PCOS. pregnancy complications. Prof. Bart CJM Fauser. Dept. Reproductive Medicine and Gynecology. University Medical Center, Utrecht, The Netherlands

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1 PCOS pregnancy complications Prof. Bart CJM Fauser Dept. Reproductive Medicine and Gynecology University Medical Center, Utrecht, The Netherlands

2 Disclosure of interest, Fauser Professor of Reproductive Medicine Chair, WHO steering committee infertility guidelines Board member Dutch Medical Research Counsel Chief Editor Reproductive Biomedicine Online COGI chair Executive boards international organisations Consultant various pharmaceutical companies Visiting professor at different international institutions

3 PCOS, a condition requiring live long attention Reproductive disorders Metabolic disease 15 yrs 60 yrs Future health child Future health women

4 PCOS, Cross generations Fertility intervention Periconception Intervention? Pregnancy Intervention? Childhood Intervention? PCOS Pregnancy Birth Childhood NATURE NURTURE Adult Health

5 Periconceptional medicine PCOS: Genetic predisposition Environmental factors 5

6 HR 2012 Cumulative pregnancy rates resulting in singleton live birth

7 Odds ratio 95% CI No Studies Gestational diabetes Pregnancy induced hypertension Hum Reprod Upd 2006 Sample size > Preeclampsia Birth weight (WMD) NICU admission Perinatal death

8 OR gestational diabetes in PCOS HRU 2006

9 pregnancy outcomes in PCOS - summary Outcome Metaanalysis1 === Boomsma, HRU 06 Metaanalysis2 === Kjerulff, AJOG 11 Population based cohort === Roos, BMJ 11 Gest. diabetes Pre-eclampsia Preterm birth

10 189 pregnant women with PCOS Factors in the model: Relatives with type 2 DM Fasting glucose Fasting insulin AD SHBG

11 Pregnancy complications in PCOS - especially in the hyperandrogenic fenotype 188 PCOS and controls

12 Neonatal complications in PCOS children - especially in the hyperandrogenic fenotype

13 2016 Uncomplicated PCOS/Uncomplicated PCOS/GDM PCOS/pre-eclampsia F&S 2016

14 JCEM 2009

15 PCOS children (3-4 years) PCOS children Reference group Adjusted mean difference P value adjusted Anthropometry (n= 42) (n=168) (95% CI) age Blood pressure Systolic blood pressure (mmhg) 93.4 ± ± (-3.0 to 2.6) 0.89 Diastolic blood pressure (mmhg) 47.7 ± ± (-5.2 to -0.7) 0.01 Mean arterial pressure (mmhg) 62.9 ± ± (-4.3 to 0.1) 0.06 Pulse pressure (mmhg) 45.7 ± ± (0.5 to 5.0) 0.02 Arterial stiffness Pulse wave velocity aorta (m/s) 5.8 ± ± (-0.2 to 0.5) 0.49 Pulse pressure aorta (mmhg) 38.0 ± ± (-0.2 to 3.9) 0.08 Systolic blood pressure on aorta (mmhg) 85.2 ± ± (-5.3 to 1.2) 0.21 Echocardiography Left ventricle internal diameter end-diastolic (mm) (PLAX) 33.7 ± ± (0.4 to 2.5) 0.01 Z-score left ventricle internal diameter end-diastolic * a 0.4 ± ± (0.2 to 0.9) Left ventricle internal diameter end-systolic (mm) (PLAX) 22.3 ± ± (0.2 to 1.9) 0.02 Tissue doppler imaging septum systole (cm/s) 6.5 ± ± (-0.7 to -0.1) 0.01 De Wilde, Submitted

16 PCOS children (6-8 years) PCOS group Reference group Adjusted mean difference *a Anthropometry (n=32) (n=130) (95% CI) P value adjusted for age & weight Endocrinology Glucose (mmol/l) 4.7 ± ± (-0.1 to 0.4) 0.07 Insulin (miu/l) 4.4 ± ± (-2.2 to 0.8) 0.34 Cholesterol (mmol/l) 4.9 ± ± (0.3 to 1.2) Triglycerides (mmol/l) 0.7 ± ± (0.1 to 0.3) HDL-cholesterol (mmol/l) 1.5 ± ± (-0.1 to 0.2) 0.39 LDL-cholesterol (mmol/l) 3.1 ± ± (0.1 to 0.9) 0.02 CRP (mg/l) 1.6 ± ± (-3.1 to 0.8) 0.25 Carotid IMT Carotid int media thickness (µm) ± ± (6.4 to 43.0) 0.01 De Wilde, Submitted

17 Summary of Case control studies; Children of women with PCOS Design Country, no childr PCOS diagnosis Offsprin g (n) Offspring age Outcomes studied Results Kent 2008 Recabarren 2008 Infants Recabarren 2008 Childhood Sir-Petermann 2007 Prepuberty Sir-Petermann 2007 Puberty Sir-Petermann 2009 Tanner I Sir-Petermann 2009 Tanner II Sir-Petermann 2009 Tanner III Sir-Petermann 2009 Tanner IV Sir-Petermann 2009 Tanner V Legro, 2017 Case Control USA NIH 1990 :7 :10 P=17, : 11 C=16 : ± ± ± ±1.3 BMI, fasting glucose, insulin, lipids, gonadotropins, sex steroids CC Chile NIH 1990 : ( ) BMI, fasting : ( ) P=80, C=56 : ( ) : ( ) Glucose, insulin, HOMA-IR, riglycerides,ldl SHBG, adiponectin, leptin, CRP CC Chile NIH 1990 : ( ) BMI, fasting : ( ) P=75, C=49 : (101-6) : (10-17) glucose, insulin, lipids gonadotropins, sex steroids, SHBG, adiponectin CC Chile NIH 1990 : ±0.9 BMI, fasting : ±1.2 CC matched P=99, C=84 USA P=76 C=80 NIH 1990 : ±1.0 : ±0.7 : ±1.5 : ±1.0 : ±1.5 : ±1.4 : ±1.7 : ±1.1 only 4-17 yrs glucose, insulin, lipids, gonadotropins, sex steroids, SHBG Gonad and sex steroids, in urine Salivary insulin No Hyperinsulinemia in PCOS children until the later. Other reproductive abnormalities may also develop later. Sons of PCOS women exhibit higher body weight from early infancy. Insulin resistance became evident as they got older, risk factor for later onset of type 2 diabetes and cardiovascular disease. Some metabolic features of PCOS present in daughters with PCOS. Adiponectin might be an early marker. PCOS daughters have hyperinsulinemia and an increased ovarian volume before the onset of puberty and persist during pubertal development. Biochemical abnormalities of PCOS appear during late puberty. No difference

18 Compromised children outcomes

19 2012 Pregnancy Conclusions (agreement) Women with PCOS may be at increased risk for adverse pregnancy outcomes, this may be exacerbated by obesity and/or IR Health should be optimized before conception (lifestyle, diet, smoking, etc) Miscarriage rates are not increased in PCOS Pregnancy should be observed closely (GDM, hypertension) Pregnancy associated risk are greater in PCOS diagnosed by NIH criteria Babies born may have increased morbidity and mortality No evidence for decreased pregnancy complications with use of metformin before conception/during pregnancy Level of evidence B B A B B B A

20 2012 Pregnancy - Knowledge gaps Any value of periconceptional diets? Should there be increased antenatal monitoring, including earlier screening for GDM, additional Doppler studies? Long-term outcome of children born from PCOS? Long-term outcome women with PCOS who develop GDM or gestational hypertension compared to women who do not conceive

21 Take Home Messages Personal considerations PCOS is heterogeneous by definition Overall infertility prognosis in PCOS is very good Compromised pregnancy / children outcomes Influence nature vs nurture on child health uncertain Need intervention studies with proper follow-up / end-points

22 Reproductive Research Group PhD students, and collaborators Rotterdam ( ) Pache, Schoot, vsantbrink, Schipper, Imani, de Jong, vheusden Eijkemans, Mulders, Hohmann, Heijnen, Baart, de Klerk, vdgaast Blok, Laven, Macklon Utrecht (2004-) Verberg, Knauff, vdisseldorp Janse, Voorhuis, Kasius, Verhulst, Broer, Hamdin, Sterrenburg, de Wilde, Daan Broekmans, Heijnen, Eijkemans Main international collaborations; Devroey (Brussels), Bouchard (Paris), Tarlatzis (Greece), Hsueh (stanford)