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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)