Polycystic Ovary Syndrome and Pregnancy

Polycystic Ovary Syndrome and Pregnancy Master thesis April 2016 Student:

Priyanka Pagh (student number: 20104452)

Supervisor: Finn Lauszus, Dep. Of Gynaecology & Obstetrics, Herning Hospital Number of characters: 22.115

Student number: 20104452

Master thesis

April 2016

Resume Polycystisk ovariesyndrom(PCOS) er den hyppigste endokrine forstyrrelse hos kvinder i den fertile alder. Sygdommen er meget heterogen, men defineret ved Rotterdam Kriterierne, hvor minimum to ud af følgende skal være opfyldt: 1)oligo- eller amenore, 2)kliniske eller biokemiske tegn på hyperandrogenisme eller 3) polycystiske ovarier. PCOS er en undergruppe af metabolisk syndrom, hvorfor kvinderne også er i øget risiko for at få diabetes mellitus og kardiovaskulære sygdomme. PCOS er grundet menstruationsforstyrrelser forbundet med infertilitet. Flere kvinder med PCOS søger derfor fertilitetsbehandling for at opnå graviditet. Litteraturen angående PCOS-kvindernes risiko for komplikationer i gravidteten såsom præeklampsi, gestationel diabetes mellitus, præterm fødsel, flerfoldsgraviditet, øget risiko for kejsersnit samt forøget brug af fertilitetsbehandling er endnu ikke konklusiv. Vi gennemgik derfor systematisk journalerne fra 98 kvinder med PCOS fra Regionshospitalet Herning for ovennævnte obstetriske events gennem graviditeten. Vi fandt en øget risiko for gestationel diabetes mellitus, præeklampsi samt en øget risiko for kejsersnit blandt kvinder med PCOS i forhold til baggrundsbefolkningen. Herudover fandt vi ingen forskel på abortraten og ingen øget forekomst af præterm fødsel sammenlignet med kvinder uden PCOS.

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Introduction Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder in women in the reproductive age13. The symptoms and objective signs are very heterogenic in women with PCOS. They may present menstrual disorders, hirsutism, acne, hyperlipidaemia, insulin resistant (IR) and infertility. In addition to that, 50 % of the patients are overweight13. Some classify PCOS as a subgroup of metabolic syndrome, which is characterized by abdominal obesity, dyslipidaemia, hypertension, and high fasting blood sugar 11. Some of these variables, like central obesity and high fasting blood sugar, are also present in women with PCOS. Because of objective and biochemical similarity, PCOS patients are at increased risk of diabetes mellitus and cardiovascular disease just like patients with metabolic syndrome4. Cardiovascular disease includes ischaemic heart disease, apoplexies, and periphery vascular disease and, thus, causes co-morbidity and mortality. Diabetes mellitus may if not well treated lead to microangiopathy, cardiovascular disease and foot ulcers34. The menstrual disorders include oligomenorrhea or anovulation resulting in infertility in PCOS women and result in PCOS women seeking treatment for getting pregnant. Weight loss and assisted reproduction therapy (ART) are often advised and instituted. ART includes medication to induce ovulation, ovarian drilling, intrauterine insemination (IUI), in vitro fertilization (IVF), or intracytoplasmic sperm injection (ICSI) 8, 27, 33. Metformin may help to normalize endocrine parameters by reducing insulin resistance and hypertesteronaemia and, thus, improve fertility 9,17,26. Because the symptoms are so heterogenic the PCOS diagnosis is defined by the Rotterdam criterions as at least two of the following: 1) oligomenorrhea or anovulation, 2) clinical or biochemical signs of hyperandrogenism or 3) polycystic ovaries20. It is not clear if PCOS is associated with miscarriages, hypertension during pregnancy, preeclampsia, gestational diabetes, preterm birth, caesarean section or higher incidence of twin pregnancies. This retrospective study aims to analyse the association of PCOS with the incidence of adverse pregnancy outcomes.

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Methods The medical records of patients with both a PCOS diagnosis and a pregnancy at the Department of Gynaecology and Obstetrics, Herning Hospital were scrutinized. The data registered were age at pregnancy or miscarriage, body mass index (BMI), parity, occurrence of hirsutism, oligomenorrhea or anovulation, diabetes mellitus, use of ART, birth of singleton or twins, occurrence of preeclampsia, gestational diabetes, gestational age at birth and delivery method (see Table 1 p. 4). The diagnosis of diabetes and hypertension were not confirmed by checking blood sugar or blood pressure before pregnancy. The data were found in the Electronic Patient Journal (EPJ). The Danish data agency approved the study (1-16-02605-15). The patients’ social security numbers were extracted from Tableau in the study period from October 1, 2010 to October 8, 2015 using the ICD-code for PCOS (DE282). The women who did not have a pregnancy diagnosis (DZ34-35 or DO-codes) were excluded, as were the patients who had abortus provocatus (KLCH00). Data from the last trimester of pregnancy and birth were unavailable in three patients, because the women moved to another region and were excluded due to missing information. Patients without pregnancies after October 1, 2010 were also excluded as EPJ commenced at this date at Herning Hospital. This left us with a total of 98 women with PCOS and a pregnancy. The data was plotted in an Excel-datasheet, anonymized and categorized into various tables. The database PubMed was used to extract literature regarding PCOS and pregnancy. As search words were used “Polycystic ovary syndrome”, “Pregnancy”, “Pregnancy outcome”, “PCOS” and “metformin”. In addition, the reference lists of retrieved articles were browsed for more information. Furthermore, the website of the Danish Society of Gynaecology and Obstetric was searched for national guidelines concerning pregnant PCOS patients26, 27. To compare our PCOS subjects, references on incidences in the general population on different pregnancy, obstetric and lifestyle issues were found on www.lægehåndbogen.dk or the website of the Danish Society of Gynaecology and Obstetrics.

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Results The study included 98 women whose age ranged from 20 to 42 years. The women’s body mass index mass index (BMI) varied from 18 to 64 kg/m2. According to the World health Organisation (WHO), overweight is defined as BMI ≥ 25 kg/m2 and obesity is defined as BMI ≥ 3032. Therefore, the average PCOS woman in our study is categorized as obese according to WHO classification. We could not retrieve from many medical journals whether the women had hirsutism. Additionally, one woman was described as having “increased hair cover” and one was described as having “increased growth of hair”. The subjects were also

screened for co-morbidity such as diabetes mellitus and hypertension (see Table 1). The diagnosis was found listed in the category “Diagnosis” in EPJ. Only two cases had known hypertension and one had type 1 diabetes mellitus and another had type 2 diabetes mellitus. In this study, the women presented with different menstrual irregularities. One subject had amenorrhea, 18 had oligomenorrhea, two had a normal cycle length and two stated as “irregular”. In the remaining women the cycle of menstruation was not

Table 1: Descriptive data (n = 98) Range Mean Age (years) 20-42 30 2 BMI (kg/m ) 18-64 30 % n 6 Hirsutism 6 1 Increased covering of hair 1 1 Increased growth of hair 1 2 Hypertension 2 2 Diabetes mellitus 2 1 - DM1 1 1 - DM2 1 Menstrual cycle 1 - Amenorrhoea 1 18 - Oligomenorrhea 18 4 - Regular cycle 4 2 - Irregular cycle 2 75 - No information 73 Parity Nulliparous 53 54 - Para 1 33 34 - Para 2 9 9 - Para 3 3 3 Abortion ≥ 1 previous abortion 25 26

described (n = 73).

DM1: Type 1 diabetes mellitus, DM2: Type 2 diabetes mellitus

SD 4.85 7.45

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Oligomenorrhea was defined as a cycle more than 35 days, but shorter than six months35 and amenorrhea was defined as no menstruation for ≥ 3 months37. 46 % of the women have had at least one child (See Table 1). Other co-morbidities were registered: Two had inflammatory bowel disease and one woman each had endometriosis and hypothyroidism. Pregnancies Most of the pregnancies were conceived spontaneously (see Table 2). The remaining couples received assisted reproduction therapy in the form of hormone treatment, IUI or IVF. 15-20 % of all Danish couples will permanently or in periods experience infertility33, so the fact that more than 40 per cent of the PCOS women need ART due to their disease is not very surprising. Table 2: Method of conception (n = 98) Spontaneous Hormone treatment IUI IVF Equals 100 % when abbreviated IUI: intrauterine insemination IVF: In vitro fertilization

n

%

56 21 3 18

57 21 3 18

Abortion As illustrated in Table 1, 26 % of the women have had at least one abortion or more prior to the index pregnancy. Out of the 98 subjects, 8 women had an abortion as their index pregnancy (8 %), of which six of these were missed abortions. The last two abortions were spontaneous (see Table 3). The abortion rate in this study was similar to the general spontaneous abortion rate among Danish women with known pregnancy28. Table 3: Abortions (n = 98) Abortion - Spontaneous abortion - Missed abortion

n 8 2 6

% 8 2 6

5

Student number: 20104452 Table 4: Births (n = 90) Births - Singleton - Twins

n 84 6

Master thesis

% 93 7

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Singletons versus twins The majority of births were singletons (see Table 4). The incidence of twin pregnancies in our study was bigger than the general population which in 2008 was 2.2 %29. Gestational diabetes mellitus Morbidity during pregnancy developed in 19 women. Six (6 %) of these had gestational diabetes mellitus (See Table 5). Gestational diabetes mellitus is defined as reduced glucose tolerance debuting during pregnancy36. The incidence in the general population is 3 %26, 31. Hence, our PCOS women had a frequency twice the general population. Pre-eclampsia Pre-eclampsia is defined as blood pressure ≥ 140/90 mmHg plus proteinuria25. In our study the incidence of pre-eclampsia (PE) was 13 % (see Table 5); thus, more than 3 times greater than the frequency of 2-3 % seen in the general population25.

Table 5: Morbidity in pregnancy (n = 98) - GDM - Pre-eclampsia GDM: Gestational diabetes mellitus

n 6 13

% 6 13

Gestational age & preterm birth The different gestational age at birth was divided into five groups: Term (GA 37+0 to 41 + 6), preterm (< 37+0), very preterm (GA < 34+0), extremely preterm ( 42+0) – see Table 6. As shown, almost 90 % (n = 80) of deliveries were at full term. Both incidences of preterm and very preterm deliveries are in consistence with data from the general population where the incidence of preterm birth is 7 %, and the incidence of

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very preterm birth is 2 %25. The incidence of extremely preterm birth in our study is double the frequency seen in the background population25. In our study the incidence is only 1% compared to the 2007 incidence of graviditas prolongata of 6 % in general25.

Table 6: Gestational age at birth (n = 90)

n

%

Term (GA 37+0 to 41+6)

80

89

Preterm (GA < 37+0)

6

7

Very preterm (GA 100% owing to use of > 1 methods in some deliveries AROM: Artificial rupture of membranes

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Discussion The purpose of this study was to evaluate PCOS’ effect on different pregnancy and obstetric outcomes. We find an increased risk of gestational diabetes mellitus, pre-eclampsia, and a risk of caesarean section among women with polycystic ovary syndrome. We cannot conclude firmly on the incidence of twin births and no differences in abortion rate or preterm birth were found compared to pregnant women without PCOS. A drawback of this study was that not all data were available, which is caused by its retrospective design; in a prospective design these data may be better registered. Additional fertility issues like the partners’ sperm count may affect the infertility problem negatively and influence more than that of PCOS. Similarly, information about anatomical abnormalities was missing. The number of cases (n =98) is relatively small and results in more variation in the incidence of the findings and making firm conclusions difficult. Likewise, information about the neonate’s hospitalization, birth weight, morbidity, and mortality were not analysed, as these was not available in EPJ of the mother. Data on different issues were also very unspecific. Because the quantity of hair varies a lot among ethnicity and the individual’s opinion of what increased growth of hair is, the term “hirsutism” cover variable phenotypes. The heterogeneity of the conception hirsutism was reflected in the data available. Also, we did not confirm the subjects’ co-morbidity such as diabetes or hypertension by searching the medical journal for blood sugar or blood pressure before pregnancy or when the diagnosis was made. Description of menstrual cycle was missing in majority of the women. Data missing from so many subjects makes it impossible to conclude if this group is subfertile and with this dilute data on PCOS’s effect on fertility. As no well-defined control group was available no statistic comparison between these are made apart from the general population. One could have extracted and used women without PCOS, but a pregnancy diagnosis in the same study period from Herning hospital as control group. A control group was not selected because of this study’s curtailment. In spite of disadvantages due to study design and lack of all desirable data, the study can evaluate more outcomes at the same time and analyse relatively rare outcome such as PE and different groups of preterm birth. We find along with others no difference between the abortion rate among PCOS cases and the general population9, 28. Even when all the PCOS women from the 2014 study were treated

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with metformin there was no difference in abortion rate9. We could not verify which PCOS patients were on metformin treatment during conception of the index pregnancy. Still the similar abortion rate suggests PCOS has no affect on the tendency to have a miscarriage. On the other hand, other studies have found an increased risk of spontaneous abortion in women with PCOS 12,15,17. Both Thatcher et al. and Joham et al. argue that the increased risk is due to high BMI and or obesity 12, 17. Palomba et al. state that IR, which is a cornerstone in PCOS, is an independent factor for abortion15. The argument is supported by the fact that some studies find the risk of spontaneous abortion reduced when the women were treated with metformin during first trimester of pregnancy10, 17. Løvvik et al. compared twin pregnancies in women without PCOS with twin pregnancies in women with PCOS and found a significant enlarged risk of preterm birth in PCOS women compared to non-PCOS women, suggesting PCOS as an independent risk factor for preterm delivery14. Romundstad et al. also support this contention concluding that adverse pregnancy and obstetric outcomes attribute to the leading cause of infertility rather than ART5. In our study we found the frequency of extremely preterm birth double the frequency seen in the background population25. Both the fact that the event is rare and a small number of cases can cause this phenomenon. In contrast, other studies conclude that ART causes the adverse obstetric outcomes15. Significant increased risk of preterm delivery is seen in singleton pregnancies in women with PCOS compared to women without PCOS1, 7, 10,18. Naver et al. also found increased risk in women with hyperandrogenism7. This implies that hyperandrogenism as seen in PCOS is causing the increased risk. Hence, it could be relevant to divide PCOS into different subgroups depending on which of the Rotterdam criterions they comply with. Many studies do not adjust for confounders such as BMI, parity or age 1, 7, 10, 18. Mumm et al. adjusted for confounders finding no difference between the PCOS and the control group6. Therefore, evidence is still inconclusive concerning the risk of preterm delivery26. The incidence of twin pregnancies has increased in recent years and ART seems to be the cause29. Boomsma et al. claim the incidence of twin pregnancies is higher in PCOS women because of further need of ART1. Our findings are consistent with the findings in Boomsma et al.1. However, we cannot conclude anything firmly on twin births among PCOS women due to 1) the small number of cases used in this study, and 2) the use of ART. Several studies have found a significant increased risk of gestational diabetes mellitus in women with PCOS 1, 6,10,12,18, 21,22. The risk according to Toulis et al. was not significant in their

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metaanalysis when dividing its different studies into subgroups on the basis of study validity. Different study designs and perhaps dissimilar risk within PCOS subgroups may be the cause of different diabetes incidences22. The link between PCOS and GDM may be due to obesity. Palomba et al. state that especially the pre-pregnancy weight determines if the women are in increased risk of GDM15. Thatcher et al. claim both pre-pregnancy weight and gained weight during pregnancy affects the risk17. Boomsma et al. on the other hand argue PCOS as a separate risk factor1. Mumm et al. support this argument, as they find an increased risk of GDM in women with PCOS compared to healthy women with the same BMI. Abdominal obesity and inflammatory cytokines may be separate or associated GDM risk factors6. Our findings suggest an increased risk of GDM in PCOS women. On the other hand Kruse et al. find the recurrence of GDM almost 50 % in women who in their first pregnancy had GDM19. As interpreting PCOS as risk factor for GDM, not all studies took parity into account. One should in the future make more of dividing PCOS women into subgroups based on their parity – or altogether exclude women with previous GDM. Currently, the Danish Society of Gynaecology & Obstetric recommends screening for gestational diabetes mellitus in PCOS women, as high risk of GDM is anticipated26. PCOS has shown to affect the patients’ risk of having PE in various studies 1, 10, 12, 15, 18, 21. Palomba et al. found the risk 2-3 times greater in PCOS women. The risk was also increased in lean patients15. Only Joham et al. adjusted for other cofounders for PE. The risk was still significant increased after adjustment12. In our study the incidence of PE is greater than 2-3 times larger than the general population. The modest number of cases in this study can explain this phenomenon. Naver et al. did not find an increased risk in general, but when they divided the women into subgroups, they found an increased risk in those with both PCOS and hyperandrogenism7. Løvvik et al. did not find any association between PCOS and PE. The authors claim the high incidence of preterm births to be the reason, so the women never came so far in their pregnancies as to develop PE14. The pathophysiology of PE in PCOS women is still being discussed. Boomsma et al. blame placenta insufficiency for being responsible for the increased risk1. Løvvik et al. state the placental dysfunction to be due to the coagulation and fibrinolysis disturbances that are caused by hyperandrogenism and IR14. Both are present in many PCOS patient and, therefore, have a larger risk of PE 7, 12.

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Literature considering delivery method is not conclusive. Some studies find increased risk of caesarean section among PCOS patients10, 12, 21, whereas other studies do not find a significant risk of caesarean section14. Boomsma et al. thus only find the risk increased when high valid studies are included in their metaanalysis. The writers claim obesity as main cause1. Løvvik et al. found no difference in caesarean section rate between future twin mothers with PCOS and future twin mothers without PCOS14. The unconvincing data so far, indicate PCOS as a risk factor for caesarean section26. As stated, we did not analyse neonatal outcome in children of PCOS mothers. An increased risk of neonatal hospitalization was reported in children born by PCOS mothers1, 10, 16. This may be secondary to obstetric complications such as GDM, preterm delivery and PE1. As women with PCOS are at higher risk of GDM it would be logic if the offspring weighed more than average, and the incidence of macrosomia was higher, but macrosomia does not occur more often in PCOS women because of placental insufficiency1. The offspring may later in life be at greater risk of diseases compared to other children due to their mothers’ PCOS. Diabetes mellitus, PCOS, cardiovascular diseases and other diseases have variably been associated with metabolic syndrome because of genetic and environmental similarity to their mothers. Boomsma et al. claim the Barker’s hypothesis of being part of the reason for bigger risk of cardiovascular diseases. Barker’s hypothesis claims, the intrauterine environment has important impact on the offspring’s consumption later in life1. PCOS is a disease affected by lifestyle – especially sedentary lifestyle and unwholesome food causing obesity. If the offspring adopts this sort of lifestyle and become obese, it results in increased risk of diseases and metabolic syndrome. Studies regarding obstetric factors like method of birth, PE and time of birth are not unanimous if PCOS affects the pregnancies or deliveries of PCOS women. Kjerulff et al. state, the different subgroups have to be taken into account when interpreting the results18. When dividing PCOS cases into four groups based on which of the Rotterdam characteristics they comply with they come up with the following groups: Full-blown PCOS, non-polycystic ovaries, non-hyperandrogenic and ovulatory phenotypes. The authors found the risk of adverse obstetric and neonatal outcomes different among the subgroups: thus, the relative risk for negative adverse outcomes was highest in the full-blown-PCOS group16. Naver et al. confirm this notion, but only find a significant enlarged risk of PE in the subgroup with hyperandrogenism7. On the other hand, Mumm et al. do not find this connection between a

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specific subgroup and an obstetric outcome, which may be due to the small number of cases in some of the groups (n = 50 in the largest group). An underestimation is suggested because some of the PCOS patients might have ended up in the control group6. All in all, it can be concluded that literature point towards an association between adverse obstetric outcomes and the degree of difficulty of PCOS. It is more accepted that PCOS is a subgroup of the metabolic syndrome11. Therefore, whether all patients with metabolic syndrome risk the adverse obstetric outcome described for PCOS would be of interest. It is likely that women with metabolic syndrome have the same increased risk of obstetric outcomes, as discussed, because these outcomes are caused by IR and obesity, which characterizes metabolic syndrome11. Jensen et al. find the incidence of adverse pregnancy outcome, e.g. shoulder dystocia, spontaneous preterm birth and macrosomia, increased in women with mild glucose intolerance 2, 3. This finding suggests women who do not meet the threshold of a positive oral glucose tolerance test are still at risk of adverse obstetric outcomes. Thus, attention should be paid to PCOS women, even though they do not have GDM, in that many of these patients have insulin resistance. Some women with PCOS do not experience fertility problems, thus they might not know what Rotterdam criterions they comply with. These women may end up in the “background population”. We did not verify which of our PCOS cases had metformin. Vanky et al. examined in 2004 in a randomized, double blind placebo controlled study if metformin treatment reduced adverse obstetric outcomes in pregnant PCOS women. They found a reduced incidence of severe pregnancy and postpartum complications23. In contrast Vanky et al. again in 2010 in a large randomized double blind study compared pregnant PCOS women treated with metformin or placebo during pregnancy, and found no effect of metformin compared to placebo24. In conclusion existing literature is not yet conclusive on whether metformin beyond first trimester should be offered to pregnant women with PCOS. Conclusion The aim of this study was to examine how polycystic ovary syndrome affects pregnancy and births. We find an increased risk of gestational diabetes mellitus, pre-eclampsia, and a risk of caesarean section among women with polycystic ovary syndrome. Additionally, we find no

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difference in abortion rate or no tendency to preterm birth compared to pregnant women without PCOS.

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References 1. Boomsma et al.: ”A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome”, Human Reproduction Update. 2006; 12(6): 673-83 2. Jensen et al.: “Adverse pregnancy outcome in women with mild glucose intolerance: is there a clinically meaningful threshold value for glucose?”. Acta Obstetricia et Gynecologica. 2008; 87:59-62 3. Jensen et al.: “Clinical impact of mild carbohydrate intolerance in pregnancy: a study of 2904 nondiabetic Danish women with risk factors for gestational diabetes mellitus”. Am J Obstet Gynecol. 2001; 185(2): 413-9 4. Grundy et al.: “Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute & American heart Association conference on scientific related to definition”. Arterioscler Thromb Vasc Biol. 2004; 24(2): e13-8 5. Romundstad et al.: “Effects of technology or maternal factors on perinatal outcome after assisted fertilisation: a populations-based cohort study”. Lancet. 2008; 372: 737-43 6. Mumm et al.: “Hyperandrogenism and phenotypes of polycystic ovary syndrome are not associated with differences in obstetric outcomes”. Acta Obstet Gynecol Scand. 2015; 94:204-211 7. Naver et al.: “Increased risk of preterm delivery and pre-eclampsia in women with polycystic ovary syndrome and hyperandrogenaemia”. BJOG. 2014; 121(5): 575-81 8. Cleemann et al.: “Laparoscopic ovarian drilling as first line of treatment in infertile women with polycystic ovary syndrome”. Gynecol Endocrinol. 2004: 18:138-143 9. Lauszus et al.: “Metformin Exposure in Early Pregnancy and Spontaneous Abortions in women with Polycystic Ovary Syndrome”. Androl Gynecol: Curr res. 2014;2: 4 10. Qin et al.: “Obstetric complications in women with polycystic ovary syndrome: a systemic review and meta-analysis”. Reproductive Biology and Endocrinology.2013; 11: 56 11. Kirkelund et al.: ”Polycystisk ovariesyndrom og spontan abort”. Ugeskriftet.2011;173/6 12. Joham et al.: “Polycystic Ovary Syndrome, Obesity and Pregnancy”. Semin Reprod Med. 2016; 34:93-101 13. Svendsen et al.: “Polycystisk ovariesyndrom Nyere patofysiologiske iagttagelser – behandlingsmæssige konsekvenser”. Ugeskriftet.2005; 167/34

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14. Løvvik et al.: “Pregnancy and perinatal outcomes in women with polycystic ovary syndrome and twin births: a population-based cohort study”. BJOG. 2015; 122(10): 1295302 15. Palomba et al.: “Pregnancy complications in women with polycystic ovary syndrome”. Human Reproduction Update. 2015; 21(5): 575-92 16. Palomba et al.: “Pregnancy in women with polycystic ovary syndrome: the effect of different phenotypes and features on obstetric and neonatal outcomes”. Fertil Steril.2010; 94(5): 1805-11 17. Thatcher et al.: “Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin”. Fertil Steril. 2006; 85(4): 1002-9 18. Kjerulff et al.: “Pregnancy outcomes in women with polycystic Ovary syndrome: a metaanalysis”. Am J Obstet Gynecol. 2011; 204:558.e1-6 19. Kruse et al.: “Recurrence of gestational diabetes in primiparous women”. Acta Obstet Gynecol Scand. 2015; 94(12): 1367-72 20. Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group: “Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome”. Fertil Steril. 2004. 81(1):19-25 21. Roos et al.: “Risk of adverse pregnancy outcomes in women with polycystic ovary syndrome: population based cohort study”. BMJ.2011; 343 22. Toulis et al.: “Risk of gestational diabetes mellitus in women with polycystic ovary syndrome: a systematic review and a metaanalysis”. Fertil Steril. 2009; 92(2): 667-77 23. Vanky et al.: ” Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study”. Human Reproduction.2004; 19(8):1734-40 24. Vanky et al.: ” Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study”. J Clin Endocrinol Metab. 2010; 95(12):E448-55 25. ”Obstetrik – en grundbog” Uldbjerg et al, Munksgaard 1. Udgave 2014 26. Dansk Selskab for Gynækologi & Obstetrik: ”PCOS og graviditet, herunder metformin – Guidelines”: http://static.squarespace.com/static/5467abcce4b056d72594db79/546e7748e4b0d969

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a4f6cf10/546e7745e4b0d969a4f6cc32/1393459292000/PCOS-metformin-oggraviditet.pdf?format=original 27. Dansk Selskab for Gynækologi & Obstetrik: ”Polycystisk ovariesyndrom – Guidelines”: http://static1.squarespace.com/static/5467abcce4b056d72594db79/t/561cb676e4b09f 2277ba139d/1444722294970/PCOS_rev2015_finalrev%5B1%5D.pdf 28. Incidence of spontaneous abortion: https://www.sundhed.dk/sundhedsfaglig/laegehaandbogen/obstetrik/tilstande-ogsygdomme/aborter/spontan-abort/#2 29. Incidence of twin births: https://www.sundhed.dk/sundhedsfaglig/laegehaandbogen/obstetrik/tilstande-ogsygdomme/risikofaktorer-i-svangerskabet/flerfoldsgraviditet/ 30. Incidence of Caesarean section: https://www.sundhed.dk/borger/sygdomme-aaa/graviditet/sygdomme/diverse/kejsersnit/ 31. Incidence of GDM: http://www.endocrinology.dk/kliniske%20retningslinier%20%20GDM.pdf 32. Incidence and definition of overweight: https://www.sundhed.dk/sundhedsfaglig/laegehaandbogen/endokrinologi/tilstande-ogsygdomme/overvaegt/overvaegt/#3 33. Assisted reproduction therapy: https://www.sundhed.dk/sundhedsfaglig/laegehaandbogen/gynaekologi/tilstande-ogsygdomme/diverse/infertilitet/#1 34. Diabetes mellitus: https://www.sundhed.dk/sundhedsfaglig/laegehaandbogen/endokrinologi/tilstande-ogsygdomme/diabetes-mellitus/diabetes-type-2/#headerFAYA 35. Oligomenore: https://www.sundhed.dk/sundhedsfaglig/laegehaandbogen/gynaekologi/symptomerog-tegn/oligomenor/ 36. Gestationel diabetes mellitus: https://www.sundhed.dk/sundhedsfaglig/laegehaandbogen/obstetrik/tilstande-ogsygdomme/risikofaktorer-i-svangerskabet/gestationel-diabetes-gdm/

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37. Amenore: https://www.sundhed.dk/sundhedsfaglig/laegehaandbogen/gynaekologi/symptomerog-tegn/sekundaer-amenor/

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