTI, measured before and after the use of different COC formulations, was performed in five RCTs. Progestin drospirenone was used in one study [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e], and norgestimate acetate, chlormadinone acetate, levonorgestrel, and desogestrel were also used in one study each [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]; these studies enrolled 83 women with PCOS. The pooled SDM was 0.636 (95% CI-0.058 to 1.331, p\u0026thinsp;=\u0026thinsp;0.073) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). The studies presented high heterogeneity (Tau\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.462, Q\u0026thinsp;=\u0026thinsp;16.95, p\u0026thinsp;=\u0026thinsp;0.002, I\u003csup\u003e2=\u003c/sup\u003e76.41). The predictive interval for different populations ranged from \u0026minus;\u0026thinsp;3.076 to 1.804.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eAssociation between COCs and visceral adiposity index\u003c/h2\u003e\n \u003cp\u003eFive RCTs reported on the effect of different COC formulations on VAI, calculated before and after COC use. This index was calculated using data already provided by each study [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]. Progestins used in each study were reported on the WTI topic, and the studies enrolled 83 women with PCOS. The pooled SDM was 0.210 (95% CI \u0026ndash; 0.362 to 0.182, p\u0026thinsp;=\u0026thinsp;0.473) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). The studies presented moderate to high heterogeneity in the measurement of this variable (Tau\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.275, Q\u0026thinsp;=\u0026thinsp;12.12, p\u0026thinsp;=\u0026thinsp;0.016, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;67.01). The predictive interval for different populations ranged from \u0026minus;\u0026thinsp;2.120 to 1.701.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eAssociation between COCs and lipid accumulation products\u003c/h2\u003e\n \u003cp\u003eLAP was calculated in five RCTs, totaling 83 patients with PCOS, published between 2008 and 2023 [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]. The progestin used in each study was already reported for calculation of WTI and VAI (drospirenone, norgestimate, chlormadinone acetate, levonorgestrel and desogestrel). The pooled SDM was \u0026minus;\u0026thinsp;0.290 (95% CI-0.597 to 0.016, p\u0026thinsp;=\u0026thinsp;0.064) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). The studies were hormogenous (Tau\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.000, Q\u0026thinsp;=\u0026thinsp;2.12, p\u0026thinsp;=\u0026thinsp;0.713, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.00). The predictive interval for other populations was not provided.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eAssociation between COCs and body mass index, triglyceride and high-density lipoprotein cholesterol levels\u003c/h2\u003e\n \u003cp\u003eBecause these variables were used only for calculation of the variables of interest in the present study, their results are shown in the supplementary material (Supplementary Tables\u0026nbsp;1, 2, 3).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSeveral conflicting reports have been published on whether many of the side effects of COC use may determine alterations in the biomarkers of adiposity in women with PCOS. Women with PCOS subphenotypes such as insulin resistance, dysglycemia, dyslipidemia, arterial hypertension, low-grade chronic inflammation, nonalcoholic fatty liver disease, and obesity have no contraindications for the use of COC; eligibility criteria 2 or 3 [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. In fact, as stated before, COCs are the first-line therapy for women with PCOS not seeking to become pregnant. This meta-analysis evaluated the effects of thirteen randomized clinical trials, comparing before and after results after the use of different COC formulations on the core clinical biomarker of adiposity in women with polycystic ovary syndrome as a whole group, including both adolescents and adults. The meta-analysis demonstrated that COCS of different compositions, used for a short period of time (3 to 12 months), have little impact on anthropometric-metabolic biomarkers of adiposity, predisposing PCOS users to cardiovascular disease. Moderate to high heterogeneity was found among several randomized trials.\u003c/p\u003e \u003cp\u003eThe nine RCTs reporting on WC published between 2004 and 2023, including 438 women with PCOS, did not show a significant effect of the different COC combinations on WC measurement. The studies showed moderate to high heterogeneity, and individually, these studies did not discuss the findings in these variables. The current meta-analysis demonstrated that COCs with different progestins do not significantly modify waist circumference in users of pills. This result supports the findings of a previous systematic review including studies of different designs [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. Additionally, the predictive interval for other populations may vary around the unit. Another previous review [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and one observational study found that COC containing CPA may determine a small increase in WC [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. Furthermore, three RCTs showed a nonsignificant small increase in WC with COCs containing drospirenone [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Otherwise, COCs with chlormadinone acetate showed a nonsignificant decrease in WC [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRegarding BFM, two RCTs analyzed the influence of COCs on the percentage of body fat mass, but they were not included in the current meta-analysis due to missing data [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Considering the BFM measure in kilograms, using DEXA, four RCTs were published between 2004 and 2020, including 110 women with PCOS, and demonstrated a significant increase in fat mass. Regarding reliability of the results, the small number of RCTs presenting moderate heterogeneity must be considered. Limited data are available on changes in body fat mass with the use of COCs. Applying bioelectric impedance analyses, one study reported a significant increase in fat percentage and central fat mass deposition with a combination of ethinylestradiol and drospirenone in lean women with PCOS [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. A systematic review published more than two decades ago [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e] and a narrative review [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] had their results confirmed by the current meta-analysis.\u003c/p\u003e \u003cp\u003eAs explained previously, the effect of the use of COCs in the WTI was estimated using data provided by five RCTs. Despite being not statistically significant, the results showed a tendency to increase these biomarkers during the use of oral contraceptives for a short period of time (p\u0026thinsp;=\u0026thinsp;0.075). Additionally, the studies were heterogeneous and analyzed a small number of women with PCOS. The results indicate that more studies, including a high number of subjects, are necessary to make a definitive conclusion. As far as we know, no study on this matter has already been published.\u003c/p\u003e \u003cp\u003eExcess visceral adipose tissue is considered a major risk factor for metabolic and cardiovascular diseases, independent of general adiposity [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e], in both adolescents and adult women with PCOS [\u003cspan additionalcitationids=\"CR59 CR60\" citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. We found that only one previous RCT reported on the association of COC use and VAI [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. In that study, it was found that users of COC, particularly containing CPA, presented a significant increase in the mean VAI. Unfortunately, this RCT was not included in the current meta-analysis because data allowing us to calculate VAI were not provided, even after tentative contact with the authors. In summary, the current meta-analysis, including only RCTs, found that COCs did not modify the VAI in women with PCOS. It is important to highlight that the included trials were heterogeneous regarding this variable. LAP is an established marker of adiposity in PCOS [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. The current meta-analysis including five RCTs published between 2008 and 2021 found a tendency to increase LAP in PCOS users of COC (P\u0026thinsp;=\u0026thinsp;0.060). Unfortunately, the RCTs included a small sample size, and the studies were heterogeneous. As already affirmed, only one RCT described the effect of oral contraceptives on LAP in women with PCOS; this study found that COCs significantly increase LAP, particularly with COC containing CPA [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. Despite this tendency, more studies, including a higher number of patients, might clarify the association of COC and LAP in women with PCOS.\u003c/p\u003e \u003cp\u003eThe meta-analysis included only studies in the English language. Additionally, the studies included adolescents and adults and used different progestins. Frequently, the studies poorly described the randomization process and most were open trials. The small sample size of several studies may have affected the SMD. Furthermore, the use of cyclic COCs to treat PCOS should be changed to a continuous regime to avoid increases in gonadotropins and testosterone during the pill-free interval. Despite the use of clinical procedures to obtain anthropometric parameters, the variables examined in the present study have shown a high correlation with DEXA, usually with Pearson coefficient correlations over 0.8.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCollectively, the available RCTs suggested that COCs with different compositions might not present significant adverse effects on adiposity biomarkers in women with PCOS, at least when used for 3\u0026ndash;12 months. Because of remarkable heterogeneity among studies, the short duration of COC use, the cyclic use of COCs instead of a continuous protocol, and the small sample size in several studies, it was made clear that further robust trials are urgently needed. Women with PCOS must be separated by phenotypes, allowinal to tailored the best protocol for each user. It is recommended that the use of pill-free regime COCs to treat PCOS should be moved to a continuous protocol.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthors\u0026rsquo; roles\u003c/h2\u003e\n\u003cp\u003eSebasti\u0026atilde;o Freitas de Medeiros: design, data\u0026rsquo;s description, data analysis, statistical analysis, and writing the manuscript.\u003c/p\u003e\n\u003cp\u003eJos\u0026eacute; Maria Soares Junior: revision of the manuscript.\u003c/p\u003e\n\u003cp\u003eMatheus Antonio Souto de Medeiros: data search, data analysis, revision of the menuscript\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAna Karine Lin Winck Yamamoto: data search, revision of the manuscript\u003c/p\u003e\n\u003cp\u003eCindy Lin Winck de Medeiros: data search, and revision of the manuscript\u003c/p\u003e\n\u003cp\u003eAnna Bethany da Silva Carvalho: data search, revision of the manuscript\u003c/p\u003e\n\u003cp\u003eM\u0026aacute;rcia Marly Winck Yamamoto: data search, data analysis, revision of the manuscript\u003c/p\u003e\n\u003cp\u003eEdmund Chada Baracat: revision of the manuscript\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eThe authors acknowledge to American Journal Experts for English revision.\u003c/p\u003e\n\u003ch2\u003eConflict of interest\u003c/h2\u003e\n\u003cp\u003eThe authors declare there are either no financial or other conflicts of interest that could be perceived as prejudicing the impartiality of this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eAzziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004;89:2745-9.\u003c/li\u003e\n \u003cli\u003eMarch WA, Moore VM, Wilson KJ, Phillips DIW, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25(2):544-51.\u003c/li\u003e\n \u003cli\u003eMcCartney CR, Marshall JC. Polycystic ovary syndrome. New Engl J Med. 2016;375:54-64.\u003c/li\u003e\n \u003cli\u003eSalm\u0026oacute;n-G\u0026oacute;mez L, Catal\u0026aacute;n V, Fr\u0026uuml;hbeck G, G\u0026oacute;mez-Ambrosi J. Relevance of body composition in phenotyping the obesities. Rev Endocr Metab Disord. 2023;24(5):809-23.\u003c/li\u003e\n \u003cli\u003eGariani K, Hugon-Rodin J, Philippe J, Righini M, Blondon M. Association between polycystic ovary syndrome and venous thromboembolism: A systematic review and meta-analysis. 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Visceral adiposity index performed better than traditional adiposity indicators in predicting unhealthy metabolic phenotype among Chinese children and adolescents. Scientific Reports. 2021 Dec;11(1):23850.\u003c/li\u003e\n \u003cli\u003eAmiri M, Nahidi F, Yarandi RB, Khalili D, Tohidi M, Tehrani FR. Effects of oral contraceptives on the quality of life of women with polycystic ovary syndrome: a crossover randomized controlled trial. Health Qual Life Outcomes. 2020;31;18(1):293.\u003c/li\u003e\n \u003cli\u003eBir A, Ghosh A, Chowdhury S. Visceral adiposity index and lipid accumulation product index: The promising role in assessing cardiometabolic risk in non-obese patients of PCOS. J Educ Health Promot. 2023;31(12):148.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eEffect of combined oral contraceptive formulations on biomarkers of adiposity in women with polycystic ovary syndrome. Randomized clinical trial\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"999\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudys year\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCountry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnostic\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ecriteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003edesing\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003esize\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003emean \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRegime\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow up\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(month)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eIba\u0026ntilde;ez\u0026nbsp;and de Zegher, 2004\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eNIH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eO-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e14.60\u0026plusmn;0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003e21/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 30/ DRSP 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eIba\u0026ntilde;ez\u0026nbsp;and de Zegher, 2004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eNIH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eO-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e18.60\u0026plusmn;0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 30/ DRSP 3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eHoeger et al, 2008\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eNIH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eO-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e15.90\u0026plusmn;1.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 30/ DRSP 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eKilic et al, 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eTurkey\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eROTTERDAM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eO-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e29.00\u0026plusmn;3.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 30/ DSG 0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eKilic et al, 2011\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eTurkey\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eROTTERDAM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eO-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e26.70\u0026plusmn;3.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 20/ DSG 0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eEssah et al, 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eROTTERDAM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eD-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e29.20\u0026plusmn;4.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 35/ NGM 0.18-0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eBhattacharya and Jha, 2012\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eIndia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eAES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eD-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e22.40\u0026plusmn;4.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003e21/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 30/ DSG 0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eBhattacharya and Jha, 2012\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eIndia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eAES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eD-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e22.32\u0026plusmn;4.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003e21/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 35/ CPA 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eBhattacharya and Jha, 2012\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eIndia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eAES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eD-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e22.32\u0026plusmn;4.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003e21/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 30/ DRSP 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eVieira et al, 2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eBrazil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eROTTERDAM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eO-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e25.00\u0026plusmn;3.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003e21/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 30/ CMA 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eGlintiborg et al, 2014\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eDenmark\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eROTTERDAM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eO-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e28(23-30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 30/ DSG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eFeng et al, 2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eROTTERDAM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eO-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e28.57\u0026plusmn;3.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003e21/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 35/ CPA 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eBhattacharya et al, 2016\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eIndia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eROTTERDAM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eO-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e22.28\u0026plusmn;3.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003e21/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 20/ DRSP 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eBhattacharya et al, 2016\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eIndia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eROTTERDAM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eO-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e21.47\u0026plusmn;4.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003e21/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 30/ DRSP 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eKumar et al, 2018\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eIndia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eROTTERDAM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eO-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e22.90\u0026plusmn;5.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003e28/28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 35/ CPA 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eMoretti et al, 2018\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eItaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eROTTERDAM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eD-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e27.4(25.39-30.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003e28/28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 30/CMA 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eIba\u0026ntilde;ez\u0026nbsp;z et al, 2020\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eNIH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eO-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e15.90\u0026plusmn;0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003e21/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEG 30/ LNG 100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.6%\" valign=\"top\"\u003e\n \u003cp\u003eMosorin et al, 2023\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eFinland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.3%\" valign=\"top\"\u003e\n \u003cp\u003eROTTERDAM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1%\" valign=\"top\"\u003e\n \u003cp\u003eO-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.6%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.7%\" valign=\"top\"\u003e\n \u003cp\u003e32.40\u0026plusmn;6.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.6%\" valign=\"top\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17%\" valign=\"top\"\u003e\n \u003cp\u003eEE 20/ DSG 150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.5%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"9\" valign=\"top\"\u003e\n \u003cp\u003eNIH= National Institute of Hearth, USA; AES= Androgen Excess Sociely; O-RCT= Open randomized clinical trial; D-RCT= double blind randomized clinical trial; NR= Not clearly reported; DRSP= drospirenona ; DSG= desogestrel; CPA= ciproterone acetate; CMA= cholrmadinone acetate; LNG= levonorgestral;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Polycystic ovary syndrome, oral contraceptive, lipids, metabolism, adiposity, biomarkers","lastPublishedDoi":"10.21203/rs.3.rs-3882087/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3882087/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground.\u003c/h2\u003e \u003cp\u003eCombined oral contraceptives (COCs) are of first line treatment of women with polycystic ovary syndrome (PCOS) who do not intend to become pregnant. PCOS is a heterogeneous condition with subphenotypes with different risks for future development of cardiovascular disease. The combination of COC and PCOS may or may not amplify the risks of cardiovascular events.\u003c/p\u003e\u003ch2\u003eObjective.\u003c/h2\u003e \u003cp\u003eTo investigate whether surrogates for adiposity may be influenced by the use of COCs with different formulations in women with PCOS.\u003c/p\u003e\u003ch2\u003eMethod.\u003c/h2\u003e \u003cp\u003eA literature search was conduct in Google Scholar and Pubmed databases. Hand search of randomized clinical trials in the references of obtained manuscripts was also performed. The search identified 3820 articles and 13 randomized clinical trials in which was possible to compare the results obtained before and after the use of COCs. Random-effects model was used to estimate the standardized mean differences (SMD) and standard erros (SE). Risk of bias was examined using the Rob2 tool.\u003c/p\u003e\u003ch2\u003eResult.\u003c/h2\u003e \u003cp\u003eThirteen heterogeneous RCTs reported no difference on waist circumference with the use of different COC formulations (p\u0026thinsp;=\u0026thinsp;0.714). On the contray, body fat mass increased with the use of pill (p\u0026thinsp;=\u0026thinsp;0.013). Anthropometric-metabolic biomarkers waist triglyceride index and visceral adiposity index did not change but the lipid accumulation product tended to be higher after use of COCs.\u003c/p\u003e\u003ch2\u003eConclusion.\u003c/h2\u003e \u003cp\u003eCombined oral contraceptives with different formulations might increase fat mass accumulation in women with PCOS. Lipids may also be accumulated in the PCOS users.\u003c/p\u003e","manuscriptTitle":"Combined oral contraceptive use and adiposity in women with polycystic ovary syndrome. A meta-analysis of randomized clinical trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-07 21:45:41","doi":"10.21203/rs.3.rs-3882087/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2024-02-04T21:16:57+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Archives of Gynecology and Obstetrics","date":"2024-01-22T13:37:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-22T07:14:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"Archives of Gynecology and Obstetrics","date":"2024-01-19T08:05:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"13f29bac-17ea-461c-8687-22352ea1c86e","owner":[],"postedDate":"February 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-01T16:20:53+00:00","versionOfRecord":{"articleIdentity":"rs-3882087","link":"https://doi.org/10.1007/s00404-024-07637-5","journal":{"identity":"archives-of-gynecology-and-obstetrics","isVorOnly":false,"title":"Archives of Gynecology and Obstetrics"},"publishedOn":"2024-07-18 16:13:14","publishedOnDateReadable":"July 18th, 2024"},"versionCreatedAt":"2024-02-07 21:45:41","video":"","vorDoi":"10.1007/s00404-024-07637-5","vorDoiUrl":"https://doi.org/10.1007/s00404-024-07637-5","workflowStages":[]},"version":"v1","identity":"rs-3882087","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3882087","identity":"rs-3882087","version":["v1"]},"buildId":"zQwnuV7TCBrMSSSToR1PI","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}