PCOS pregnancy complications

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

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

PCOS, a condition requiring live long attention

Metabolic disease

Reproductive disorders

15 yrs 60 yrs

Future health women Future

health child

PCOS, Cross generations

PCOS

Pregnancy

Birth

Childhood

Adult Health

Fertility intervention

NATURE

NURTURE

Periconception Intervention?

Pregnancy Intervention?

Childhood Intervention?

5

Periconceptional medicine

PCOS: Genetic predisposition Environmental factors

HR 2012

Cumulative pregnancy rates resulting in singleton live birth

Odds ratio

95% CI No Studies

Sample size

Gestational diabetes 2.9 1.7 - 5.1 13 > 5.000

Pregnancy induced hypertension

3.7 2.0 - 6.8 8 1.341

Pre-eclampsia 3.5 2.0 - 6.2 8 2.289

Birth weight (WMD) 38 14 - 62 11 4.646

NICU admission 2.3 1.3 - 4.3 4 888

Perinatal death 3.1 1.0 - 9.2 5 1.579

Hum Reprod Upd 2006

HRU 2006

OR gestational diabetes in PCOS

pregnancy outcomes in PCOS - summary

Outcome

Meta-analysis1 === Boomsma, HRU’06

Meta-analysis2 === Kjerulff, AJOG’11

Population based cohort === Roos, BMJ ’11

Gest. diabetes 2.9 2.8 2.3

Pre-eclampsia 3.5 4.2 1.5

Preterm birth 1.8 2.2 2.2

Factors in the model: Relatives with type 2 DM Fasting glucose Fasting insulin AD SHBG

189 pregnant women with PCOS

Pregnancy complications in PCOS - especially in the hyperandrogenic fenotype

188 PCOS and 2.889 controls

Neonatal complications in PCOS children - especially in the hyperandrogenic fenotype

Uncomplicated

PCOS/pre-eclampsia PCOS/GDM

PCOS/Uncomplicated

2016

F&S 2016

JCEM 2009

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 ± 6.7 94.2 ± 6.7 -0.2 (-3.0 to 2.6) 0.89 Diastolic blood pressure (mmHg) 47.7 ± 5.6 50.4 ± 5.4 -2.9 (-5.2 to -0.7) 0.01 Mean arterial pressure (mmHg) 62.9 ± 5.3 65.0 ± 5.3 -2.1 (-4.3 to 0.1) 0.06 Pulse pressure (mmHg) 45.7 ± 5.6 43.8 ± 5.5 2.7 (0.5 to 5.0) 0.02

Arterial stiffness

Pulse wave velocity aorta (m/s) 5.8 ± 0.84 5.6 ± 0.7 0.1 (-0.2 to 0.5) 0.49 Pulse pressure aorta (mmHg) 38.0 ± 4.0 36.3 ± 4.3 1.9 (-0.2 to 3.9) 0.08 Systolic blood pressure on aorta (mmHg) 85.2 ± 6.2 86.7 ± 6.8 -2.1 (-5.3 to 1.2) 0.21

Echocardiography

Left ventricle internal diameter end-diastolic (mm) (PLAX) 33.7 ± 2.6 33.0 ± 2.9 1.5 (0.4 to 2.5) 0.01

Z-score left ventricle internal diameter end-diastolic*a 0.4 ± 0.8 -0.05 ± 0.9 0.5 (0.2 to 0.9) 0.002 Left ventricle internal diameter end-systolic (mm) (PLAX) 22.3 ± 2.2 21.7 ± 2.2 1.0 (0.2 to 1.9) 0.02

Tissue doppler imaging septum systole (cm/s) 6.5 ± 0.5 6.9 ± 0.8 -0.4 (-0.7 to -0.1) 0.01

De Wilde, Submitted

PCOS children (6-8 years)

PCOS group Reference

group Adjusted mean

difference *a P value adjusted for

age & weight Anthropometry (n=32) (n=130) (95% CI)

Endocrinology

Glucose (mmol/L) 4.7 ± 0.4 4.6 ± 0.3 0.2 (-0.1 to 0.4) 0.07 Insulin (mIU/L) 4.4 ± 1.9 5.6 ± 2.5 -0.7 (-2.2 to 0.8) 0.34 Cholesterol (mmol/L) 4.9 ± 1.3 4.4 ± 0.7 0.7 (0.3 to 1.2) 0.002 Triglycerides (mmol/L) 0.7 ± 0.2 0.5 ± 0.2 0.2 (0.1 to 0.3) 0.001 HDL-cholesterol (mmol/L) 1.5 ± 0.3 1.4 ± 0.2 0.1 (-0.1 to 0.2) 0.39 LDL-cholesterol (mmol/L) 3.1 ± 1.3 2.8 ± 0.6 0.5 (0.1 to 0.9) 0.02 CRP (mg/L) 1.6 ± 4.0 2.5 ± 3.1 -1.2 (-3.1 to 0.8) 0.25

Carotid IMT

Carotid int media thickness (µm) 413.5 ± 41.6 382.4± 36.8 24.7 (6.4 to 43.0) 0.01

De Wilde, Submitted

Summary of Case control studies; Children of women with PCOS

Design

Country, no childr

PCOS

diagnosis

Offspring (n) Offspring age Outcomes

studied Results

Kent 2008

Case Control

USA

NIH 1990 ♀:7 ♂:10

11.6 ±2.5 11.1 ±2.1

BMI, fasting glucose, insulin, lipids, gonadotropins, sex steroids

No Hyperinsulinemia in PCOS children until the later. Other reproductive abnormalities may also develop later.

P=17, C=16

♀: 11 ♂: 6

11.1 ±2.5 12.0 ±1.3

Recabarren 2008 Infants

CC

Chile

NIH 1990

♂: 20 2.0 (2.0–3.0) BMI, fasting Glucose, insulin, HOMA-IR, riglycerides,LDL SHBG, adiponectin, leptin, CRP

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.

♂: 20 2.0 (2.0 –3.0)

Recabarren 2008 Childhood

P=80, C=56

♂: 31 6.0 (4.0–7.5) ♂: 17 5.1 (4.0–7.0)

Sir-Petermann 2007 Prepuberty

CC Chile

NIH 1990 ♀: 53 6.0 (4.0-9.0) BMI, fasting glucose, insulin, lipids gonadotropins, sex steroids, SHBG, adiponectin

Some metabolic features of PCOS present in daughters with PCOS. Adiponectin might be an early marker.

♀: 32 6.0 (4.0-9.0)

Sir-Petermann 2007 Puberty

P=75, C=49

♀: 22 12.5 (101-6) ♀: 17 12.4 (10-17)

Sir-Petermann 2009 Tanner I

CC Chile NIH 1990

♀: 30 8.2 ±0.9 BMI, fasting glucose, insulin, lipids, gonadotropins, sex steroids, SHBG

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.

♀: 20 8.5 ±1.2

Sir-Petermann 2009 Tanner II

♀: 13 9.6 ±1.0 ♀: 15 9.7 ±0.7

Sir-Petermann 2009 Tanner III

♀: 21 10.8 ±1.5 P=99, C=84

♀: 19 10.7 ±1.0

Sir-Petermann 2009 Tanner IV

♀: 20 12.1 ±1.5 ♀: 16 12.0 ±1.4

Sir-Petermann 2009 Tanner V

♀: 15 13.1 ±1.7 ♀: 14 13.2 ±1.1

Legro, 2017 CC matched

USA P=76 C=80

NIH 1990 ♀ only 4-17 yrs

Gonad and sex steroids, in urine Salivary insulin

No difference

Compromised children outcomes

Pregnancy Conclusions (agreement) Level of evidence

Women with PCOS may be at increased risk for adverse pregnancy outcomes, this may be exacerbated by obesity and/or IR

B

Health should be optimized before conception (lifestyle, diet, smoking, etc)

B

Miscarriage rates are not increased in PCOS A

Pregnancy should be observed closely (GDM, hypertension)

B

Pregnancy associated risk are greater in PCOS diagnosed by NIH criteria B

Babies born may have increased morbidity and mortality B No evidence for decreased pregnancy complications with use of metformin before conception/during pregnancy A

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

2012

Take Home Messages

Personal considerations

1 PCOS is heterogeneous by definition

2 Overall infertility prognosis in PCOS is very good

3 Compromised pregnancy / children outcomes

4 Influence nature vs nurture on child health uncertain

5 Need intervention studies with proper follow-up / end-points

Reproductive Research Group PhD students, and collaborators

Rotterdam (1998-2003) 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)