Human Reproduction Update Advance Access originally published online on August 4, 2006
Human Reproduction Update 2006 12(6):673-683; doi:10.1093/humupd/dml036
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A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome
1 Department of Reproductive Medicine and Gynaecology, University Medical Center Utrecht, Utrecht, 2 Department of Public Health, Erasmus MC, University Medical Center, Rotterdam, The Netherlands, 3 Department of Obstetrics and Gynaecology, McMaster University, Hamilton, Ontario, Canada, 4 Department of Obstetrics, 5 Department of Reproductive Medicine and Gynaecology, University Medical Center Utrecht and 6 Department of Reproductive Medicine and Gynaecology, University Medical Center Utrecht, Utrecht, The Netherlands
7 To whom correspondence should be addressed at: Department of Reproductive Medicine and Gynaecology, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands. E-mail: c.m.boomsma{at}umcutrecht.nl.
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Abstract |
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Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with many characteristic features, including hyperandrogenaemia, insulin resistance and obesity which may have significant implications for pregnancy outcomes and long-term health of the woman. This meta-analysis was conducted to evaluate the risk of pregnancy and neonatal complications in women with PCOS. Electronic databases were searched for the following MeSH headings: PCOS, hyperandrogenism, pregnancy outcome, pregnancy complications, diabetes mellitus, type II. A handsearch of human reproduction and fertility and sterility was also conducted. Studies in which pregnancy outcomes in women with PCOS were compared with controls were considered for inclusion in this meta-analysis. Fifteen of 525 identified studies were included, involving 720 women presenting with PCOS and 4505 controls. Women with PCOS demonstrated a significantly higher risk of developing gestational diabetes [odds ratio (OR) 2.94; 95% confidence interval (CI): 1.70–5.08], pregnancy-induced hypertension (OR 3.67; 95% CI: 1.98–6.81), pre-eclampsia (OR 3.47; 95% CI: 1.95–6.17) and preterm birth (OR 1.75; 95% CI: 1.16–2.62). Their babies had a significantly higher risk of admission to a neonatal intensive care unit (OR 2.31; 95% CI: 1.25–4.26) and a higher perinatal mortality (OR 3.07; 95% CI: 1.03–9.21), unrelated to multiple births. In conclusion, women with PCOS are at increased risk of pregnancy and neonatal complications. Pre-pregnancy, antenatal and intrapartum care should be aimed at reducing these risks.
Key words: meta-analysis / neonatal outcome / PCOS / pregnancy outcome
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Introduction |
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Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age (Franks, 2001
). The estimated prevalence of this disease is 
5–10%, as reported in population-based studies (Archer and Chang, 2004). Over 70% of women suffering from normogonadotrophic anovulation (World Health Organisation type II anovulation) present with ultrasound or endocrine features associated with PCOS (Laven et al., 2002). PCOS is characterized by a combination of oligo/amenorrhoea, clinical or endocrine signs of hyperandrogenaemia and polycystic ovaries (The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group, 2004a). Approximately 50% of women with PCOS are overweight or obese (Norman et al., 2004). PCOS coincides with the metabolic syndrome, characterized by resistance to the action of insulin, dyslipidemia and hypertension, which is associated with increased chances for cardiovascular disease later in life (Wild, 2002). By the age of 40 years, up to 40% of all women with PCOS will have developed type II diabetes or impaired glucose tolerance (in the United States) (Dunaif, 1995). Thus, PCOS represents a major health issue affecting young women today. The current epidemic of obesity in young adults (Haslam and James, 2005) suggests that the prevalence of PCOS may even rise further in the future.
There is an increasing body of evidence suggesting a negative effect of PCOS on pregnancy outcome. Normal pregnancy induces a state of insulin resistance which may become manifest as impaired glucose tolerance or gestational diabetes (Sivan and Boden, 2003). Because women with PCOS have an incidence of insulin resistance of 25–70%, they would appear to be at increased risk of developing gestational diabetic complications (Legro et al., 2004). Moreover, the ‘Barker hypothesis’ of fetal programming in utero suggests that the fetal nutrition and endocrine environment (e.g. hyperinsulinaemia) may effect neuroendocrine systems regulating body weight, food intake and metabolism, with consequences for long-term health in the offspring (Barker, 2002).
While there have been several reports indicating that PCOS pregnancies may be at increased risk of diabetic, hypertensive and other complications, results of these small studies have been often inconsistent.
To conceive, many women with PCOS require ovulation induction or IVF and are at increased risk of multiple pregnancy (Balen et al., 1994; Eijkemans et al., 2003; Fauser et al., 2005). However, it is uncertain to what extent the medical condition itself influences pregnancy and neonatal outcomes. A recent meta-analysis of early pregnancy outcomes after IVF in women with PCOS showed no significant difference in the live birth, pregnancy or miscarriage rate versus controls (Heijnen et al., 2006). To evaluate the risks for late pregnancy and neonatal outcomes in women with PCOS versus controls, we have performed a systematic review and meta-analysis of the best available trials.
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Materials and methods |
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Criteria for considering studies for this review
All published studies in which pregnancy outcomes in women with PCOS were compared with non-PCOS controls were considered for inclusion in this meta-analysis. To be included, the criteria given for the diagnosis of PCOS had to be consistent with those of the recent Rotterdam consensus (The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group, 2004b) (two of three of the following criteria: oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism and polycystic ovaries visible with ultrasound). Controls were required to be women without PCOS. Studies in which control patients were matched for most important prognostic indicators such as age, BMI and parity were designated as ‘higher validity’.
Search strategy for the identification of studies
The following electronic databases were searched: MEDLINE (1966 to October 2005), EMBASE (1974 to October 2005), Science Direct (1966 to October 2005), Cochrane Central Register of Controlled Trials (CENTRAL) and Cumulated Index to Nursing and Allied Health Literature (CINAHL; 1982 to October 2005). A search strategy was carried out based on the following terms in MEDLINE: [‘Polycystic Ovary Syndrome’ (MeSH) OR Hyperandrogenism (MeSH)] AND [‘Pregnancy Outcome’ (MeSH) OR ‘Pregnancy Complications’ (MeSH) OR ‘Diabetes Mellitus, Type 2’ (MeSH) OR PIH OR pre-eclampsia OR GDM OR fetal outcome OR neonatal outcome]. In addition, a handsearch of Human Reproduction (1991–2005) and Fertility and Sterility (1991–2005) was conducted, including a handsearch of the abstracts from the annual meetings of the American Society for Reproductive Medicine and the European Society for Human Reproduction and Embryology. The reference lists of included studies were also handsearched. When necessary, additional information was sought from the authors. The search was not restricted by language.
The MeSH headings strategy yielded 525 publications. One additional publication was identified after a handsearch of Human Reproduction and Fertility and Sterility, and three additional publications were identified after searching the reference lists of relevant publications. Two hundred and forty-five publications were excluded because it was clear from the title that they did not fulfil the selection criteria. Five of the 245 publications were read in full (C.B.) to check the validity of this selection procedure. From the remaining 284 articles, 245 were excluded on the basis of the abstract (C.B.). Thirty-nine articles were read in full by two reviewers (N.M. and C.B.). C.B. and N.M. independently selected the trials to be included in accordance with the described selection criteria. Full agreement on study selection occurred. Study characteristics, quality assessment and data extraction was performed by C.B. Two studies were excluded because they reported pregnancy outcomes of women with PCOS using metformin during pregnancy versus non-PCOS controls (Glueck et al., 2004a,b). One study (Sir-Petermann et al., 2002) was excluded because the data were included in a later publication (Sir-Petermann et al., 2005). Twenty-one articles were excluded because they did not fulfil the described selection criteria. Fifteen studies were finally included in the meta-analysis (Diamant et al., 1982; Levran et al., 1990; Wortsman et al., 1991; Cardenas et al., 1996; Urman et al., 1997; Fridstrom et al., 1999; Radon et al., 1999; Kashyap and Claman, 2000; Vollenhoven et al., 2000; Mikola et al., 2001; Bjercke et al., 2002; Haakova et al., 2003; Turhan et al., 2003; Weerakiet et al., 2004; Sir-Petermann et al., 2005).
The following information was extracted from relevant studies: study design, study characteristics, patient population characteristics (age, BMI, parity and history), constitution of the control group, definition of PCOS and method of conceiving. These characteristics are summarized in Table I. The end-points of interest were the incidence of gestational diabetes mellitus (definition differed, diagnosed with a 50–100 g oral glucose challenge test), pregnancy-induced hypertension (definition: BP 
140/90 mmHg without proteinuria at a gestational age of >20 weeks) or pre-eclampsia (definition differed: BP 140/90 mmHg with proteinuria >0.3 g/24h/2 + albustick at a gestational age of >20 weeks). In addition, the following end-points were assessed: the incidence of delivery by Caesarean section, instrumental vaginal delivery, length of gestation (weeks), premature delivery (<37 weeks), birthweight (g), macrosomia (definition differed: >90th percentile/>4000/4500 g), small for gestational age (SGA) (definition differed: <5/10th percentile/<2500 g), admission to a neonatal intensive care unit (NICU), neonatal malformations and perinatal mortality (Table II). Outcome measures were included if at least two studies reported a similar outcome characteristic.
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For dichotomous data, the results for each study are expressed as odds ratios (OR) with 95% confidence intervals (CI) and combined using the Peto method and a random effect model. Continuous data were combined using the weighted mean difference (WMD) with 95% CI and a random effects model. Where possible, the outcomes were pooled statistically. Because gestational diabetes, pre-eclampsia and pregnancy-induced hypertension are considered as negative consequences, a higher proportion was considered to be detrimental and increased odds signifies relative harm. Heterogeneity between the results of different studies was examined by inspecting the scatter in the data points on the graphs, the overlap in their CIs and by Chi-squared tests for significance (P < 0.1: significant statistical heterogeneity). To assess the extent of publication bias, we carried out funnel plots of the different outcome measures when more than seven studies addressing the given outcome were available.
To minimize the effect of confounding factors frequently associated with PCOS, such as BMI, we identified studies in which these factors did not differ between the PCOS and control populations. These were designated as higher validity studies. For gestational diabetes mellitus, higher validity studies were identified as those in which a similar BMI and age were reported among women with PCOS and their controls. We have not excluded studies with a difference in multiple pregnancy rate, as this has not been shown to be an independent predictor of gestational diabetes mellitus (Buhling et al., 2003). For pregnancy-induced hypertension, a similar parity, BMI and multiple pregnancy rate was required. For preterm delivery and gestational age, a similar incidence of multiple pregnancies was required, and when birthweight was the outcome assessed, higher validity studies were identified as those in which a similar BMI and a similar incidence of multiple pregnancies were reported. Some studies included in the meta-analysis incorporated more pregnancies than women (Table I), resulting in paired observations. These studies were excluded in subgroup analyses.
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Results |
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The fifteen studies included in the meta-analysis reported data on 720 women with PCOS (778 pregnancies) and 4505 controls (4562 pregnancies). The sample sizes varied from 22 to 80 women with PCOS and from 27 to 2306 controls. One study did not report the maternal age or BMI (Wortsman et al., 1991
). All other studies reported a similar age or matched their controls for age. Unless otherwise stated, no significant statistical heterogeneity was detected between the analysed studies. Women with PCOS demonstrated a significantly higher chance of developing gestational diabetes, OR 2.94 (95% CI: 1.70–5.08). However, significant heterogeneity between the studies was detected. A subgroup analysis of five higher validity studies showed an OR 3.66 (95% CI: 1.20–11.16) but significant statistical heterogeneity remained (P < 0.1) (Figure 1).
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Pregnancy-induced hypertension and pre-eclampsia
Women with PCOS demonstrated a significantly higher chance of developing pregnancy-induced hypertension, OR 3.67 (95% CI: 1.98–6.81). A subgroup analysis of two higher validity studies also revealed a significant increased risk, OR 3.71 (95% CI: 1.72–17.49) (Figure 2). Women with PCOS also demonstrated a significantly higher chance of developing pre-eclampsia, OR 3.47 (95% CI: 1.95–6.17) (Figure 3). All studies in which pre-eclampsia was an end-point reported a lower parity, higher BMI or more multiple pregnancies among women with PCOS versus controls. Therefore, no subgroup analysis on higher validity studies could be performed.
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Length of gestation and premature delivery rate
Women with PCOS demonstrated a significantly higher chance of delivering prematurely, OR 1.75 (95% CI: 1.16–2.62) (Figure 4). However, this difference is small, and when mean length of gestation was analysed, no significant difference was observed, WMD –0.13 weeks (95% CI: –0.43–0.18) (Cardenas et al., 1996; Fridstrom et al., 1999; Vollenhoven et al., 2000; Mikola et al., 2001; Haakova et al., 2003; Turhan et al., 2003; Weerakiet et al., 2004; Sir-Petermann et al., 2005).
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Although none of the studies included in this analysis reported an unequal incidence of multiple pregnancies in women with PCOS versus controls, significant statistical heterogeneity in the results between the studies was observed. Unfortunately, none of the studies stratified preterm delivery for cause (e.g. premature ruptures of membranes, cervical insufficiency) or spontaneous versus induced preterm delivery. Ideally, only spontaneous preterm deliveries would have been included.
Birthweight, macrosomia and SGA
Infants from women with PCOS demonstrated a significantly lower neonatal birthweight, WMD –38.4 g (95% CI: –62.2–14.6). However, when only higher validity studies were analysed, no significant difference was found, WMD 26.5 g (95% CI: –35.5–88.5) (Figure 5). PCOS babies also showed no significant increase in the incidence of macrosomia, OR 1.13 (95% CI: 0.73–1.75) (Cardenas et al., 1996; Urman et al., 1997; Vollenhoven et al., 2000; Mikola et al., 2001; Haakova et al., 2003; Turhan et al., 2003; Sir-Petermann et al., 2005). A finding confirmed in a subgroup analysis of higher validity studies, OR 1.08 (95% CI: 0.6–1.96) (Sir-Petermann et al., 2005; Vollenhoven et al., 2000; Haakova et al., 2003). No significant increase in the incidence of SGA neonates in women with PCOS was observed, OR 1.16 (95% CI: 0.31–5.12) (Urman et al., 1997; Vollenhoven et al., 2000; Haakova et al., 2003; Turhan et al., 2003; Sir-Petermann et al., 2005). However, significant statistical heterogeneity was evident (P < 0.1). A subgroup analysis of higher validity studies revealed similar results, OR 0.66 (95% CI: 0.05–7.91) (Vollenhoven et al., 2000; Haakova et al., 2003; Sir-Petermann et al., 2005).
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Admission to an NICU, neonatal malformations and perinatal mortality
Infants from women with PCOS demonstrated a significantly higher rate of admission to an NICU, OR 2.31 (95% CI: 1.25–4.26) (Figure 6). As would be expected because of the small numbers included, no significant difference in incidence of neonatal malformations was observed, OR 0.70 (95% CI: 0.11–4.39) (Urman et al., 1997; Turhan et al., 2003; Sir-Petermann et al., 2005).
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However, a significantly increased perinatal mortality was observed among women with PCOS versus controls, OR 3.07 (95% CI: 1.03–9.21) (Figure 7). A similar incidence of multiple pregnancies among women with PCOS and controls was reported.
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Caesarean section and instrumental vaginal delivery rate
Women with PCOS demonstrated a significantly higher chance of delivering by Caesarean section, OR 1.56 (95% CI: 1.20–2.02). However, when a subgroup analysis was confined to higher validity studies, no significant increased risk was observed, OR 0.92 (95% CI: 0.54–1.58) (Fridstrom et al., 1999; Vollenhoven et al., 2000; Haakova et al., 2003). In an analysis of three studies reporting the chance of delivering by vacuum or forceps (as a percentage of vaginal deliveries) of women with PCOS versus controls, no significant difference was observed, OR 1.37 (95% CI: 0.80–2.35) (Diamant et al., 1982; Vollenhoven et al., 2000; Bjercke et al., 2002).
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Discussion |
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This meta-analysis shows that women with PCOS are at an increased risk of developing serious complications during pregnancy, such as gestational diabetes, pregnancy-induced hypertension and pre-eclampsia. Their babies are also at greater risk of neonatal complications (Panel 1). The increased risk of developing gestational diabetes occurs independent of obesity, because it remained evident after excluding all studies in which a higher BMI among women with PCOS was reported. The higher risk of developing pregnancy-induced hypertension also remained after excluding all studies in which a higher BMI, multiple pregnancy rate and a lower parity among women with PCOS was reported. Women with PCOS also demonstrated an increased incidence of pre-eclampsia of an order similar to that associated with multiple pregnancies.
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Although women with PCOS demonstrated an increased risk of delivering by Caesarean section, this may be secondary to obesity, because women with PCOS with similar BMI to controls did not demonstrate an increased risk. The higher incidence of admission to an NICU and a higher incidence of perinatal mortality observed following PCOS pregnancy may reflect in part the higher incidence of prematurity, because reported reasons for admission to an NICU included hypoglycaemia, jaundice and respiratory distress syndrome. Reported causes for perinatal mortality included lethal malformations, cervical insufficiency, sepsis and placental abruption. The increased risk may partly be explained by the higher BMI among women with PCOS in most studies included in this particular outcome (Kristensen et al., 2005).
Multiple pregnancy is the most important cause of the increased perinatal morbidity observed following fertility treatments such as ovulation induction, ovarian stimulation and IVF (Fauser et al., 2005). In general, twin pregnancies are at 10-fold increased risk of delivering growth-retarded babies, and perinatal mortality rate is approximately six times higher and admission to an NICU is approximately three times higher when compared with singletons. This is largely because of a 6-fold increased risk of premature delivery (Campbell and Templeton, 2004; Rao et al., 2004). The higher incidence of multiple pregnancy in PCOS might therefore underlie the poorer observed outcomes. However, all the studies analysed showed no difference in multiple pregnancy rates between women with PCOS and controls. Comparison of outcomes from multiple pregnancy in PCOS with controls was not possible because of lack of stratification in the studies analysed.
Given the higher rate of gestational diabetes in women with PCOS, an increased incidence of macrosomia might be expected. However, in the present analysis, neonates from women with PCOS were shown to have significantly lower birthweights compared with controls, although the extent of this difference (mean 40 g) is likely to be of limited clinical significance. In PCOS pregnancies, the fetus is exposed to an increased glucose load, but placental insufficiency may mitigate against the manifestation of macrosomia. The association of PCOS and pre-eclampsia and pregnancy-induced hypertension indeed suggests an increase in placental insufficiency (especially in women delivered preterm). The combination of chronic hypoxia in the presence of increased glucose load confers considerable and sometimes lethal stress on the fetus.
When drawing conclusions from this meta-analysis, the completeness of the reporting of primary analysis findings and clinical heterogeneity between studies should be considered (Scholten et al., 1999). Caution is always required when examining outcomes on the basis of diagnosis rather than intervention, because only non-experimental studies (case control and cohort designs) can be used. These are vulnerable to both known and unknown confounding variables. In the present analysis, a higher multiple pregnancy rate, parity, age and BMI in women with PCOS were important potential confounders. These were addressed by performing subgroup analyses on higher validity studies in which known confounding variables were minimized. However, we were unable to control for possible differences in the incidence of other factors, such as smoking and concurrent medical disease. Funnel plot analysis revealed no indication of publication bias (data not shown). Furthermore, we need to consider the heterogeneity in the fertility treatment received by the women (outlined in Table I). Studies have shown higher rates of low birthweight among singleton infants conceived with IVF versus spontaneous conceptions (Schieve et al., 2002). De Sutter et al. (2005) and Nuojua-Huttunen et al. (1999) reported no increase in other obstetric or neonatal complications comparing pregnancies derived from intra uterine inseminations versus IVF. However, significant higher rates of pregnancy-induced hypertension, increased rates of Caesarean sections and admission to a neonatal care unit among women who conceived singleton pregnancies by IVF versus spontaneous means have been reported (Tanbo et al., 1995).
The possible confounding factors of coexistent obesity on outcomes in PCOS women were limited in our study by identifying studies in which the BMI did not differ between both study groups. However, to fully differentiate between the effects of PCOS and obesity on pregnancy outcomes, future studies should either carefully match for BMI or analyse whether BMI is an independent predictor of outcome, in an otherwise well-defined PCOS population.
Despite the limitations of this meta-analysis, we consider the findings to have important implications for the periconceptional and antenatal care of women with PCOS. Before conceiving, women with PCOS should be informed of the additional risks their pregnancies may carry and of appropriate steps taken to minimize these. Most important among these is the avoidance of multiple pregnancy and the role of lifestyle adjustment aimed at optimizing the BMI (Norman et al., 2004). Although prospective studies are required to demonstrate their value in PCOS, additional antenatal surveillance and interventions for the detection of pre-eclampsia and detection and early treatment of hypertension and gestational diabetes would appear warranted. Moreover, considering the increased risk of perinatal mortality and admission to an NICU, the fetus should be considered as being ‘at risk’. Therefore, the fetus should be appropriately monitored throughout pregnancy and labour.
There is an increasing awareness that PCOS is a condition associated with an increased morbidity and long-term health problems beyond infertility. This study shows that these risks also extend to pregnancy and neonatal outcomes.
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Acknowledgements |
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We are grateful to Dr S.Weerakiet (Mahidol University, Bangkok, Thailand), Dr T.Sir-Petermann (School of medicine, Santiago, Chile), Dr B.Vollenhoven (Monash University, Melbourne, Australia), Prof Dr E.Lunenfeld (Ben Gurion University of the Negev, Israel), Dr D.Cibula (General Faculty Hospital, Prague, Czech Republic), Dr D.Romualdi (Universita Cattolica del S., Rome) and Prof Dr N.Turhan (Fatih University Medical School, Ankara), who all provided additional information or data on their trials. We are also indebted to M.Kosterman (University Medical Center Utrecht), for her help in handsearching the journals. Dr C.M.B. made substantial contributions to the conception and design of the article, acquisition of data, analysis and interpretation of data, drafting the manuscript and the statistical analysis. Dr M.J.C.E. made substantial contributions to the analysis and interpretation of data, critical revision of the manuscript for important intellectual content and the statistical analysis. Prof E.G.H. and Prof G.H.A.V. made substantial contributions to the interpretation of data and critical revision of the manuscript for important intellectual content. Prof. B.C.J.M.F. made substantial contributions to the conception of the manuscript, made substantial contributions to the interpretation of data, critical revision of the manuscript for important intellectual content and gave his supervision. Prof N.S.M. made substantial contributions to the conception and design of the manuscript, made substantial contributions to the analysis and interpretation of data, drafting and critical revision of the manuscript for important intellectual content and gave administrative and technical support and supervision. The research was funded by the University Medical Center Utrecht, The Netherlands.
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References |
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