DOI: 10.1111/1471-0528.12558

Fertility and assisted reproduction

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Increased risk of preterm delivery and pre-eclampsia in women with polycystic ovary syndrome and hyperandrogenaemia KV Naver,a J Grinsted,b SO Larsen,c PL Hedley,c,d FS Jørgensen,a M Christiansen,c L Nilasa a

Department of Obstetrics and Gynaecology, Hvidovre University Hospital, University of Copenhagen, Hvidovre, Denmark b The Fertility Clinic Trianglen, Hellerup, Denmark c Department of Clinical Biochemistry, Immunology, and Genetics, Statens Serum Institut, Copenhagen, Denmark d Department of Biomedicine, University of Stellenbosch, Cape Town, South Africa Correspondence: Dr KV Naver, Department of Obstetrics and Gynaecology, Hvidovre University Hospital, University of Copenhagen, Kettega˚rd alle 30, DK–2650, Hvidovre, Denmark. Email [email protected] Accepted 18 October 2013. Published Online 13 January 2014.

Objective To study the risk of adverse pregnancy outcomes in

women with polycystic ovary syndrome (PCOS), and to examine the role of hyperandrogenaemia. Design Cohort study. Setting Singleton pregnancies in women with PCOS identified at

a private fertility clinic during 1997–2010 and a background population including all singleton deliveries at Hvidovre Hospital, Denmark, in 2005. Population A cohort of 459 women with PCOS and a background

population of 5409 women. Methods Obstetric outcomes were extracted from national Danish registries and odds ratios (ORs) were calculated by multiple logistic regression analysis, adjusting for age, parity, and body mass index. Main outcome measures Risk of pre-eclampsia, preterm delivery,

and small for gestational age offspring in the entire PCOS population and in a subsample with hyperandrogenaemia.

Results Women with PCOS had an increased risk of preterm delivery 35 days and 6 months without bleeding). If only ‘oligomenorrhoea’ or ‘amenorrhoea’ was noted by the doted, this was accepted. The ovaries were classified as polycystic or normal, as described by the gynaecologist. The method of conception was registered as natural conception, intrauterine insemination homologue, or donor [including: ovulation induction (IUI); in vitro fertilization (IVF); frozen embryo replacement (FER); or intracytoplasmic sperm injection (ICSI)]. A transvaginal ultrasound examination was performed in the first trimester confirming the gestational age and expected date of delivery. The first singleton pregnancy with available information from patient files on mode of fertilisation was chosen as the index pregnancy. In the case of a multiple pregnancy we selected the singleton pregnancy prior to the multiple pregnancy (first choice) or the singleton pregnancy following the multiple pregnancies, if available.

The background population was represented by a birth cohort including all singleton deliveries from the year 2005 at the Copenhagen University Hospital Hvidovre, the largest obstetrical department in Denmark. The public hospital is located in an urban area 13 km from the fertility clinic, and treats women of both high and low education and income status. The year 2005 was chosen as first-trimester screening was introduced in Denmark in 2004 with a high rate of attendance. As a consequence, gestational age and estimated date of delivery was estimated from crown–rump length (CRL) measurements at a first-trimester transvaginal or transabdominal ultrasound. Information on baseline characteristics and obstetric outcome were identical, with reference to the tenth edition of the International Classification of Diseases (ICD10) codes, to the data retrieved regarding the PCOS population. Eight women were excluded from the background population as they were patients at the fertility clinic Trianglen and already part of the PCOS population. All data available were prospectively collected. Information on PCOS diagnosis, fertility treatment, or androgen measurements were not available in the total background population. The background population consisted of 5409 women with a singleton delivery after 22 weeks of gestation. BMI was available for 96% (n = 5207).

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Measurements of androgens During the study period all measurements of androgens were performed at the Statens Serum Institut (SSI), Copenhagen, Denmark. Using the unique Danish personal identification number of each woman, all androgen measurements in the PCOS population taken at the time of diagnosis or treatment were retrieved from the files at SSI. These measurements included total testosterone and sex

ª 2014 Royal College of Obstetricians and Gynaecologists

Preterm delivery and pre-eclampsia in women with PCOS

hormone-binding globulin (SHBG), and were used in the determination of free testosterone. Testosterone was measured by radioimmunoassay (RIA) after ether extraction followed by celite chromatography. The intra- and inter-assay variations were 8.2 and 13.8%, respectively. The detection limit was 0.05 nmol/l. SHBG was analysed by a double-monoclonal immunofluorometric assay (AutoDelfia; Wallac, Oy, Turku, Finland). Intra- and inter-assay variations were 5.2 and 7.5%, respectively. Free testosterone was estimated as described previously,5 based on the measured concentrations of SHBG, total testosterone and dihydrotestosterone, and the use of the law of mass action, using the binding constant of testosterone and dihydrotestosterone to SHBG, and including a calculation of testosterone binding to albumin.6 The normal range for plasma total testosterone levels was 0.55–1.8 nmol/l, and the range for plasma free testosterone levels in premenopausal women was 0.006–0.034 nmol/l. SHBG values exceeding the upper normal level of 170 nmol/l were excluded from statistical analysis. A woman with PCOS was considered hyperandrogenaemic if total testosterone was above 1.8 nmol/l, and/or free testosterone was above 0.034 nmol/l. In cases with several measurements of androgens, we chose the androgens measured at the date closest to the index pregnancy.

Obstetric outcome Information on all births was retrieved from the Danish Medical Birth Register and the Danish National Patient Register.7,8 The Danish Medical Birth Register includes information on all live-born children and stillbirths after 22 weeks of gestation in Denmark using ICD10 codes. Information on maternal age, parity, maternal BMI (from 2004 and onwards), birthweight, gender, gestational age, birth length, pre-eclampsia, hypertension during pregnancy, caesarean section, induction of labour, and neonatal death was extracted from the Danish Medical Birth Register, and the diagnosis of gestational diabetes was extracted from the Danish National Patient Register. Pre-eclampsia was diagnosed if proteinuria (>3 g during 24 hours or ≥+1 on a sterile dipstick) and a blood pressure above 140/90 mmHg were present. According to national guidelines gestational diabetes was defined as plasma glucose levels > 10.0 mmol/ l or more after a 2–hour oral glucose tolerance test (with 75 g of glucose). Data from the patient files and the Danish Medical Birth Register were linked using the unique personal identification number. The diagnosis of PCOS is not registered in the Danish Medical Birth Register, and is rarely available in obstetrical patient files. Our primary end points were pre-eclampsia, preterm delivery prior to 37 weeks of gestation, and small for gestational age offspring (z–score < 78%).9

ª 2014 Royal College of Obstetricians and Gynaecologists

Statistics Offspring size at birth was expressed as a z–score: the deviation of the observed fetal weight from the estimated birthweight adjusted for sex and gestational age, and expressed as a percentage.9 An offspring size at birth of 122% corresponds to a large for gestational age offspring (LGA). Continuous data were summarised as means  SDs or medians (interquartile ranges), and compared using a two-sided Student’s t–test. Categorical variables were summarised as counts and compared using the chi-square test (Table 2). Skewed data were log transformed and tested for normality. Multiple logistic regression analysis was used to identify variables with a significant impact on the risk of adverse pregnancy outcome in the background population and PCOS population. P < 0.05 was considered to be statistically significant. We used SAS 9.2 (SAS Institute Inc., Cary, NC, USA) and S–PLUS 2000 (MathSoft, Inc., Seattle, WA, USA) for the analyses.

Results The women with PCOS were slightly older (31.6 versus 30.7 years, P < 0.001), were more likely to be nulliparous (72.4 versus 57.1%, P < 0.001), and had a lower mean BMI (22.9 versus 23.4, P = 0.008) compared with the background population. In the PCOS population 19.2% of the women (n = 54) had a BMI ≥ 25 kg/m2, versus 24.9% (n = 1297) in the background population.

Obstetric outcome Women with PCOS had a shorter gestation (P = 0.04) and an increased risk of preterm delivery before 37 weeks of gestation (P = 0.0002), but not of very early delivery ( 30 kg/m2 Nulliparity Age > 39 years PCOS diagnosis

PCOS and background population Odds ratio adjusted*

95% CI

P

1.14 1.31 2.35 2.28 1.77 3.18 2.02 1.69

0.73–1.77 1.01–1.70 1.27–4.36 1.51–3.45 1.11–2.84 2.18–4.62 0.86–4.73 0.99–2.88

0.559 0.040** 0.007** 39 years PCOS diagnosis BMI > 30 kg/m2 Nulliparity Age > 39 years PCOS diagnosis

PCOS with hyperandrogenaemia, compared with a background population

PCOS without hyperandrogenaemia, compared with a background population

OR adj*

95% CI

P

OR adj*

95% CI

P

1.04 1.32 2.25 2.78 1.66 3.20 2.07 2.41

0.66–1.64 1.01–1.72 1.18–4.27 1.62–4.77 1.02–2.69 2.18–4.68 0.88–4.86 1.26–4.58

0.875 0.039** 0.013**

Increased risk of preterm delivery and pre-eclampsia in women with polycystic ovary syndrome and hyperandrogenaemia.

To study the risk of adverse pregnancy outcomes in women with polycystic ovary syndrome (PCOS), and to examine the role of hyperandrogenaemia...
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