Hum. Reprod. Advance Access originally published online on March 16, 2007
Human Reproduction 2007 22(6):1532-1539; doi:10.1093/humrep/dem028
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Vascular dysfunction during pregnancy in women with polycystic ovary syndrome
1 Academic Department of Obstetrics and Gynaecology London, UK 2 Vascular Haemodynamic Unit, Department of Surgery, Royal Free and University College Medical School, London, UK
3 To whom correspondence should be addressed at: Academic Department of Obstetrics and Gynaecology, Royal Free and University College Medical School, The Royal Free Hospital, Pond Street, London NW3 2PF, UK. Tel.: +44 20 7830 2435; Fax: +44 20 7830 2261; E-mail: p.hardiman{at}medsch.ucl.ac.uk
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Abstract |
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BACKGROUND: An association has been proposed between polycystic ovary syndrome (PCOS) and pregnancy-induced hypertensive disorders. Ambulatory blood pressure and carotid artery elasticity were therefore prospectively investigated in matched PCOS and control pregnancies.
METHODS: Twenty two PCOS–control subject pairs with singleton pregnancies, matched for age, body mass index, parity and ethnicity, were recruited in the first trimester (T1, 11–13 weeks). Ambulatory blood pressure recording for 24 h and carotid artery ultrasound for elasticity estimation were performed in T1 and in the second (T2, 22–24 weeks) and third (T3, 32–34 weeks) trimesters.
RESULTS: At nearly all time points during gestation, ambulatory systolic, diastolic and mean arterial pressures were elevated in PCOS versus control pregnancies. Carotid artery stiffness index was greater and compliance was less in PCOS pregnancies compared with controls. Differences in night-time systolic pressure and carotid artery elasticity were greatest in T3. PCOS also increased the incidence of pregnancy-induced hypertension (6 of 22 cases versus 0 of 22 in controls; P = 0.011).
CONCLUSIONS: Pregnant women with PCOS have higher baseline ambulatory blood pressure and impaired arterial elasticity, suggestive of disturbed vascular adaptation to pregnancy.
Key words: arterial function/blood pressure/heart rate/polycystic ovary syndrome/pregnancy-induced hypertension
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Introduction |
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Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in the human and is associated with long-term morbidity, due to type II diabetes and endometrial cancer, and cardiovascular risk markers, including obesity (Balen et al., 1995
), dyslipidaemia (Wild et al., 1985; Conway et al., 1992; Talbott et al., 1998), hypertension (Conway et al., 1992; Talbott et al., 1998), impaired glucose tolerance (Dunaif et al., 1987; Conway et al., 1990; Robinson et al., 1993) and insulin resistance (Dunaif, 1993). In the USA, 46% of women with PCOS have the metabolic syndrome, which is twice the rate in the adult female population (Glueck et al., 2003). Indeed, PCOS is associated with a 5–10-fold increased lifetime risk of type II diabetes (Ovalle and Azziz, 2002).
Arterial function is modified in women with PCOS: we have noted decreased arterial viscoelasticity and resistance (Lakhani et al., 2000, 2002), abnormal arterial vasodilatory responses (Lakhani et al., 2000) and increased carotid artery intima-media thickness (Lakhani et al., 2004), all suggestive of early vascular disease, in women with PCOS aged <35 years. The association between PCOS and hypertension is less well defined as some studies have found conclusive evidence of this association (Conway et al., 1992; Elting et al., 2001), although others have not (Sampson et al., 1996), due to differences in study design and measurement methods. Several studies (Zimmermann et al., 1992; Sampson et al., 1996; Meyer et al., 2005) have found no effect of PCOS on ambulatory blood pressure in age and body mass index (BMI)-matched subjects, whereas blood pressure assessed by sphygmomanometer is sometimes elevated in women with PCOS (Conway et al., 1992; Talbott et al., 1995). Such elevations tend however to be correlated with elevated BMI in the PCOS subjects and are not seen when case–control pairs are BMI-matched (Faloia et al., 2004). Conversely, Holte et al. (1996) noted elevations of 6 mmHg in ambulatory daytime systolic and mean arterial blood pressure in PCOS versus control subjects, even after adjusting for BMI, fat distribution and insulin resistance.
In pregnancy, PCOS is associated with an increased prevalence of gestational diabetes (Urman et al., 1997) and of ‘small for gestational age’ babies with a lower mean birthweight, relative to controls, but not a general decrease in birthweight (Sir-Petermann et al., 2005). An association between PCOS and pregnancy-induced hypertensive disorders including pre-eclampsia has been proposed (Gjonnaess, 1989; de Vries et al., 1998; Mikola et al., 2001), and this influences American College of Physicians guidelines regarding the treatment of pregnancies complicated by PCOS. Other studies have however found no increased prevalence of pre-eclampsia in women with PCOS (Haakova et al., 2003). If such an association exists, it is unclear whether or not PCOS is an independent risk factor, because risk factors co-associated with PCOS, such as increased body mass index, have not been controlled for in most studies (Gjonnaess, 1989; de Vries et al., 1998; Mikola et al., 2001). Studies have also been retrospective and have used diagnostic criteria for PCOS which are inconsistent with the current ESHRE/ASRM consensus criteria (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004). The present study was designed to test the hypothesis that PCOS disturbs vascular adaptation to pregnancy, leading to modifications in arterial elasticity and blood pressure in pregnant women with PCOS. We prospectively compared ambulatory blood pressure and heart rate and arterial elasticity in women with PCOS and well-matched healthy controls in the first (T1), second (T2) and third (T3) trimesters of pregnancy.
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Materials and Methods |
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This prospective study was performed between July 2003 and March 2005 on 22 pregnant women with PCOS, pair-matched to 22 pregnant controls for age (±3 years), (BMI) at 11–13 week gestation (±3.0 kg m–2), ethnicity and parity (nulliparous/parous). Subjects, with singleton pregnancies at 8–13-week gestation, were recruited from the antenatal and gynaecology clinics at the Royal Free Hospital, London, UK. Subjects with PCOS were identified by questioning after referral; medical records were investigated to confirm the PCOS diagnosis using the 2004 ESHRE/ASRM criteria (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004
). Controls were healthy pregnant women with no PCOS symptoms. All subjects achieved pregnancy without pharmacological fertility treatment, and none were on prescription medication. Exclusion criteria included metformin treatment, gonadotrophin treatment, in vitro fertilization procedures, a history of diabetes, smoking, drug/alcohol abuse, chronic hypertension or respiratory, cardiovascular, renal or thyroid disease. The study was approved by the Royal Free Hospital Ethics Committee, and consent was obtained from all subjects.
The date of confinement was calculated relative to the last menstrual period and was confirmed, with the singleton nature of the pregnancy, by ultrasound scan at 11–13-week gestation. Diagnoses of pregnancy induced hypertension in antenatal clinics were obtained from medical records after delivery. Systolic and diastolic blood pressures were clinically normal (<140/90 mmHg) in all subjects in early pregnancy (i.e. <20 weeks); none suffered from chronic hypertension (Baumgart and Kamp, 1998). Gestational hypertension was defined as systolic pressure/diastolic pressure >140/90 mmHg on two measurements >6 h apart, at >20-week gestation or more, normalizing by 4–6 weeks post-partum (Williams et al., 2004). Pre-eclampsia was defined as gestational hypertension with proteinuria (>300 mg per day) (Williams et al., 2004). Pregnancy-induced hypertension defined subjects with gestational hypertension or pre-eclampsia.
Ambulatory blood pressure monitoring was performed in the first (11–13 weeks), second (22–24 weeks) and third (32–34 weeks) trimesters using a Spacelabs 90217 monitor (Spacelabs, Washington, USA) (Baumgart and Kamp, 1998). Measurements were made on the non-dominant arm two hourly for 24-hr. Non-physiological readings were deleted and the 24-h data rejected if the deletion rate was >20%. Subjects were instructed to continue with normal activities and diet but to minimize movement of the measured arm during the two hourly blood pressure measurements, which each took 
60 s, to improve accuracy of the reading. Blood pressure was also taken with a sphygmomanometer each time the ambulatory monitor was fitted, using Korotkoff sound phase V to determine diastolic pressure. Carotid artery stiffness index and compliance were also measured within 1 week of the ambulatory blood pressure, using established ultrasound methods (Lakhani et al., 2002). Subjects were rested supine for 15 min, then the right common carotid artery was examined by ultrasound with the head extended to the left. Real-time B-mode and M-mode images of the arterial wall motion were recorded using a 7.5 MHz linear array probe, perpendicular to the artery, with a duplex scanning system (Pie 350; Pie Medical Systems, Maastricht, The Netherlands). Signal output was to an echo-locked wall tracking system (Wall Track; Pie Medical Systems) (Lakhani et al., 2002). Changes in luminal diameter in a cardiac cycle were measured at discrete points in triplicate within 3 cm proximal to the carotid bifurcation. Arterial stiffness index and compliance were calculated as described (Lakhani et al., 2002), with the stiffness index being less dependent on blood pressure than compliance (Hayashi, 1993).
Preliminary arterial elasticity data indicated coefficients of variation of 22%, greater than for ambulatory pressure data. Power analysis calculated that 22 PCOS–control pairs provided a Power of 0.95 to detect a 25% difference in arterial elasticity between groups, and thus a Power >0.95 to detect a 25% difference in blood pressure. Statistical testing of data was performed using SPSS version 11. PCOS–control and daytime–night-time differences were tested by paired t-test, after verifying that differences were normally distributed. Differences between subgroups, or related to gestational stage, were tested by ANOVA, after data were confirmed as satisfying homogeneity of variance and normality requirements. Bonferroni's test was used for post hoc analysis, and differences in pregnancy-induced hypertension prevalence were tested using Fisher's exact test. All values are means ± SEM unless noted. A significant level of P 
0.05 was used, but P values approaching this level are noted.
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Results |
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No significant differences between PCOS and control women were noted in height, weight and BMI at 11–13-week gestation, or in age, parity or ethnicity (Table 1); thus PCOS–control pair-matching was successful. All pregnancies were singleton on ultrasound in T1 and at delivery. There were no differences between PCOS and control subjects in the estimated gestational ages in T1 and T2 at which ambulatory blood pressure and arterial elasticity measurements were performed (Table 1). There was a small difference in T3, with blood pressure and arterial elasticity being measured
0.5 weeks earlier in PCOS subjects than in controls (Table 1).
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Systolic, diastolic and mean arterial pressures were nearly always elevated in PCOS subjects relative to controls during 24-h ambulatory monitoring in T1, T2 and T3, and the differences seemed more pronounced in late gestation (Fig. 1A and B). In contrast, heart rate was more variable and was not consistently different (data not shown). Blood pressure and heart rate parameters seemed to vary diurnally (Fig. 1A and B) therefore night-time (00.00–06.00), daytime (16.00–22.00) and 24 h (00.00–24.00) averaged systolic, diastolic and mean arterial pressures and heart rates were calculated (Table 2). Mean daytime systolic, diastolic and mean arterial blood pressures and heart rate were indeed higher than mean night-time values in both control and PCOS subjects throughout gestation. Moreover, daytime, night-time and 24 h systolic, diastolic and mean arterial pressures were elevated in PCOS versus control pregnancies throughout gestation, as was daytime and 24-h, but not night-time, heart rate (Table 2). Gestational stage had no effect on daytime, night-time or 24-h systolic, diastolic and mean arterial pressures or heart rates in controls, but in PCOS pregnancies, night-time systolic pressure increased 8% between T2 and T3, and night-time mean arterial pressure also tended (P = 0.053) to do so.
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Carotid artery stiffness index and compliance in women with PCOS were greater and less, respectively, than in controls in each trimester (Fig. 2). Stiffness index increased in women with PCOS as pregnancy progressed (P = 0.001), by 30% between T2 and T3 (P = 0.004), whereas it did not vary with gestation in controls (P = 0.380). Thus, stiffness index in PCOS subjects was 1.6-fold greater in T1 and T2 and 2.1-fold greater in T3 than in controls (Fig. 2A). Compliance increased in controls (P = 0.039) but decreased in PCOS subjects (P = 0.007) as pregnancy progressed. Thus in T3, compliance was 17% greater in controls (P = 0.035) and 20% less in PCOS pregnancies (P = 0.022) than in T1. PCOS therefore reversed the normal increase in compliance during pregnancy, so that compliance was 37% less in women with PCOS than in controls in T1 and 56% less in T3.
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A review of clinical records post-delivery revealed that the prevalence of clinically diagnosed pregnancy-induced hypertension was greater in PCOS pregnancies (three cases each of pre-eclampsia and gestational hypertension; P = 0.011) than in controls, who were all clinically normotensive (Table 3). Birthweight was 10% lower in PCOS women than in controls (Table 3), but this was not due to a difference in the baby sex ratio (male:female 13 : 9 versus 15 : 7 in controls; p = 0.755 by Fishers Exact test) or gestation length (Table 3).
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Clinically normotensive and pregnancy-induced hypertensive PCOS pregnancies both exhibited comparable changes to the total PCOS group, relative to matched controls, in 24-h, daytime and night-time averaged blood pressures and arterial elasticity parameters throughout gestation (data not shown). Differences between normotensive PCOS pregnancies and controls were nearly always significant, whereas differences between hypertensive PCOS pregnancies and controls, though often greater, were generally not significant due to variability and the small sample size (n = 6). In contrast, 24-h, daytime and night-time averaged heart rate was, throughout gestation, 10–13 beats per minute higher in hypertensive PCOS pregnancies than in matched controls, but were not different between normotensive PCOS pregnancies and controls (Table 4).
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Birthweight was reduced by 11% in normotensive PCOS women relative to matched controls (Table 3), but was unaffected in hypertensive PCOS pregnancies, because low birthweight in the three pre-eclamptic PCOS subjects (2.72 ± 0.08 kg versus 3.60 ± 0.10 kg in matched controls, P < 0.02) was balanced by high birthweight in the three PCOS subjects with gestational hypertension (3.99 ± 0.43 kg versus 3.60 ± 0.15 kg in matched controls; not significant). Gestation length was reduced in the hypertensive, but not in normotensive, PCOS pregnancies relative to controls (Table 3).
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Discussion |
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These results demonstrate for the first time in a prospective study that blood pressure is elevated throughout pregnancy in women with PCOS who spontaneously conceived, compared with matched controls; these increases are independent of age, BMI, parity and ethnicity. Their clinical importance is underscored by our findings that 27% of the women with PCOS developed pregnancy-induced hypertension and that mean birthweight was 360 g less in PCOS pregnancies than in matched controls. Our data provide the first evidence of vascular maladaptation in pregnancy in women with PCOS in that arterial elasticity, which is impaired in T1, decreases during T2 and T3 in women with PCOS, whereas increasing in healthy controls.
Systolic, diastolic and mean arterial pressures were elevated throughout pregnancy at nearly all times of the day and night in women with PCOS versus age, BMI, parity and ethnicity matched controls. Daytime and 24-h heart rate were also elevated in PCOS pregnancies. Mean night-time systolic pressure increased in women with PCOS as gestation progressed, such that control–PCOS differences in this parameter were greater near term. The effects of PCOS were not related to measurements being made at different gestational ages, as there were no differences in mean measuring times in T1 and T2 between PCOS and control pregnancies and only a 0.5-week difference in T3. Blood pressure and heart rate parameters also tended not to change or to increase only marginally (e.g. night-time systolic pressure) as gestation progressed.
No ambulatory blood pressure data were collected before pregnancy because subjects were recruited in antenatal and gynaecology clinics when their pregnancies were first confirmed. This study design was adopted because it would have been logistically difficult to perform prospective pre-pregnancy measurements on enough subjects to ensure recruitment of the 22 pregnant matched PCOS–control pairs, which Power analysis indicated were required. Ideally, pre-pregnancy data would be presented and it is possible that our results reflect blood pressure differences existing prior to pregnancy. We think this unlikely because several studies (Zimmermann et al., 1992; Sampson et al., 1996; Meyer et al., 2005) found no effect of PCOS on ambulatory blood pressure in age and BMI-matched non-pregnant subjects. In addition, blood pressure assessed by sphygmomanometer is sometimes elevated in women with PCOS (Conway et al., 1992; Talbott et al., 1995) but not when subjects are BMI-matched (Faloia et al., 2004). Conversely, Holte et al. (1996) noted elevations of 6 mmHg in ambulatory daytime systolic and mean arterial blood pressure in non-pregnant PCOS versus control subjects, even after adjusting for BMI, fat distribution and insulin resistance. In the present study, women with PCOS exhibited elevations in these blood pressure parameters of 14 and 10 mmHg, respectively, in T1, and 18 and 14 mmHg, respectively, in T3. Thus, even if PCOS does influence ambulatory blood pressure in non-pregnant women to the degree found by Holte et al. (1996), our data suggest PCOS-related elevations in blood pressure are exacerbated during pregnancy.
Elevated blood pressure has been noted in pregnant women with PCOS in late gestation (Fridstrom et al., 1999; Sir-Petermann et al., 2005), but not in well-matched subjects with ambulatory blood pressure monitoring, which reduces variability associated with the sphygmomanometer and ‘white coat’ hypertension. An increased incidence of pregnancy-induced hypertension and pre-eclampsia in PCOS pregnancies has also been noted in some (Diamant et al., 1982; Gjonnaess, 1989; de Vries et al., 1998; Fridstrom et al., 1999; Radon et al., 1999; Mikola et al., 2001) but not all (Haakova et al., 2003) studies and ascribed to PCOS (Fridstrom et al., 1999) or associated factors such as ovulation induction (Diamant et al., 1982), hyperinsulinaemia (Radon et al., 1999), elevated BMI (Gjonnaess, 1989) and nulliparity (Mikola et al., 2001). The independent effects of BMI, pre-pregnancy endocrine profile and infertility treatment have been questioned however (de Vries et al., 1998). In the present study, BMI was controlled for and ovulation induction was excluded, yet elevations in ambulatory blood pressure were still observed in women with PCOS throughout pregnancy. These blood pressure elevations were seen in PCOS subjects who developed pregnancy-induced hypertension (n = 6), although statistical significance was often limited by sample size, and also (with a good significance level) in women with PCOS who were normotensive by current clinical criteria (n = 16). Normotensive women with PCOS also exhibited an 11% reduction in birthweight relative to matched controls.
Arterial vasodilatation and elasticity increase early in pregnancy to accommodate increased maternal total blood and cardiac output volumes (Spaanderman et al., 2000b). This occurs to a degree in the carotid artery (Spaanderman et al., 2000b) as noted in controls in this study. In women with a history of pre-eclampsia, vascular adaptation can fail in subsequent pregnancies leading to hypertension (Spaanderman et al., 2000b). Even when not pregnant, arterial elasticity is reduced and endothelial function is abnormal in such women (Spaanderman et al., 2000a), as also seen in women with PCOS (Lakhani et al., 2002). We noted that reduced arterial elasticity was seen in PCOS pregnancies, which worsened as gestation progressed. This novel finding can be considered both a risk factor and marker of hypertension (Franklin, 2005) and may be related to their increased risk of pregnancy-induced hypertension (Spaanderman et al., 2000b), although arterial elasticity reductions were seen in PCOS pregnancies that were clinically normotensive as well as in those which developed pregnancy-induced hypertension. Our results show a failure of arterial adaptation in PCOS pregnancies; carotid compliance fell as pregnancy progressed rather than rising as in the controls (Poppas et al., 1997). The mechanisms causing this difference are unclear, but non-enzymatic glycation of vessel wall elastin and collagen influence elasticity in type II diabetes (Ilegbusi et al., 1999); PCOS complicated with hyperglycaemia and hyperinsulinaemia may also be influenced. There were no differences in the mean times of arterial elasticity measurement in T1 and T2, but measurements in PCOS subjects were made 0.45 weeks earlier than in controls in T3. It is unlikely that this difference, given the rates of gestational change in arterial elasticity, could explain the PCOS–control differences in these parameters.
This study was controlled for age, BMI, ethnicity and parity, thus the elevations in blood pressure, heart rate and pregnancy-induced hypertension incidence are likely PCOS related, perhaps to co-associated hyperandrogenaemia, hyperinsulinaemia or insulin resistance. Serum androgens are elevated in PCOS, more so in pregnancy (Sir-Petermann et al., 2002), and androgens induce production of the vasoconstrictors endothelin (van Kesteren et al., 1998) and angiotensinogen (Ellison et al., 1989). Indeed, serum androgens are raised in T2 in women who develop pre-eclampsia (Carlsen et al., 2005). Pre-pregnancy endocrine profile has however been said to be similar, irrespective of whether PCOS pregnancies are normotensive or hypertensive, albeit supporting data were not presented (de Vries et al., 1998). Thus it remains possible that androgens influence blood pressure in PCOS pregnancies. In the present study, serum total testosterone in T1 was elevated in PCOS versus control pregnancies (2.96 ± 0.10 versus 1.50 ± 0.14 nM, respectively, P < 0.001), but dehydroepiandrosterone sulphate was not (4.22 ± 0.40 versus 5.29 ± 0.65 µM, respectively, P = 0.234). Serum total testosterone in T1 was correlated with many of the blood pressure parameters in T1 when all data were analysed, but few correlations were noted within the separate PCOS and control data sets. This suggests blood pressure parameters are influenced by PCOS–control status rather than by the co-variant serum total testosterone. Serum total testosterone is not however an ideal indicator of bioactive testosterone levels and serum free testosterone would ideally have been assayed, and levels correlated with blood pressure parameters. Unfortunately, the quantity of serum stored was insufficient to allow serum free testosterone assay.
Hyperinsulinaemia is also common in PCOS and can increase blood pressure via activation of the sympathoadrenal system (Reaven et al., 1996) and renal cation transport (Doria et al., 1991) or by disturbing endothelial function (Gibbons and Dzau, 1994). Indeed, endothelial dysfunction is important in the pathology of pre-eclampsia (Davis et al., 2001; Ramsay et al., 2002; Takata et al., 2002) and is seen in non-pregnant PCOS women (Orio et al., 2004; Lakhani et al., 2005). It was not possible to estimate insulin in this study, as appropriate blood samples were not available. Insulin resistance was also not measured, systemically or in arterial biopsies, yet variation in arterial insulin resistance could also cause blood pressure modifications. The increases in daytime and 24 h heart rate in PCOS pregnancies may therefore result from sympathoadrenal activation related to hyperinsulinaemia (Reaven et al., 1996). Increases in heart rate in women with PCOS, even in the first trimester, were greater in those who went on to develop pregnancy-induced hypertension, albeit the sample size in which this occurred was modest (n = 6). It is interesting to speculate though whether first trimester ambulatory heart rate monitoring might allow prediction of hypertension risk later in pregnancy. Interestingly, the effects of hyperinsulinaemia and raised serum androgens have been shown to be greatly reduced by a high protein and low carbohydrate diet and metformin (Glueck et al., 2004b).
PCOS decreased birthweight and increased incidence of pregnancy-induced hypertension. In contrast, Sir-Petermann et al. (2005) reported similar mean birthweights in PCOS and control pregnancies, but an increased prevalence of small for gestational age babies with greater growth restriction in PCOS mothers. Other studies have also found PCOS to have no effect on birthweight (Fridstrom et al., 1999; Mikola et al., 2001; Haakova et al., 2003). Differences between studies may arise because of variability in subject matching and exclusion criteria, as well as in subject age, socio-economic status, diet, parity and ethnicity.
These results support the hypothesis that PCOS, which affects up to 1 in 10 women, impairs the physiological vascular adaptation to pregnancy, resulting in maternal hypertension and impaired fetal growth. These effects were noted in women who conceived spontaneously without pharmacological fertility treatments. Deficits may be worse in women with PCOS who conceive after fertility treatment, since they tend to have more severe PCOS symptomatology. The increased prevalence of pregnancy-induced hypertension and reduced birthweight in PCOS pregnancies noted in this study indicate that appropriate surveillance should be targeted at PCOS pregnancies to manage the risks to mother and baby associated with these conditions. Treatment with metformin may be a suitable option since it appears to be safe when used in pregnancy and may help to protect women with PCOS against the development of pre-eclampsia (Glueck et al., 2004a).
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This study was supported by a grant from the Annie McCall Trust and by a Clinical Research Fellowship, held by SH, from the North London Nuffield Hospital.
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Submitted on August 10, 2006; resubmitted on November 6, 2006; accepted on December 1, 2006.
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