http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, Early Online: 1–5 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.974535
REVIEW ARTICLE
Pregnancy complications in polycystic ovary syndrome patients Krzysztof Katulski1, Adam Czyzyk1, Agnieszka Podfigurna-Stopa1, Andrea R. Genazzani2, and Blazej Meczekalski1 Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland and 2Department of Reproductive Medicine and Child Development, Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy
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Abstract
Keywords
Infertility is a widely disputed problem affecting patients suffering from polycystic ovary syndrome (PCOS). As a serious dysfunction, it frequently occurs in PCOS patients. It is, therefore, important to devote more attention to pregnancy in PCOS sufferers. According to various data, the risk of miscarriage in PCOS women is three times higher than the risk of miscarriage in healthy women. Unfortunately, the risk of most frequent pregnancy pathologies is also higher for PCOS patients, as gestational diabetes (GD), pregnancy-induced hypertension and preeclampsia, and small for gestational age (SGA) children. Impaired glucose tolerance and GD in pregnant PCOS patients occur more frequently than in healthy women. A quadruple increase in the risk of pregnancy-induced hypertension linked to arterial wall stiffness has also been observed in PCOS patients. The risk of pre-eclampsia, the most severe of all complications, is also four times higher in those suffering from PCOS. Pre-eclampsia is also more frequent in patients presenting additional risk factors accompanying PCOS, such as obesity or GD. At that point, it should be mentioned that PCOS patients are under 2.5 higher risk of giving birth to SGA children than healthy women. It appears that SGA can be linked to insulin resistance and insulin-dependent growth dysfunction. Therefore, PCOS pregnant women are patients of special obstetrical care.
Gestational diabetes, gestational hypertension, insulin resistance, PCOS, pregnancy
Polycystic ovary syndrome – diagnostic criteria Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women in child-bearing age. Principal clinical symptoms of PCOS include ovulation disorders as well as clinical or laboratory test indicators of androgens excess and polycystic ovaries morphology [1]. The symptoms as well as the intensity vary significantly among different patients. The underlying causes of the syndrome remain unknown, still, it has been determined that immunity to insulin, very often a secondary effect of obesity, is strongly connected with PCOS [1]. The diagnosis of PCOS is based on specific diagnostic criteria. The earlier established criteria of National Institutes of Health (NIH) date back to 1990. The so-called Rotterdam criteria were developed in 2003 [2]. According to NIH criteria [2], PCOS is diagnosed when the following symptoms are found in a patient: the symptoms of excessive androgens’ amount (clinical and biochemical) and rare ovulation, having excluded other disorders that could cause a similar clinical image. The diagnostic criteria established by ESHRE/ASRM (European Society of Human Reproduction and Embryology/ American Society of Reproduction Medicine) in Rotterdam require that the two out of the following three criteria are met
Address for correspondence: Blazej Meczekalski MD PhD, Department of Gynecological Endocrinology, Poznan University of Medical Sciences, ul. Polna 33, Poznan, 60-535 Poland. E-mail: blazejmeczekalski@ yahoo.com
History Received 6 April 2014 Revised 31 August 2014 Accepted 6 October 2014 Published online 30 October 2014
to make the diagnosis [1]: rare ovulation or lack of ovulation, symptoms of androgens’ excess (clinical or biochemical), polycystic morphology of at least one ovary – found in USG examination with at least 12 follicles measuring 2–9 mm in diameter or ovarian volume greater than 10 cm. To make the diagnosis, it is necessary to exclude other underlying causes of such clinical image. The Rotterdam definition is broader and it encompasses a greater number of patients, especially ones without androgens’ excess, whereas in the NIH definition, excessive amount of androgens is the necessary condition. Critics claim that the results of tests carried out on patients with excessive amount of androgens may not necessarily refer to patients without excessive androgens, therefore, the application of specific diagnostic criteria is still raising a lot of controversy [1,3]. The number of parallel definitions of PCOS makes it difficult to precisely determine the frequency of the syndrome. However, reliable and convincing data have been elaborated indicating that PCOS affects 10–15% of women in the general population. Moreover, it has been recognized to be the most common endocrine disorder in women in child-bearing age, thus it constitutes a serious problem in the public health domain [1]. The types of complications observed during pregnancy in PCOS patients were determined quite specifically in 2012 at the expert meeting sponsored by ESHRE/ASRM in Amsterdam [1]. Women with PCOS often have cardiovascular disease (CVD) risk factors. The Androgen Excess and PCOS (AE-PCOS) Society created a panel to provide evidence-based reviews of studies assessing PCOS-CVD risk relationships and to develop guidelines for preventing cardiovascular disease [4].
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PCOS – early pregnancy complications For PCOS patients, infertility is often the key clinical problem related to the syndrome. It should be kept in mind that ovulation disorders cover a wide range of irregularities, corresponding to and coexisting with the maturation of the ovum, which should be taken into consideration alongside the mere fact of the presence or absence of a healthy egg cell. Both hormonal and metabolic disorders may impact the development of early pregnancy in this group of patients [1,5–7]. First irregularities may be observed already during ovulation whose most apparent consequence may be improper quality when it comes to the level of ovum maturity [8]. Still, we have to keep in mind that except for the ovum the ovulation disorders may preclude implantation at many other levels as well. Both quantitative and qualitative disorders are most often related to the hormonal function of granulosa cells and they result in the uterine mucous membrane not being properly prepared to implantation of the embryo [8,9]. Another limitation hindering fertility lies in the lack of proper environment in the area of cervical mucus, which is related to irregular process of capacitation and confirmed lack of coordination in the movement of oviduct cilia, which leads to a slowdown in the migration of the embryo [5]. These disorders may occur with varying intensity, which results in different qualities of oocytes. Consequently, we cannot exclude a situation when full maturity of an ovum is possible and the implantation in a PCOS patient may proceed properly [8]. A lot of attention is given to the probability of disorders occurring in the process of development and growth of ovarian follicles. It is indicated that the probability of disorders occurring at the stage of consumption of nutrients and energy substrates by the growing oocyte from the follicular fluid is a considerable one. Metabolic disorders are quite commonly observed in PCOS, in the first place ones related to glucose homeostasis. The obvious systemic consequence of these disorders is the change in metabolic processes also at the level of ovarian follicles [10]. In the research of granulosa cells’ functions during in vitro fertilization programs, it has been pointed out many times that glucose metabolism in ovarian follicles is significantly disturbed in PCOS patients. Most importantly it has been found that in the granulosa cells’ grown, the use of glucose dependent on insulin is largely reduced [10,11]. It seems highly probable that initial metabolic disorders in the ovarian follicle may intensify throughout the entire oogenesis. This may result in disturbed production of energy for oocytes precluding their proper development [12,13]. Recently, more attention is being given to the possible effect of excessive androgens on the embryo development in early pregnancy. Hyperandrogenemia in PCOS patients may have a long-lasting effect on the development of the embryo first and then the fetus, especially in female offspring. Fetus hyperandrogenisation may cause abnormal epigenetic programming especially for genes that regulate the reproductive and metabolic processes [14].
PCOS – abnormalities during pregnancy Many studies suggest an increase in the risk of obstetric pathology: early miscarriage, gestational hypertension, preeclampsia, gestational diabetes (GD) mellitus-diagnosed during early pregnancy, prematurity, low birth weight or macrosomia, neonatal complications, and cesarean sections. However, it is difficult to conclude clearly about it, because of the heterogeneity of definition of PCOS in different studies. In addition, many confounding factors inherent in PCOS including obesity that are not always taken into account and generate a problem of interpretation. However, it seems possible to conclude that
Gynecol Endocrinol, Early Online: 1–5
Table 1. PCOS and pregnancy complications.
Risk of miscarriage Risk of pre-eclampsia Impaired glucose tolerance Type 2 diabetes
Patients with PCOS (%)
General population (%)
30–50 10 31–35 7.5–10
10–16.6 5 1.6 2.2
PCOS does not increase the risk of placental abruption, HELLP syndrome, liver disease, postpartum hemorrhage, late miscarriage, and stillbirth [15].
Gestational hypertension and pre-eclampsia According to the basic statistical data, 2–5% healthy pregnant women are diagnosed with pregnancy-induced hypertension. In one-third of the women in this group, the problem develops into more severe form of hypertension – pre-eclampsia. There are undoubtedly many risk factors for the development of hypertension during pregnancy. One of these factors is the co-existence of PCOS. It has been found that in pregnant women with PCOS, the systolic, diastolic, and average blood pressure are statistically higher and increased arterial stiffness is observed [16,17]. According to the basic statistical data, the frequency of preeclampsia occurrence is estimated to be 5% in the population of healthy pregnant women and approximately 10% among primaparas (Table 1) [18]. The analysis of available test results indicates that the increased risk is independent from other coexisting factors including age, BMI, abnormal glucose management, medications used in ovulation induction, and arterial hypertension [19–21]. It has to be emphasized although that the risk of developing pre-eclampsia is even higher by coexistence of additional risk factors, which often co-occur with PCOS, particularly obesity and GD. It should be kept in mind that oocyte donation and insemination with donor’s semen also constitute an independent risk factor for pre-eclampsia [20]. Thus, patients affected by PCOS and additional risk factors must be under special control with regard to pre-eclampsia occurrence. Women with PCOS with obesity, dyslipidemia, hypertension, and impaired glucose tolerance are at risk, whereas those with metabolic syndrome or type 2 diabetes mellitus are at a high risk for cardiovascular disease. Body mass index, serum lipid, and blood pressure determinations are recommended for all women with PCOS, as is oral glucose tolerance testing in those with obesity, advanced age, and personal history of GD. Mood disorder assessment is suggested in all PCOS patients [4].
Low birth weight (SGA) and high birth weight (large for gestational age – LGA) According to the data presented in the literature on the subject, infants born to women diagnosed with PCOS are found to be more often SGA. As suggested by the authors of the above-mentioned studies, the main cause of low birth weight occurring more often in infants born to women with PCOS is insulin resistance and insulin-dependent growth disorder [22,23]. There are also several recent reports suggesting that there is a reverse cause and effect relationship. It should be noted that the studies on the increased risk of later occurrence of PCOS symptoms in children with low birth weight remain contradictory. On one hand, the studies by Ibanez [24] in 1998 and Benitez [25] in 2001 document the above correlation as well as the increased
Pregnancy complications
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DOI: 10.3109/09513590.2014.974535
risk of PCOS occurrence in women born with low birth weight. On the other hand, the tests carried out by Laitinen et al. [26] in 2003 have not demonstrated any correlation between low birth weight and PCOS. The opposite situation consisting in high birth weight (LGA) in infants born to women diagnosed with PCOS is insignificantly – approximately 1.5 times – higher than the frequency in infants born to healthy women [19]. Therefore, it should be emphasized that all three groups of complications, i.e. abnormal glucose management, hypertension, and pre-eclampsia as well as fetus growth disorders, have a common etiological background. It is believed that the basic mechanism underlying these disorders may be obesity, abnormal glucose management, and uterine blood flow disorders. Another argument supporting the existence of these correlations is provided by the observation of changes in resistance of blood flow in uterine arteries in women with PCOS and it is observed during the first and second trimesters of pregnancy [27,28]. It should be strongly underlined that obesity itself is connected with several unfavorable consequences during pregnancy. It may on its own be a cause of spontaneous miscarriage, pre-eclampsia, GD, congenital disorders (e.g. heart disorder and spina bifida – split spine), and fetal macrosomia [29,30].
Insulin resistance and GD Impaired glucose tolerance is a commonly observed and predictable disorder in PCOS. According to Legro et al. [31], abnormal glucose tolerance is found in 31–35% patients with this syndrome in comparison to 1.6% in healthy women population. Type 2 diabetes in turn affects 7.5–10% patients in comparison with 2.2% in general population (Table 1) [32]. In women not affected by PCOS, insulin resistance is observed during pregnancy [33]. It should be emphasized that in PCOS patients, insulin resistance may be considerably more intense and may lead to GD. This results in abnormalities during pregnancy [34]. Therefore, GD in PCOS patients is found to occur three times more often than in healthy women [35]. Along with pregnancyinduced hypertension and premature birth, it is one of the most common complications in PCOS patients who got pregnant. D’Anna et al. [36] evaluated retrospectively the prevalence of GD in pregnancies obtained with myo-inositol administration in women with PCOS. The prevalence of GD in the myo-inositol group was 17.4% versus 54% in the control group. Consequently, in the control group, the risk of GD occurrence was more than double compared with the myo-inositol group, with an odds ratio of 2.4 (95% CI 1.3–4.4). There was no difference between the groups in relation to secondary outcome measures [36]. Another observation made by a growing number of authors is that in PCOS patients, the risk of persistent impaired glucose tolerance after GD is raised [37].
PCOS – risk of miscarriage On one hand, the risk of miscarriage in PCOS patients is increased and amounts to 30–50%, which means that for these women, it is three times as high as for healthy women [38]. The results of prospective, randomized trials suggest that the miscarriage instances in PCOS patients occur only in 15–25% of cases, which is a percentage comparable with the frequency of miscarriage in the general population (Table 1) [39,40]. The presented data derived from literature references on the subject reflect huge discrepancies between particular clinical trials conducted with regard to this problem. On the other hand, it should be kept in mind that ultrasound features of PCOS are to be found in 82% of women affected by
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Table 2. Birth complications in patients with PCOS. Complications of birth in patients with PCOS Preterm delivery Cesarean section Operating births Admission to a neonatal intensive care unit Perinatal mortality
OR: OR: OR: OR:
2.20; 1.41; 1.56; 2.31;
95% 95% 95% 95%
CI CI CI CI
1.59–3.04 0.96–2.07 0.93–2.63 1.25–4.26
OR: 3.07; 95% CI 1.03–9.21
recurrent miscarriage. At the same time, the induction of ovulation in women with the syndrome relates to 30% of miscarriage instances. Many authors suggest that there is a relationship between increased LH concentration in the serum and recurrent miscarriage. Proper LH concentration relates to 12% when it comes to miscarriage frequency and high LH concentration to 65% frequency. Raised concentration of LH in follicular phase may lead to premature development of the oocyte, whereas high concentration of LH in the luteal phase may cause abnormalities in the functions of endometrium during implantation [41].
PCOS – delivery complications The current state of knowledge allows us to state that the risk of complications occurring during delivery in PCOS patients is not sufficiently well determined. This pertains both to the percentage and to the nature of complications predicted. Based on the meta-analyses for PCOS patients, it has been found that there is an increased risk of premature birth (OR: 2.20; 95% CI 1.59–3.04), Cesarean section (OR: 1.41; 95% CI 0.96– 2.07), and necessity of operating births (OR: 1.56; 95% CI 0.93– 2.63) (Table 2) [19]. The data presented are unfortunately only preliminary ones. It seems necessary to extend the research, especially statistical, to large groups of PCOS patients to make the results obtained commonly acceptable [19]. Based on the current state of knowledge, i.e. on one hand, with regard to the observed general increase of the risk of obstetric complications and, on the other hand, the disorders in infants’ birth weight, it is also proposed that differentiation of risk levels be introduced depending on the different phenotypic characteristics of PCOS. Therefore, the relations presented above should provide a tentative basis to determine appropriate criteria, which would enable to identify quite unequivocally high-risk PCOS patients in the future. Consequently, it will be further possible to develop proper procedures for obstetric treatment in these cases in order to avoid or reduce the risk of obstetric complications [19,42].
PCOS – metformin treatment and pregnancy complications It should be unequivocally stated that the use of metformin in patients with PCOS who pursue pregnancy is a controversial issue. There are many reports where it is emphasized that no significant changes have been observed as for improving fertility and obtaining a better birth rate as compared with the group of PCOS patients who have not taken metformin [43,44]. Based on these observations, there is nowadays a rather widely held view that routine use of metformin in PCOS patients is not recommended. On one hand, meta-analysis published in 2009 demonstrating that the use of metformin before pregnancy did not affect the risk
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of miscarriage in PCOS patients [32] should provide quite a moderate argument supporting the view presented above. On the other hand, there are several studies indicating that there is a relationship between the use of metformin in PCOS patients already during pregnancy and the reduction of severe obstetric complications frequency [42]. To counterbalance such standpoint one may refer to extensive, multicenter studies, which do not validate the benefits arising from the use of metformin neither with regard to the reduction of pregnancy complications nor the change in fetal body weigh [32]. With the current knowledge, the issue of possible benefits arising from the use of metformin has not been unequivocally resolved. Further multicenter research is required.
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Summary To sum up, it needs to be stated that extensive scientific and clinical research is necessary to determine better criteria for PCOS diagnosis. The effort put in proper diagnostics of PCOS will be beneficial for patients and clinical practitioners alike, improving the effects of treatment of this common syndrome. As for abnormalities and complications during pregnancy and delivery in PCOS patients, it has been noted that in the recent years, there has been an increased number of tests conducted to assess the course of pregnancy and pregnancy complications in patients with this disorder. Such tests may contribute to developing studies and recommendations regarding pregnant women who have been earlier diagnosed with PCOS. It should be strongly emphasized that there is a huge need to conduct research including an extensive group of PCOS patients during pregnancy and in postnatal period with the aim of developing the standards for treatment of this group of patients.
Declaration of interest The authors report that they have no conflicts of interest.
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9. Lindenberg S. New approach in patients with polycystic ovaries, lessons for everyone. Fertil Steril 2013;99:1170–2. 10. Rice S, Christoforidis N, Gadd C, et al. Impaired insulin-dependent glucose metabolism in granulosa-lutein cells from an ovulatory women with polycystic ovaries. Hum Reprod 2005;20:373–81. 11. Wood JR, Dumesic DA, Abbott DH, et al. Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis. J Clin Endocrinol Metab 2007;92:705–13. 12. Harris SE, Maruthini D, Tang T, et al. Metabolism and karyotype analysis of oocytes from patients with polycystic ovary syndrome. Hum Reprod 2010;25:2305–15. 13. Katulski K, Meczekalski B, Ghrelin and fertility. Prz. Menopauz 2012;11:26–30. 14. Hickey TE, Legro RS, Norman RJ. Epigenetic modification of the X chromosome influences susceptibility to polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:2789–91. 15. Bruyneel A, Cattea u-Jonard S, Decanter C, et al. Polycystic ovary syndrome: what are the obstetrical risks? Gynecol Obstet Fertil 2014;42:104–11. 16. Hu S, Leonard A, Seifalian A, Hardiman P. Vascular dysfunction during pregnancy in women with polycystic ovary syndrome. Hum Reprod 2007;22:1532–9. 17. Sir-Petermann T, Ladro´n de Guevara A, Villarroel AC, et al. Polycystic ovary syndrome and pregnancy. Rev Med Chil 2012;140: 919–25. 18. ACOG. Committee on Practice Bulletins-Obstetrics. Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol 2011; 98:159–67. 19. de Vries MI, Dekker GA, Schoemaker J. Higher risk of preeclampsia in the polycystic ovary syndrome. A case control study. Eur J Obstet Gynecol Reprod Biol 2008;76:91–5. 20. Kashyap S, Claman P. Polycystic ovary disease and the risk of pregnancy-induced hypertension. J Reprod Med 2009;45: 991–4. 21. Qin JZ, Pang LH, Li MJ, et al. Obstetric complications in women with polycystic ovary syndrome: a systematic review and metaanalysis. Reprod Biol Endocrinol 2013;11:56. 22. Hattersley AT, Tooke JE. The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 2009;353:1789–92. 23. Shayeb AG, Harrild K, Bhattacharya S. Birth weight and ovulatory dysfunction. BJOG 2014;121:281–9. 24. Ibanez L, Potau N, Francois L, de Zegher F. Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J Clin Endocrinol Metab 2008;83: 3558–62. 25. Benitez R, Sir-Petermann T, Palomino A, et al. Prevalence of metabolic disorders among family members of patients with polycystic ovary syndrome. Rev Med Chil 2011;129:707–12. 26. Laitinen J, Taponen S, Martikainen H, et al. Body size from birth to adulthood as a predictor of self-reported polycystic ovary syndrome symptoms. lnt J Obes Relat Metab Disord 2003;27:710–15. 27. Palomba S, Falbo A, Russo T, et al. Uterine blood flow in pregnant patients with polycystic ovary syndrome: relationships with clinical outcomes. BJOG 2010;117:711–21. 28. Nahuis MJ, Oude Lohuis EJ, Bayram N, et al. Pregnancy complications and metabolic disease in women with clomiphene citrate-resistant anovulation randomized to receive laparoscopic electrocautery of the ovaries or ovulation induction with gonadotropins: a 10-year follow-up. Fertil Steril 2014;101:270–4. 29. Wax JR. Risks and management of obesity in pregnancy: current controversies. Curr Opin Obstet Gynecol 2009;21:117–23. 30. Galazis N, Docheva N, Nicolaides KH, Atiomo W. Proteomic biomarkers of preterm birth risk in women with polycystic ovary syndrome (PCOS): a systematic review and biomarker database integration. PLoS One 2013;8:53801. 31. Legro RS, Kunselman AR, Dodson WC. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 2009;84: 165–9. 32. Glueck CJ, Goldenberg N, Pranikoff J, et al. Effects of metformindiet intervention before and throughout pregnancy on obstetric and
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neonatal outcomes in patients with polycystic ovary syndrome. Curr Med Res Opin 2013;29:55–62. Ryan EA. Hormones and insulin resistance during pregnancy. Lancet 2009;362:1777–8. Nelson SM, Matthews P, Poston L. Maternal metabolism and obesity: modifiable determinants of pregnancy outcome. Hum Reprod 2010;16:255–75. Boomsma CM, Eijkemans MI, Hughes EG, et al. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod 2006;12:673–8. D’Anna R, Di Benedetto V, Rizzo P, et al. Myo-inositol may prevent gestational diabetes in PCOS women. Gynecol Endocrinol 2012;28: 440–2. Palomba S, Falbo A, Russo T, et al. The risk of a persistent glucose metabolism impairment after gestational diabetes mellitus is increased in patients with polycystic ovary syndrome. Diabetes Care 2012;35:861–7. Homburg R. Pregnancy complications in PCOS. Best Pract Res Clin Endocrinol Metab 2006;20:281–92.
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39. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–66. 40. Giudice LC. Endometrium in PCOS: implantation and predisposition to endocrine CA. Best Pract Res Clin Endocrinol Metab 2006; 20:235–44. 41. Boomsma CM, Fauser BC, Macklon NS. Pregnancy complications in women with polycystic ovary syndrome. Semin Reprod Med 2008;1:72–84. 42. Palomba S, Falbo A, Russo T, 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: 1805–11. 43. Carmina E. Diagnosis of polycystic ovary syndrome: from NIH criteria to ESHRE-ASRM guidelines. Minerva Gynecol 2004;56:1–6. 44. Vanky E, Stridsklev S, Heimstad R, 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:E448–55.
REVIEW ARTICLE
Pregnancy complications in polycystic ovary syndrome patients Krzysztof Katulski1, Adam Czyzyk1, Agnieszka Podfigurna-Stopa1, Andrea R. Genazzani2, and Blazej Meczekalski1 Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland and 2Department of Reproductive Medicine and Child Development, Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy
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1
Abstract
Keywords
Infertility is a widely disputed problem affecting patients suffering from polycystic ovary syndrome (PCOS). As a serious dysfunction, it frequently occurs in PCOS patients. It is, therefore, important to devote more attention to pregnancy in PCOS sufferers. According to various data, the risk of miscarriage in PCOS women is three times higher than the risk of miscarriage in healthy women. Unfortunately, the risk of most frequent pregnancy pathologies is also higher for PCOS patients, as gestational diabetes (GD), pregnancy-induced hypertension and preeclampsia, and small for gestational age (SGA) children. Impaired glucose tolerance and GD in pregnant PCOS patients occur more frequently than in healthy women. A quadruple increase in the risk of pregnancy-induced hypertension linked to arterial wall stiffness has also been observed in PCOS patients. The risk of pre-eclampsia, the most severe of all complications, is also four times higher in those suffering from PCOS. Pre-eclampsia is also more frequent in patients presenting additional risk factors accompanying PCOS, such as obesity or GD. At that point, it should be mentioned that PCOS patients are under 2.5 higher risk of giving birth to SGA children than healthy women. It appears that SGA can be linked to insulin resistance and insulin-dependent growth dysfunction. Therefore, PCOS pregnant women are patients of special obstetrical care.
Gestational diabetes, gestational hypertension, insulin resistance, PCOS, pregnancy
Polycystic ovary syndrome – diagnostic criteria Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women in child-bearing age. Principal clinical symptoms of PCOS include ovulation disorders as well as clinical or laboratory test indicators of androgens excess and polycystic ovaries morphology [1]. The symptoms as well as the intensity vary significantly among different patients. The underlying causes of the syndrome remain unknown, still, it has been determined that immunity to insulin, very often a secondary effect of obesity, is strongly connected with PCOS [1]. The diagnosis of PCOS is based on specific diagnostic criteria. The earlier established criteria of National Institutes of Health (NIH) date back to 1990. The so-called Rotterdam criteria were developed in 2003 [2]. According to NIH criteria [2], PCOS is diagnosed when the following symptoms are found in a patient: the symptoms of excessive androgens’ amount (clinical and biochemical) and rare ovulation, having excluded other disorders that could cause a similar clinical image. The diagnostic criteria established by ESHRE/ASRM (European Society of Human Reproduction and Embryology/ American Society of Reproduction Medicine) in Rotterdam require that the two out of the following three criteria are met
Address for correspondence: Blazej Meczekalski MD PhD, Department of Gynecological Endocrinology, Poznan University of Medical Sciences, ul. Polna 33, Poznan, 60-535 Poland. E-mail: blazejmeczekalski@ yahoo.com
History Received 6 April 2014 Revised 31 August 2014 Accepted 6 October 2014 Published online 30 October 2014
to make the diagnosis [1]: rare ovulation or lack of ovulation, symptoms of androgens’ excess (clinical or biochemical), polycystic morphology of at least one ovary – found in USG examination with at least 12 follicles measuring 2–9 mm in diameter or ovarian volume greater than 10 cm. To make the diagnosis, it is necessary to exclude other underlying causes of such clinical image. The Rotterdam definition is broader and it encompasses a greater number of patients, especially ones without androgens’ excess, whereas in the NIH definition, excessive amount of androgens is the necessary condition. Critics claim that the results of tests carried out on patients with excessive amount of androgens may not necessarily refer to patients without excessive androgens, therefore, the application of specific diagnostic criteria is still raising a lot of controversy [1,3]. The number of parallel definitions of PCOS makes it difficult to precisely determine the frequency of the syndrome. However, reliable and convincing data have been elaborated indicating that PCOS affects 10–15% of women in the general population. Moreover, it has been recognized to be the most common endocrine disorder in women in child-bearing age, thus it constitutes a serious problem in the public health domain [1]. The types of complications observed during pregnancy in PCOS patients were determined quite specifically in 2012 at the expert meeting sponsored by ESHRE/ASRM in Amsterdam [1]. Women with PCOS often have cardiovascular disease (CVD) risk factors. The Androgen Excess and PCOS (AE-PCOS) Society created a panel to provide evidence-based reviews of studies assessing PCOS-CVD risk relationships and to develop guidelines for preventing cardiovascular disease [4].
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PCOS – early pregnancy complications For PCOS patients, infertility is often the key clinical problem related to the syndrome. It should be kept in mind that ovulation disorders cover a wide range of irregularities, corresponding to and coexisting with the maturation of the ovum, which should be taken into consideration alongside the mere fact of the presence or absence of a healthy egg cell. Both hormonal and metabolic disorders may impact the development of early pregnancy in this group of patients [1,5–7]. First irregularities may be observed already during ovulation whose most apparent consequence may be improper quality when it comes to the level of ovum maturity [8]. Still, we have to keep in mind that except for the ovum the ovulation disorders may preclude implantation at many other levels as well. Both quantitative and qualitative disorders are most often related to the hormonal function of granulosa cells and they result in the uterine mucous membrane not being properly prepared to implantation of the embryo [8,9]. Another limitation hindering fertility lies in the lack of proper environment in the area of cervical mucus, which is related to irregular process of capacitation and confirmed lack of coordination in the movement of oviduct cilia, which leads to a slowdown in the migration of the embryo [5]. These disorders may occur with varying intensity, which results in different qualities of oocytes. Consequently, we cannot exclude a situation when full maturity of an ovum is possible and the implantation in a PCOS patient may proceed properly [8]. A lot of attention is given to the probability of disorders occurring in the process of development and growth of ovarian follicles. It is indicated that the probability of disorders occurring at the stage of consumption of nutrients and energy substrates by the growing oocyte from the follicular fluid is a considerable one. Metabolic disorders are quite commonly observed in PCOS, in the first place ones related to glucose homeostasis. The obvious systemic consequence of these disorders is the change in metabolic processes also at the level of ovarian follicles [10]. In the research of granulosa cells’ functions during in vitro fertilization programs, it has been pointed out many times that glucose metabolism in ovarian follicles is significantly disturbed in PCOS patients. Most importantly it has been found that in the granulosa cells’ grown, the use of glucose dependent on insulin is largely reduced [10,11]. It seems highly probable that initial metabolic disorders in the ovarian follicle may intensify throughout the entire oogenesis. This may result in disturbed production of energy for oocytes precluding their proper development [12,13]. Recently, more attention is being given to the possible effect of excessive androgens on the embryo development in early pregnancy. Hyperandrogenemia in PCOS patients may have a long-lasting effect on the development of the embryo first and then the fetus, especially in female offspring. Fetus hyperandrogenisation may cause abnormal epigenetic programming especially for genes that regulate the reproductive and metabolic processes [14].
PCOS – abnormalities during pregnancy Many studies suggest an increase in the risk of obstetric pathology: early miscarriage, gestational hypertension, preeclampsia, gestational diabetes (GD) mellitus-diagnosed during early pregnancy, prematurity, low birth weight or macrosomia, neonatal complications, and cesarean sections. However, it is difficult to conclude clearly about it, because of the heterogeneity of definition of PCOS in different studies. In addition, many confounding factors inherent in PCOS including obesity that are not always taken into account and generate a problem of interpretation. However, it seems possible to conclude that
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Table 1. PCOS and pregnancy complications.
Risk of miscarriage Risk of pre-eclampsia Impaired glucose tolerance Type 2 diabetes
Patients with PCOS (%)
General population (%)
30–50 10 31–35 7.5–10
10–16.6 5 1.6 2.2
PCOS does not increase the risk of placental abruption, HELLP syndrome, liver disease, postpartum hemorrhage, late miscarriage, and stillbirth [15].
Gestational hypertension and pre-eclampsia According to the basic statistical data, 2–5% healthy pregnant women are diagnosed with pregnancy-induced hypertension. In one-third of the women in this group, the problem develops into more severe form of hypertension – pre-eclampsia. There are undoubtedly many risk factors for the development of hypertension during pregnancy. One of these factors is the co-existence of PCOS. It has been found that in pregnant women with PCOS, the systolic, diastolic, and average blood pressure are statistically higher and increased arterial stiffness is observed [16,17]. According to the basic statistical data, the frequency of preeclampsia occurrence is estimated to be 5% in the population of healthy pregnant women and approximately 10% among primaparas (Table 1) [18]. The analysis of available test results indicates that the increased risk is independent from other coexisting factors including age, BMI, abnormal glucose management, medications used in ovulation induction, and arterial hypertension [19–21]. It has to be emphasized although that the risk of developing pre-eclampsia is even higher by coexistence of additional risk factors, which often co-occur with PCOS, particularly obesity and GD. It should be kept in mind that oocyte donation and insemination with donor’s semen also constitute an independent risk factor for pre-eclampsia [20]. Thus, patients affected by PCOS and additional risk factors must be under special control with regard to pre-eclampsia occurrence. Women with PCOS with obesity, dyslipidemia, hypertension, and impaired glucose tolerance are at risk, whereas those with metabolic syndrome or type 2 diabetes mellitus are at a high risk for cardiovascular disease. Body mass index, serum lipid, and blood pressure determinations are recommended for all women with PCOS, as is oral glucose tolerance testing in those with obesity, advanced age, and personal history of GD. Mood disorder assessment is suggested in all PCOS patients [4].
Low birth weight (SGA) and high birth weight (large for gestational age – LGA) According to the data presented in the literature on the subject, infants born to women diagnosed with PCOS are found to be more often SGA. As suggested by the authors of the above-mentioned studies, the main cause of low birth weight occurring more often in infants born to women with PCOS is insulin resistance and insulin-dependent growth disorder [22,23]. There are also several recent reports suggesting that there is a reverse cause and effect relationship. It should be noted that the studies on the increased risk of later occurrence of PCOS symptoms in children with low birth weight remain contradictory. On one hand, the studies by Ibanez [24] in 1998 and Benitez [25] in 2001 document the above correlation as well as the increased
Pregnancy complications
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DOI: 10.3109/09513590.2014.974535
risk of PCOS occurrence in women born with low birth weight. On the other hand, the tests carried out by Laitinen et al. [26] in 2003 have not demonstrated any correlation between low birth weight and PCOS. The opposite situation consisting in high birth weight (LGA) in infants born to women diagnosed with PCOS is insignificantly – approximately 1.5 times – higher than the frequency in infants born to healthy women [19]. Therefore, it should be emphasized that all three groups of complications, i.e. abnormal glucose management, hypertension, and pre-eclampsia as well as fetus growth disorders, have a common etiological background. It is believed that the basic mechanism underlying these disorders may be obesity, abnormal glucose management, and uterine blood flow disorders. Another argument supporting the existence of these correlations is provided by the observation of changes in resistance of blood flow in uterine arteries in women with PCOS and it is observed during the first and second trimesters of pregnancy [27,28]. It should be strongly underlined that obesity itself is connected with several unfavorable consequences during pregnancy. It may on its own be a cause of spontaneous miscarriage, pre-eclampsia, GD, congenital disorders (e.g. heart disorder and spina bifida – split spine), and fetal macrosomia [29,30].
Insulin resistance and GD Impaired glucose tolerance is a commonly observed and predictable disorder in PCOS. According to Legro et al. [31], abnormal glucose tolerance is found in 31–35% patients with this syndrome in comparison to 1.6% in healthy women population. Type 2 diabetes in turn affects 7.5–10% patients in comparison with 2.2% in general population (Table 1) [32]. In women not affected by PCOS, insulin resistance is observed during pregnancy [33]. It should be emphasized that in PCOS patients, insulin resistance may be considerably more intense and may lead to GD. This results in abnormalities during pregnancy [34]. Therefore, GD in PCOS patients is found to occur three times more often than in healthy women [35]. Along with pregnancyinduced hypertension and premature birth, it is one of the most common complications in PCOS patients who got pregnant. D’Anna et al. [36] evaluated retrospectively the prevalence of GD in pregnancies obtained with myo-inositol administration in women with PCOS. The prevalence of GD in the myo-inositol group was 17.4% versus 54% in the control group. Consequently, in the control group, the risk of GD occurrence was more than double compared with the myo-inositol group, with an odds ratio of 2.4 (95% CI 1.3–4.4). There was no difference between the groups in relation to secondary outcome measures [36]. Another observation made by a growing number of authors is that in PCOS patients, the risk of persistent impaired glucose tolerance after GD is raised [37].
PCOS – risk of miscarriage On one hand, the risk of miscarriage in PCOS patients is increased and amounts to 30–50%, which means that for these women, it is three times as high as for healthy women [38]. The results of prospective, randomized trials suggest that the miscarriage instances in PCOS patients occur only in 15–25% of cases, which is a percentage comparable with the frequency of miscarriage in the general population (Table 1) [39,40]. The presented data derived from literature references on the subject reflect huge discrepancies between particular clinical trials conducted with regard to this problem. On the other hand, it should be kept in mind that ultrasound features of PCOS are to be found in 82% of women affected by
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Table 2. Birth complications in patients with PCOS. Complications of birth in patients with PCOS Preterm delivery Cesarean section Operating births Admission to a neonatal intensive care unit Perinatal mortality
OR: OR: OR: OR:
2.20; 1.41; 1.56; 2.31;
95% 95% 95% 95%
CI CI CI CI
1.59–3.04 0.96–2.07 0.93–2.63 1.25–4.26
OR: 3.07; 95% CI 1.03–9.21
recurrent miscarriage. At the same time, the induction of ovulation in women with the syndrome relates to 30% of miscarriage instances. Many authors suggest that there is a relationship between increased LH concentration in the serum and recurrent miscarriage. Proper LH concentration relates to 12% when it comes to miscarriage frequency and high LH concentration to 65% frequency. Raised concentration of LH in follicular phase may lead to premature development of the oocyte, whereas high concentration of LH in the luteal phase may cause abnormalities in the functions of endometrium during implantation [41].
PCOS – delivery complications The current state of knowledge allows us to state that the risk of complications occurring during delivery in PCOS patients is not sufficiently well determined. This pertains both to the percentage and to the nature of complications predicted. Based on the meta-analyses for PCOS patients, it has been found that there is an increased risk of premature birth (OR: 2.20; 95% CI 1.59–3.04), Cesarean section (OR: 1.41; 95% CI 0.96– 2.07), and necessity of operating births (OR: 1.56; 95% CI 0.93– 2.63) (Table 2) [19]. The data presented are unfortunately only preliminary ones. It seems necessary to extend the research, especially statistical, to large groups of PCOS patients to make the results obtained commonly acceptable [19]. Based on the current state of knowledge, i.e. on one hand, with regard to the observed general increase of the risk of obstetric complications and, on the other hand, the disorders in infants’ birth weight, it is also proposed that differentiation of risk levels be introduced depending on the different phenotypic characteristics of PCOS. Therefore, the relations presented above should provide a tentative basis to determine appropriate criteria, which would enable to identify quite unequivocally high-risk PCOS patients in the future. Consequently, it will be further possible to develop proper procedures for obstetric treatment in these cases in order to avoid or reduce the risk of obstetric complications [19,42].
PCOS – metformin treatment and pregnancy complications It should be unequivocally stated that the use of metformin in patients with PCOS who pursue pregnancy is a controversial issue. There are many reports where it is emphasized that no significant changes have been observed as for improving fertility and obtaining a better birth rate as compared with the group of PCOS patients who have not taken metformin [43,44]. Based on these observations, there is nowadays a rather widely held view that routine use of metformin in PCOS patients is not recommended. On one hand, meta-analysis published in 2009 demonstrating that the use of metformin before pregnancy did not affect the risk
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of miscarriage in PCOS patients [32] should provide quite a moderate argument supporting the view presented above. On the other hand, there are several studies indicating that there is a relationship between the use of metformin in PCOS patients already during pregnancy and the reduction of severe obstetric complications frequency [42]. To counterbalance such standpoint one may refer to extensive, multicenter studies, which do not validate the benefits arising from the use of metformin neither with regard to the reduction of pregnancy complications nor the change in fetal body weigh [32]. With the current knowledge, the issue of possible benefits arising from the use of metformin has not been unequivocally resolved. Further multicenter research is required.
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Summary To sum up, it needs to be stated that extensive scientific and clinical research is necessary to determine better criteria for PCOS diagnosis. The effort put in proper diagnostics of PCOS will be beneficial for patients and clinical practitioners alike, improving the effects of treatment of this common syndrome. As for abnormalities and complications during pregnancy and delivery in PCOS patients, it has been noted that in the recent years, there has been an increased number of tests conducted to assess the course of pregnancy and pregnancy complications in patients with this disorder. Such tests may contribute to developing studies and recommendations regarding pregnant women who have been earlier diagnosed with PCOS. It should be strongly emphasized that there is a huge need to conduct research including an extensive group of PCOS patients during pregnancy and in postnatal period with the aim of developing the standards for treatment of this group of patients.
Declaration of interest The authors report that they have no conflicts of interest.
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