OBJECTIVE: To estimate the potential association of chorionic villus sampling (CVS) with subsequent development of hypertensive disorders of pregnancy and to evaluate whether any such potential association remains significant after adjusting for maternal characteristics and components of first-trimester screening.
METHODS: We included live singleton pregnancies at 11 0/7 to 13 6/7 weeks surviving to beyond 23 weeks of gestation with available measurements of free β-hCG and pregnancy-associated plasma protein A. We excluded pregnancies resulting in miscarriage or termination before 24 weeks of gestation, women with no known pregnancy outcome, and women who had an amniocentesis. Multiple logistic regression analysis was used to determine whether CVS, in addition to factors in the maternal history and characteristics, made a significant contribution to the development of preeclampsia and gestational hypertension.
RESULTS: Included in the study were 31,138 women, of whom 697 (2.2%) had preeclampsia subsequently develop, and 857 (2.8%) had gestational hypertension develop. In 2,278 (7.3%) individuals, a CVS was performed. Multiple logistic regression analysis demonstrated that although there were significant contributions from maternal factors and serum biochemistry, a CVS in the first trimester did not contribute significantly to subsequent development of early preeclampsia (P=.677), late preeclampsia (P=.535), or gestational hypertension (P=.848).
CONCLUSION: There is no association between performing a CVS in the first trimester and subsequent development of hypertensive disorders of pregnancy.
LEVEL OF EVIDENCE: II
There is no association between performing a chorionic villus sampling in the first trimester and subsequent development of hypertensive disorders of pregnancy.
From the Department of Fetal Medicine, Institute for Women's Health, University College Hospital, and Department of Fetal Medicine, Kings College Hospital, London, United Kingdom.
Supported by a grant from The Fetal Medicine Foundation (UK Charity number 1037116).
Corresponding author: Professor K. H. Nicolaides, Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, Denmark Hill, London SE5 9RS; e-mail: email@example.com.
Financial Disclosure The authors did not report any potential conflicts of interest.
There is conflicting evidence in the literature about whether chorionic villus sampling (CVS) in early pregnancy increases the risk of preeclampsia. A randomized study comparing the safety of CVS and early amniocentesis at 11 to 14 weeks reported that in the CVS group the rates of preeclampsia and/or gestational hypertension were significantly increased and hypothesized that focal placental disruption may lead to subsequent development of maternal hypertension.1,2 Three subsequent case–control studies reported contradictory results. Adsumalli et al3 compared 1,540 women who had CVS and 840 control women who did not have an invasive test and reported that, although the overall risk for hypertensive disorders was similar in the two groups, CVS was associated with an increase in the incidence of severe preeclampsia. Grobman et al4 compared 152 women who had CVS and 653 control women who did not have an invasive procedure and reported that, although the overall risk for hypertensive disorders was similar in the two groups, in nulliparous women CVS was associated with an increase in the incidence of preeclampsia. Odibo et al5 compared 5,096 women who had CVS with 4,002 women who did not have any invasive procedure and reported that, in the CVS group, the incidence of preeclampsia was decreased.
These conflicting results may be the consequence of differences in study design, including the selection of control women and failure to adjust for some or all maternal characteristics that contribute to the development of preeclampsia, including maternal body mass index (BMI) and personal or family history of preeclampsia. In addition, none of these studies examined the contribution of maternal serum levels of pregnancy-associated plasma protein-A (PAPP-A). This protein is routinely measured in the first trimester for assessing patient-specific risk of chromosomal defects and is known to be lower in women destined to have preeclampsia.6,7 The aim of our study was to estimate the potential association of CVS at 11 to 14 weeks of gestation with subsequent development of hypertensive disorders in pregnancy by comparison with a large, unselected screening population and to estimate whether any such association remains significant after adjusting for maternal serum concentration of PAPP-A and maternal characteristics that are known to contribute to the development of preeclampsia.8
MATERIALS AND METHODS
At King's College Hospital, London, United Kingdom, we examine women referred from other hospitals for CVS because routine screening has identified them as being at increased risk of chromosomal defects. In addition, we offer first-trimester combined screening for chromosomal defects to all women attending for pregnancy care. In both the referred and the screened women, we perform an ultrasound scan to measure fetal crown–rump length and nuchal translucency thickness and to measure the maternal serum concentration of PAPP-A and free β-hCG (Delfia Xpress Analyzer; Perkin Elmer Life and Analytical Sciences, Waltham, MA). The results of maternal age, fetal nuchal translucency, and serum-free β-hCG and PAPP-A are used to estimate the patient-specific risk for trisomy 21.9,10 In women identified as being at high risk of chromosomal defects, CVS is offered for fetal karyotyping and this is performed within 2 days of screening. Maternal characteristics, ultrasound and biochemistry findings, and the results from analysis of the CVS samples are entered into a fetal database.
This study, in which we estimated the possible contribution of CVS to the development of preeclampsia and gestational hypertension, is part of a large prospective study on early prediction of pregnancy complications. The study was approved by King's College Hospital Ethics Committee, and all participants gave written informed consent.
Women were asked to complete a questionnaire on age, racial origin (white, black, South Asian, East Asian, or mixed), cigarette smoking during pregnancy (yes or no), method of conception (spontaneous, assisted by ovulation drugs, or in vitro fertilization), medical history (including chronic hypertension and preexisting diabetes mellitus), parity (parous or nulliparous if no delivery beyond 23 6/7 weeks of gestation), obstetric history (including previous pregnancy with preeclampsia), and family history of preeclampsia in the mother (yes or no). The questionnaire was then reviewed by a doctor together with the woman. The maternal weight and height were measured, and BMI was calculated in kg/m2.
Data on pregnancy outcome were obtained from the computerized maternity unit records. The obstetric records of all women with preexisting or pregnancy- associated hypertension were examined to determine if the condition was chronic hypertension, preeclampsia, or gestational hypertension. The definitions of preeclampsia and gestational hypertension were those of the International Society for the Study of Hypertension in Pregnancy.11 In gestational hypertension the systolic blood pressure should be 140 mm Hg or more, the diastolic blood pressure should be 90 mm Hg or more, or a combination of both on at least two occasions 4 hours apart, developing after 20 weeks of gestation in a previously normotensive woman in the absence of significant proteinuria. In preeclampsia, there should be gestational hypertension with proteinuria of 300 mg or more in 24 hours, or two readings of at least ++ on dipstick analysis of midstream or catheter urine specimens if no 24-hour collection is available. In preeclampsia superimposed on chronic hypertension, significant proteinuria (as defined) should develop after 20 weeks of gestation in women with known chronic hypertension (history of hypertension before conception or at the booking visit before 20 weeks of gestation in the absence of trophoblastic disease).
The entry criteria were singleton pregnancy with live fetus at 11 0/7 to 13 6/7 weeks and surviving to beyond 23 weeks of gestation, with available measurements of free β-hCG and PAPP-A. We excluded pregnancies resulting in miscarriage or termination before 24 weeks of gestation, women with unknown pregnancy outcome, and women who had an amniocentesis.
Comparison of the maternal and fetal characteristics in the CVS and non-CVS groups was by the χ2 test for categorical variables and Mann-Whitney test for continuous variables. The prevalence of hypertensive disorders in the two groups was compared using the χ2 test. Multiple logistic regression analysis with backward stepwise elimination was used to determine whether CVS, in addition to factors among the maternal and fetal characteristics, made a significant contribution to the development of preeclampsia and gestational hypertension. The statistical software package SPSS 16.0 (SPSS, Chicago, IL) was used for data analysis.
During the study period (March 2006 to June 2009), we examined 34,491 singleton pregnancies. We excluded 3,353 (9.7%) because they had missing outcome data (n=2,052), the pregnancies resulted in miscarriage before 24 weeks (n=398), the pregnancies were terminated (n=747), or they had amniocentesis (n=156). In the remaining 31,138 individuals, 697 (2.2%) subsequently had preeclampsia develop, including 106 who required delivery before 34 weeks of gestation (early preeclampsia) and 591 with late preeclampsia; 857 (2.8%) had gestational hypertension develop, and 29,584 (95.0%) were unaffected by preeclampsia or gestational hypertension. In 2,278 (7.3%) of the 31,138 cases, a CVS was performed at 11 to 13 weeks. The baseline characteristics of the women with no follow-up were similar to those included in the study, but in the former the median maternal age was significantly lower (30.8 compared with 32.3 years), the BMI was lower (23.6 compared with 24.2 kg/cm2), the prevalence of nonwhite racial origin was higher (32.7 compared with 28.1%), and there was a lower prevalence of parous women (38.8% compared with 52.1%) and those with chronic hypertension (0.3% compared with 1.1%) and diabetes mellitus (0.2% compared with 0.8%).
The maternal and fetal characteristics of the outcome groups are compared in Table 1. In the group that had CVS, compared with the control group, women were older, there were fewer blackwomen, more parous women with no history of preeclampsia, more women had used ovulation induction drugs for conception, and the median PAPP-A multiples of the median (MoM) was lower and free β-hCG MoM was higher. There was no significant difference in the prevalence of early preeclampsia, late preeclampsia, or gestational hypertension between the CVS and the non-CVS groups (Table 2). In the group who underwent CVS, compared with the control group, women were older, there were fewer black women, and more women had used ovulation induction drugs for conception. There was no significant difference in the prevalence of early preeclampsia, late preeclampsia, or gestational hypertension between the CVS and the non-CVS groups (Table 2).
Multiple logistic regression analysis demonstrated that, in women who subsequently had early preeclampsia develop, there were significant contributions from black and Asian racial origin, maternal BMI, assisted conception, chronic hypertension, personal or family history of preeclampsia, log PAPP-A MoM, and log free β-hCG MoM, but not from CVS (P=.677), maternal age (P=.414), smoking (P=.054), or maternal diabetes (P=.292, R2=0.145, P<.001; Table 3).
In the prediction of late preeclampsia, there were significant contributions from black, South Asian, and South East Asian racial origin, maternal BMI, chronic hypertension, personal or family history of preeclampsia, and log PAPP-A MoM, but not from CVS (P=.535), maternal age (P=.088), mode of conception (P=.514), maternal diabetes (P=.623), smoking (P=.644), or log free β-hCG MoM (P=.062, R2=0.106, P<.001; Table 3). Similarly, in the case of gestational hypertension, there were significant contributions from black racial origin, maternal age, higher BMI, personal or family history of preeclampsia, smoking, assisted conception, and log PAPP-A MoM, but not from CVS (P=.848), chronic hypertension (P=.178), maternal diabetes (P=.509), or log free β-hCG MoM (P=.323, R2=0.071, P<.001; Table 3).
The results of our study demonstrate that there is no association between performing a CVS in the first trimester and subsequent development of hypertensive disorders of pregnancy. There was no significant contribution of CVS in univariable analysis as an independent factor to the development of early preeclampsia, late preeclampsia, or gestational hypertension, or in multivariable analysis after adjusting for maternal characteristics and the components of first trimester screening that led to invasive testing. Our results do not support the hypothesis that anatomic focal disruption of the placenta at 11 to 14 weeks of gestation leads to an increase in the risk of either preeclampsia or gestational hypertension.
There is extensive evidence that impaired placentation, which is thought to be the cause of preeclampsia, is evident from the first trimester of affected pregnancies, and this is reflected in Doppler measurement of increased resistance to flow in the uterine arteries.6,12–15 Additionally, there is indirect evidence that CVS does not affect placental perfusion. Cohen-Overbeek et al16 measured uterine artery pulsatility index in a group of women undergoing CVS and reported no significant differences in the values before and after the invasive test. Another potential mechanism for CVS increasing the risk of preeclampsia subsequently developing is placental damage with consequent release into the maternal circulation of apoptotic syncytiotrophoblast fragments that contain fetal DNA, which could, in turn, cause maternal endothelial dysfunction and the development of the clinical symptoms of the disease. Several studies reported that the fetal cell-free DNA concentration in maternal blood is increased not only during the clinical phase of preeclampsia but also from the first trimester of pregnancy.17–19 However, a recent study reported that there was no significant difference in maternal plasma cell-free fetal DNA levels before and after CVS.20
Our results contradict those of previous studies that reported that CVS either increases or decreases the subsequent development of hypertensive disorders in pregnancy. The possibility that CVS may be associated with increased risk of the development of pregnancy hypertension was a coincidental finding of a randomized study comparing CVS and early amniocentesis;1 this study was not designed to address the issue of preeclampsia and gestational hypertension. The authors acknowledged this limitation, stating that they relied on the referring physician for the diagnosis of preeclampsia and gestational hypertension, raising the possibility of misclassification of the hypertensive disorder. In our study, the obstetric records of all women with the suspected diagnosis of pregnancy hypertension were scrutinized to ascertain whether the disease had truly developed and whether this was chronic hypertension, preeclampsia, or gestational hypertension. Adusumalli et al,3 who reported that CVS was associated with an increase in the incidence of severe preeclampsia, examined only 840 control women and did not adjust for any maternal characteristics, despite their finding that BMI in the CVS group was higher than in control women, a confounding factor that could explain, at least in part, the higher incidence of severe preeclampsia. Grobman et al,4 who reported that CVS was associated with an increased incidence of preeclampsia in nulliparous women, examined only 59 such cases of CVS and 270 control cases. In our study, which included 801 nulliparous women in the CVS group and 14,100 in the control group, there was no such association. Odibo et al5 examined a large number of case and control women and reported that the incidence of preeclampsia was lower in the CVS group. However, the authors acknowledged that, despite adjusting for certain maternal characteristics, there were large differences between case and control women in factors such as racial origin and chronic medical conditions, which may have contributed to their findings.
The strengths of our study are comparison of the CVS group with a large unselected screening population; we distinguished between the different types of hypertensive disorders of pregnancy; and the use of multivariable logistic regression analysis to take into account maternal characteristics and serum concentration of PAPP-A, factors associated with an increased risk of preeclampsia subsequently developing.8 We subdivided hypertensive disorders into early preeclampsia, late preeclampsia, and gestational hypertension because they differ in both their pathophysiology and clinical implications. Early preeclampsia is commonly associated with fetal growth restriction and is thought to be the consequence of impaired placental perfusion whereas in late preeclampsia and gestational hypertension, placentation and fetal growth are usually normal.15,21–23 If the hypothesis that CVS causes pregnancy hypertension through early placental damage were correct, then it would be expected that the strongest association of CVS would be with early preeclampsia rather than late preeclampsia or gestational hypertension. Multivariable logistic regression analysis confirmed previous reports that factors in the maternal history, such as maternal age, BMI, personal and family history of preeclampsia, racial origin, method of conception, and preexisting chronic hypertension and diabetes, made a significant contribution to the increased risk of hypertensive disorders in pregnancy.6,24–28 Additionally, for both preeclampsia and gestational hypertension, there was a significant contribution from serum PAPP-A. This is particularly important in the context of the investigation of the possible association between CVS and preeclampsia because low PAPP-A is not only a marker of all major aneuploidies,9 and therefore a contributory factor leading to CVS, but also a marker of impaired placentation leading to the development of preeclampsia.6
In summary, our study found no association between first-trimester CVS and subsequent development of hypertensive disorders of pregnancy. Therefore, it does not support the hypothesis that CVS may contribute to the development of these disorders.
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