Polycystic Ovary Syndrome: Pathophysiology, Phenotype Expression and Clinical Implications

Annemarie Geerdina Maria Geertruida Johanna Mulders was born on the 29th of April 1972 in Waalwijk, The Netherlands. She passed secondary school at the Dr. Mollercollege in Waalwijk. She attended Medical School at the Erasmus University in Rotterdam from 1992 - 1999 from which she graduated cum laude. From December 1999 - August 2000 she worked as a resident at the department of Obstetrics and Gynaecology of the Sint Lucas Andreas Hospital (head: Dr. J.Th.M. van der Schoot) in Amsterdam. From August 2000 -December 2003 she worked as a PhD student at the division of Reproductive Medicine (head: Prof. Dr. B.C.J.M. Fauser) of the department of Obstetrics and Gynaecology of the Erasmus MC in Rotterdam performing the studies described in this thesis. In January 2004 she started her training in Obstetrics and Gynaecology at the Amphia Hospital in BredaPolycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive age women and a major cause of subfertility. Women with PCOS might present with a number of various features and hence PCOS does not seem to be a clear-cut clinical phenomenon. In order to elucidate the background and pathophysiology of all symptoms displayed in PCOS it might be helpful to focus on these specific characteristics and features. In this chapter pathophysiology of ovarian dysfunction is highlighted. Additionally, several characteristic PCOS features used for classification and involved in phenotypical heterogeneity, will be briefly described. Furthermore, the complexity of research regarding the genetic c

Polycystic Ovary Syndrome: Pathophysiology, Phenotype Expression and Clinical Implications

Annemarie Geerdina Maria Geertruida Johanna Mulders was born on the 29th of April 1972 in Waalwijk, The Netherlands. She passed secondary school at the Dr. Mollercollege in Waalwijk. She attended Medical School at the Erasmus University in Rotterdam from 1992 - 1999 from which she graduated cum laude. From December 1999 - August 2000 she worked as a resident at the department of Obstetrics and Gynaecology of the Sint Lucas Andreas Hospital (head: Dr. J.Th.M. van der Schoot) in Amsterdam. From August 2000 -December 2003 she worked as a PhD student at the division of Reproductive Medicine (head: Prof. Dr. B.C.J.M. Fauser) of the department of Obstetrics and Gynaecology of the Erasmus MC in Rotterdam performing the studies described in this thesis. In January 2004 she started her training in Obstetrics and Gynaecology at the Amphia Hospital in BredaPolycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive age women and a major cause of subfertility. Women with PCOS might present with a number of various features and hence PCOS does not seem to be a clear-cut clinical phenomenon. In order to elucidate the background and pathophysiology of all symptoms displayed in PCOS it might be helpful to focus on these specific characteristics and features. In this chapter pathophysiology of ovarian dysfunction is highlighted. Additionally, several characteristic PCOS features used for classification and involved in phenotypical heterogeneity, will be briefly described. Furthermore, the complexity of research regarding the genetic c

Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: a meta-analysis

A systematic review was conducted to determine whether initial screening characteristics of wo

High singleton live birth rate following classical ovulation induction in normogonadotrophic anovulatory infertility (WHO 2)

BACKGROUND: Medical induction of ovulation using clomiphene citrate (CC) as first line and exogenous gonadotrophins as second line forms the classical treatment algorithm in normogonadotrophic anovulatory infertility. Because the chances of success following classical ovulation induction are not well established, a shift in first-line therapy can be observed towards alternative treatment. The study aim was to: (i) reliably assess the probability of singleton live birth following classical induction of ovulation; and (ii) construct a prediction model, based on individual patient characteristics assessed upon standardized initial screening, to help identify patients with poor chances of success. METHODS: A total of 240 consecutive women visiting a specialist academic fertility unit with a history of infertility, oligomenorrhoea or amenorrhoea, and normal FSH and estradiol serum concentrations (WHO group 2) was prospectively followed. The women had not been previously treated with ovulation-inducing agents. All patients commenced with CC. Patients who did not ovulate within three treatment cycles of incremental daily doses up to 150 mg for 5 consecutive days or ovulatory CC patients who did not conceive within six cycles, subsequently underwent gonadotrophin induction of ovulation applying a step-down dose regimen. The main outcome measure was pregnancy resulting in singleton live birth. Cox regression was used to construct a multivariable prediction model. RESULTS: Overall, there were 134 pregnancies ending in a singleton live birth (56% of women). The cumulative pregnancy rate after 12 and 24 months of follow-up was 50% and 71% respectively. Polycystic ovary syndrome (PCOS) patients (49%), clearly non-PCOS patients (13%) and the in-between group did not differ in prognosis (P = 0.9). The multivariable Cox regression model contained the woman's age, the insulin:glucose ratio and duration of infertility. With a cut-off value of 30% for low chance, the model predicted probabilities at 12 months lower than this cut-off for 25 out of 240 patients (10.4%). CONCLUSIONS: Classical ovulation induction produces very good results in normogonadotrophic anovulatory infertility. Alternative treatment options may not be indicated as first-line therapy in these patients, except for subgroups with poor prognosis. These women can be identified by older age, longer duration of infertility and higher insulin:glucose ratio

Population screening for gestational hypertensive disorders using maternal, fetal and placental characteristics

Objective: To determine screening performance of maternal, fetal and placental characteristics for selecting pregnancies at risk of gestational hypertension and preeclampsia in a low-risk multi-ethnic population. Method: In a prospective population-based cohort among 7124 pregnant women, we collected maternal characteristics including body mass index, ethnicity, parity, smoking and blood pressure in early-pregnancy. Fetal characteristics included second and third trimester estimated fetal weight and sex determined by ultrasound. Placental characteristics included first and second trimester placental growth factor concentrations and second and third trimester uterine artery resistance indices. Results: Maternal characteristics provided the best screening result for gestational hypertension (area-under-the-curve [AUC] 0.79 [95% Confidence interval {CI} 0.76-0.81]) with 40% sensitivity at 90% specificity. For preeclampsia, the maternal characteristics model led to a screening performance of AUC 0.74 (95% CI 0.70-0.78) with 33% sensitivity at 90% specificity. Addition of second and third trimester placental ultrasound characteristics only improved screening performance for preeclampsia (AUC 0.78 [95% CI 0.75-0.82], with 48% sensitivity at 90% specificity). Conclusion: Routinely measured maternal characteristics, known at the start of pregnancy, can be used in screening for pregnancies at risk of gestational hypertension or preeclampsia within a low-risk multi-ethnic population. Addition of combined second and third trimester placental ultrasound characteristics only improved screening for preeclampsia

Second and third trimester fetal ultrasound population screening for risks of preterm birth and small-size and large-size for gestational age at birth: a population-based prospective cohort study

BACKGROUND: Preterm birth, small size for gestational age (SGA) and large size for gestational age (LGA) at birth are major risk factors for neonatal and long-term morbidity and mortality. It is unclear which periods of pregnancy are optimal for ultrasound screening to identify fetuses at risk of preterm birth, SGA or LGA at birth. We aimed to examine whether single or combined second and third trimes

First trimester anomaly scan using virtual reality (VR FETUS study): study protocol for a randomized clinical trial

BACKGROUND: In recent years it has become clear that fetal anomalies can already be detected at the end of the first trimester of pregnancy by two-dimensional (2D) ultrasound. This is why increasingly in developed countries the first trimester anomaly scan is being offered as part of standard care. We have developed a Virtual Reality (VR) approach to improve the diagnostic abilities of 2D ultrasound. Three-dimensional (3D) ultrasound datasets are used in VR assessment, enabling real depth perception and unique interaction. The aim of this study is to investigate whether first trimester 3D VR ultrasound is of additional value in terms of diagnostic accuracy for the detection of fetal anomalies. Health-related quality of life, cost-effectiveness and also the perspective of both patient and ultrasonographer on the 3D VR modality will be studied. METHODS: Women in the first trimester of a high risk pregnancy for a fetus with a congenital anomaly are eligible for inclusion. This is a randomized controlled trial with two intervention arms. The control group receives 'care as usual': a second trimester 2D advanced ultrasound examination. The intervention group will undergo an additional first trimester 2D and 3D VR ultrasound examination. Following each examination participants will fill in validated questionnaires evaluating their quality of life and healthcare related expenses. Participants' and ultrasonographers' perspectives on the 3D VR ultrasound will be surveyed. The primary outcom

Associations of maternal age at the start of pregnancy with placental function throughout pregnancy: The Generation R Study

Objective: To examine the associations of maternal age at the start of pregnancy across the full range with second and third trimester uterine and umbilical artery flow indices, and placental weight. Study design: In a population-based prospective cohort study among 8271 pregnant women, we measured second and third trimester uterine artery resistance and umbilical artery pulsatility indices and the presence of third trimester uterine artery notching using Doppler ultrasound. Results: Compared to women aged 25−29.9 years, higher maternal age was associated with a higher third trimester uterine artery resistance index (difference for women 30−34.9 years was 0.10 SD (95% Confidence Interval (CI) 0.02 to 0.17), and for women aged ≥40 years 0.33 SD (95% CI 0.08 to 0.57), overall linear trend 0.02 SD (95% CI 0.01 to 0.03) per year). Compared to women aged 25−29.9 years, women younger than 20 years had an increased risk of third trimester uterine artery notching (Odds Ratio (OR) 1.97 (95% CI 1.30–3.00)). A linear trend was present with a decrease in risk of third trimester uterine artery notching per year increase in maternal age (OR 0.96 (95% CI 0.94 to 0.98)). Maternal age was not consistently associated with umbilical artery pulsatility indices or placental weight. Conclusions: Young maternal age is associated with higher risk of third trimester uterine artery notching, whereas advanced maternal age is associated with a higher third trimester uterine artery resistance index, which may predispose to an increased risk of pregnancy complications

Customized versus population birth weight charts for identification of newborns at risk of long-term adverse cardio-metabolic and respiratory outcomes: A population-based prospective cohort study

Background: Customized birth weight charts take into account physiological maternal characteristics that are known to influence fetal growth to differentiate between physiological and pathological abnormal size at birth. It is unknown whether customized birth weight charts better identify newborns at risk of long-term adverse outcomes than population birth weight charts. We aimed to examine whether birth weight classification according to customized charts is superior to population charts at identification of newborns at risk of adverse cardio-metabolic and respiratory health outcomes. Methods: In a population-based prospective cohort study among 6052 pregnant women and their children, we measured infant catch-up growth, overweight, high blood pressure, hyperlipidemia, liver steatosis, clustering of cardio-metabolic risk factors, and asthma at age 10. Small size and large size for gestational age at birth was defined as birth weight in the lowest or highest decile, respectively, of population or customized charts. Association with birth weight classification was assessed using logistic regression models. Results: Of the total of 605 newborns classified as small size for gestational age by population charts, 150 (24.8%) were reclassified as appropriate size for gestational age by customized charts, whereas of the total of 605 newborns classified as large size for gestational age by population charts, 129 (21.3%) cases were reclassified as appropriate size for gestational age by customized charts. Compared to newborns born appropriate size for gestational age, newborns born small size for gestational age according to customized charts had increased risks of infant catch-up growth (odds ratio (OR) 5.15 (95% confidence interval (CI) 4.22 to 6.29)), high blood pressure (OR 2.05 (95% CI 1.55 to 2.72)), and clustering of cardio-metabolic risk factors at 10 years (OR 1.66 (95% CI 1.18 to 2.34)). No associations were observed for overweight, hyperlipidemia, liver steatosis, or asthma. Newborns born large-size for gestational age according to customized charts had higher risk of catch-down-growth only (OR 3.84 (95% CI 3.22 to 4.59)). The direction and strength of the observed associations were largely similar when we used classification according to population charts. Conclusions: Small-size-for-gestational-age newborns seem to be at ris

Larger First-Trimester Placental Volumetric Parameters Are Associated With Lower Pressure and More Flow-Mediated Vasodilation of the Fetoplacental Vasculature After Delivery

Objective: To explore the correlation between in vivo placental volumetric parameters in the first trimester of pregnancy and ex vivo parameters of fetoplacental vascular function after delivery. Methods: In ten singleton physiological pregnancies, placental volume (PV) and uteroplacental vascular volume (uPVV) were measured offline in three-dimensional ultrasound volumes at 7, 9, and 11 weeks gestational age (GA) using Virtual Organ Analysis and Virtual Reality. Directly postpartum, term placentas were ex vivo dually perfused and pressure in the fetoplacental vasculature was measured to calculate baseline pressure (pressure after a washout period), pressure increase (pressure after a stepwise fetal flow rate increase of 1 mL/min up to 6 mL/min) and flow-mediated vasodilation (FMVD; reduction in inflow hydrostatic pressure on the fetal side at 6 mL/min flow rate). Correlations between in vivo and ex vivo parameters were assessed by Spearman’s correlation coefficients (R). Results: Throu