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Chorionic villus sampling and risk for hypertensive disorders of pregnancy
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Chorionic villus sampling and risk for hypertensive disorders of pregnancy Jasvant Adusumalli, MD; Christina S. Han, MD; Stephen Beckham, BS; Marguerite L. Bartholomew, MD; John Williams III, MD OBJECTIVE: This study was undertakin to evaluate the relationship between chorionic villus sampling at 10-13 weeks’ gestational age and hypertensive disorders of pregnancy. STUDY DESIGN: The prevalence of hypertensive disorders of pregnancy in women with singleton gestations, undergoing transcervical or transabdominal chorionic villus sampling between 10 weeks 0 days’ and 13 weeks 6 days’ gestational age was compared with that of control women with singleton gestations having first-trimester screening with nuchal translucency and biochemistry between 11 weeks 0 days’ and 13 weeks 6 days’ gestational age. Patients having invasive prenatal diagnosis (chorionic villus sampling or amniocentesis) were excluded from the control group. All patients delivered at Cedars-Sinai Medical Center.
RESULTS: There were 1540 women who had chorionic villus sampling and 840 controls. Hypertensive disorders of pregnancy were diagnosed in 76 (4.9%) patients in the chorionic villus sampling group and in 37 (4.4%) of the controls (2 ⫽ 0.34, P ⫽ .31). CONCLUSION: Chorionic villus sampling at 10 to 13 weeks’ gestational age does not appear to increase the overall risk for hypertensive disorders of pregnancy. However, there appears to be an association between chorionic villus sampling and severe hypertensive disorders including severe preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelet count syndrome.
Key words: chorionic villus sampling, gestational hypertension, preeclampsia, pregnancy
Cite this article as: Adusumalli J, Han CS, Beckham S, Bartholomew ML, Williams J III. Chorionic villus sampling and risk for hypertensive disorders of pregnancy. Am J Obstet Gynecol 2007;196:591.e1-591.e7.
C
horionic villus sampling (CVS) provides first-trimester prenatal diagnosis of genetic disorders. The procedure may be performed by either the transabdominal or transcervical route, involving sampling of the placenta between 10 weeks 0 days and 13 weeks 6 days of gestation. When compared with second-trimester genetic amniocentesis, the availability of CVS in the first trimester provides earlier results for patients, aiding in patient privacy and safer pregnancy termination. Both genetic amniocentesis and CVS provide diagnostic ac-
curacy of 99% for the diagnosis of chromosomal abnormalities. Risks include the mild discomfort of an invasive procedure, a 0.5-1% risk of pregnancy loss after amniocentesis, and a 1-2% risk of pregnancy loss after CVS.1-4 In the late 1990s, the introduction of First Trimester Aneuploidy Screening (FTAS) provided an alternative to invasive diagnostic testing. First-trimester ultrasound measurement of the fetal nuchal translucency (NT) and biochemical evaluation of pregnancy-associated plasma protein A (PAPP-A) and free
From the Division of Maternal-Fetal Medicine (Drs Adusumalli, Bartholomew, and Williams) and the Department of Obstetrics and Gynecology (Dr Han), Cedars-Sinai Medical Center, Los Angeles, CA; the David Geffen School of Medicine, University of California, Los Angeles, CA (Mr Beckham); and the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI (Dr Bartholomew). Presented at the 73rd Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Sun Valley, ID, Oct. 4-8, 2006. Received Aug. 31, 2006; revised Nov. 30, 2006; accepted March 2, 2007. Reprints: Jasvant Adusumalli, MD, Department of Obstetrics/Gynecology, Division of MaternalFetal Medicine, 8635 W. 3rd St, Suite 160W, Los Angeles, CA 90048; [email protected] 0002-9378/$32.00 © 2007 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2007.03.015
beta subunit of human chorionic gonadotropin (free beta-HCG), used separately or together, predict with acceptable sensitivity the risk of fetal aneuploidy, particularly trisomy 21. When measured, the NT (in combination with maternal age) has a 77% detection rate for trisomy 21.5 When maternal age, NT, PAPP-A, and free beta-HCG are used in combination there is a 90% detection rate for trisomy 21.6,7 By using screening methods, only those whose results place them at increased risk would be offered invasive testing in the form of CVS or amniocentesis. The risks of CVS are not limited to fetal loss and procedural discomfort. Premature rupture of membranes, fetomaternal hemorrhage, and infection are all rare risks encountered with CVS.8,9 Long-term outcome studies of CVS performed after 10 weeks have found no increase in rates of congenital malformations, neonatal morbidity, pediatric morbidity, functional disturbance, or delayed physical growth.10 CVS performed before 10 weeks has been associated with an increased risk of limb reduction defects.11
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PCOG Papers In 2005, Silver et al12 suggested a relationship between placental disruption during transabdominal CVS in late first trimester (13-14 weeks) and an increased risk of hypertension and preeclampsia later in pregnancy. In their study, a retrospective database review of 3698 cytogenetically normal pregnancies was performed and a higher rate of hypertension and preeclampsia in the late CVS group (5.4%) compared with early amniocentesis group (3.5%) was noted. However, the study was limited by nonstandard definitions of preeclampsia and a control group that potentially had the placenta traversed during the procedure. Referring physician diagnoses were used to identify gestational hypertension and preeclampsia, without categorization of severity. Severe preeclampsia was then defined by preterm delivery (⬍37 weeks) or presence of fetal growth restriction (⬍5th percentile). To date, there have been no other published studies examining the relationship between CVS and subsequent development of hypertensive disorders of pregnancy. The aim of our study was to compare the rates of hypertensive disorders of pregnancy in patients who underwent CVS (with or without preceding FTAS), with those who did not undergo any invasive procedures (FTAS only) and to determine whether CVS increases the risk of developing hypertensive disorders.
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FIGURE 1
Process in patient selection
CVS Patient Selection CVS Patients N = 7042
Multiple Gestation
Singletons
N = 628
N = 6414
Fetal Abnormality
No Abnormality
N = 196
N = 6218
Elective Ab N = 41 Spontaneous Ab N = 118
Continuing Pregnancy N = 6059
Delivered Elsewhere
Delivered at CSMC
N = 4212
N = 1847
M ATERIALS AND M ETHODS The study involved a single-site retrospective medical record review located at the Cedars-Sinai Medical Center, a tertiary care teaching hospital. Study subjects were identified with databases from the Cedars-Sinai Prenatal Diagnosis Center (PDC). The PDC CVS database was used to identify subjects who had undergone CVS. The FTAS database was used to identify subjects who had FTAS. Those subjects that had FTAS without subsequent CVS or amniocentesis served as the control group. The 2 groups were compared with regard to development of preeclampsia: a study group (CVS with or without FTAS) and a control group, (FTAS only). CVS was performed either 591.e2
Medical Complications* N=26
Complete Records
Incomplete Records N = 281
N = 1540
Ab, abortion; CSMC, Cedars-Sinai Medical Center. *Chronic hypertension (n ⫽ 9), systemic lupus erythematosus (n ⫽ 5), pregestational diabetes mellitus (n ⫽ 5), antiphospholipid syndrome (n ⫽ 4), chronic renal disease (n ⫽ 2), inherited thrombophilia (n ⫽ 1).
transcervically or transabdominally by primarily 1 operator (J.W.). Transcervical CVS was performed by using a 16gauge catheter and transabdominal CVS
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was performed by using a 20-gauge needle, both under direct ultrasound guidance. A maximum of 2 device insertions was allowed per procedure.
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FIGURE 2
Process in selection of control subjects
Control Patient Selection 1st Trimester Screening Patients N = 2197
Multiple Gestation
Singletons
N = 65
N = 2132
CVS N = 384
No Procedure
Amnio N = 191
N = 1557
Elective Ab N = 6 Spontaneous Ab N = 26
Continuing Pregnancy N = 1525
Delivered Elsewhere
Delivered at CSMC
N = 538
N = 987
Medical Complications* N = 14
Complete Records
Incomplete Records N = 133
N = 840
Ab, abortion; CSMC, Cedars-Sinai Medical Center *Chronic hypertension (n ⫽ 3), systemic lupus erythematosus (n ⫽ 2), pregestational diabetes mellitus (n ⫽ 4), antiphospholipid syndrome (n ⫽ 2), chronic renal disease (n ⫽ 2), inherited thrombophilia (n ⫽ 1).
Patient data were collected from outpatient, inpatient, and newborn records. The nature of the data included nonidentifying demographics, medical his-
tory, ultrasound, CVS, amniocentesis, laboratory, delivery, preeclampsia, and birth outcome-related information. Intrapartum vital signs, medical records,
and laboratory information were all thoroughly examined for each subject with potential hypertensive disorders. Inclusion criteria included subjects who underwent either CVS or FTAS at the Cedars-Sinai Prenatal Diagnosis Center from 1999-2005, delivered at Cedars-Sinai Medical Center and had singleton intrauterine pregnancies. Exclusion criteria included pregnancies with the following: multiple gestation (including cotwin demise, vanishing twin, or multifetal reduction), known congenital anomalies, known chromosomal abnormalities, and suspected confined placental mosaicism. Additional exclusion criteria included subjects with the following medical conditions: pregestational diabetes mellitus, pregestational or chronic hypertension, sickle cell anemia, chronic renal disease, autoimmune/rheumatologic disorders, inherited thrombophilias, and antiphospholipid antibody syndrome. The study was approved by the Cedars-Sinai Medical Center Institutional Review Board. Preeclampsia was defined according to standard American College of Obstetrics and Gynecology guidelines. Hypertensive conditions were defined by criteria set forth by the National High Blood Pressure Education Working Group Report. Mild preeclampsia was defined using the following criteria: (1) blood pressure greater than 140/90 that occurs after 20 weeks of gestation in a woman with previously normal blood pressure and (2) proteinuria of at least 300 mg in a 24-hour specimen or 1⫹ on urine dipstick.13 Severe preeclampsia was defined with the use of the following criteria: (1) blood pressure of 160/110 measured on 2 occasions at least 6 hours apart with the patient at bed rest, (2) proteinuria of at least 5 g in a 24-hour collection or 3⫹ or greater by dipstick on 2 random urine samples collected 4 hours apart, (3) oliguria of less than 500 mL in 24 hours, (4) thrombocytopenia, (5) elevated hepatic enzymes or impaired liver function, (6) persistent headache or other cerebral or visual disturbances, (7) persistent epigastric pain or right upper-quadrant pain, and (8) fetal growth restriction.14
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PCOG Papers
www.AJOG.org ery, gestational age at delivery, and birthweight. Statistical analyses were performed by using Analyse-it, (Analyse-it Software Ltd, Leeds, United Kingdom).
TABLE 1
Ethnicity of CVS and control patients CVS group n ⴝ 1540
Control group n ⴝ 840
1320 (85.7%)
688 (82.0%)
.08
125 (8.1%)
45 (5.2%)
.19
Hispanic
20 (1.3%)
35 (4.2%)
⬍.001
Asian
74 (4.8%)
71 (8.6%)
⬍.001
White
P value*
..............................................................................................................................................................................................................................................
African American
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Other
1 (0.06%)
Eclampsia was defined as the presence of preeclampsia and seizures not attributable to any other cause.13 Additional disease entities in the spectrum of hypertensive disorders of pregnancy are chronic hypertension, gestational hypertension, and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Gestational hypertension was defined as blood pressure elevation detected for the first time after midpregnancy without proteinuria.13 Chronic hypertension was defined as hypertension that is present and observable before the 20th week of gestation.13 HELLP syndrome was identified by those subjects exhibiting hemolysis, elevated liver enzymes, and low platelet counts.
1 (0.12%)
.15
Sample size calculation The sample size needed to detect a difference between a 5% prevalence of preeclampsia in the control group and a 7.5% prevalence in the CVS group (relative risk [RR] ⫽ 1.5) with 80% power was calculated to be 1471 patients in each group.
Statistical analysis Differences in continuous variables between the study and control groups were analyzed by using the Student t test, and categorical variables were evaluated by using 2y when appropriate. The variables analyzed included maternal age, parity, body mass index (BMI) at deliv-
R ESULTS From January 1999 to December 2005, 7042 women underwent CVS at CedarsSinai Medical Center. Of these women, 5502 were excluded from the study that was based on the flow-diagram shown in Figure 1. There were 1540 subjects who met inclusion criteria and had complete records. During the same time period, FTAS was performed on 2197 women. Of these women, there were 840 subjects who met the same inclusion criteria as shown in Figure 2. There were 384 women in the CVS group who also had FTAS. The ethnic backgrounds of the patients in the CVS and control groups are shown in Table 1. The percentage of white and African American patients was similar between the CVS and the control groups. There were significantly fewer Hispanic women in the CVS group compared with the controls, and there were significantly fewer Asian women in the control group compared with the CVS group. The maternal characteristics and
TABLE 2
Maternal characteristics and delivery outcomes CVS group (n ⴝ 1540)
95% CI
Control group (n ⴝ 840)
95% CI
P value*
Maternal age (y)
.......................................................................................................................................................................................................................................................................................................................................................................
Range
22–49
19–48
.......................................................................................................................................................................................................................................................................................................................................................................
Mean (SD)
38.6 (3.1)
38.4–38.7
33.6 (4.3)
33.3–33.9
⬍.001
................................................................................................................................................................................................................................................................................................................................................................................
Parity
.......................................................................................................................................................................................................................................................................................................................................................................
Range
0–9
0–8
.......................................................................................................................................................................................................................................................................................................................................................................
Mean (SD)
0.81 (0.9)
0.8–0.9
0.63 (0.87)
0.6–0.7
⬍.001
................................................................................................................................................................................................................................................................................................................................................................................ 2
Maternal BMI at delivery (kg/m )
.......................................................................................................................................................................................................................................................................................................................................................................
Range
19.2–62.0
Mean (SD)
29.3 (5.5)
16.3–53.6
.......................................................................................................................................................................................................................................................................................................................................................................
28.8–29.4
25.5 (5.0)
25.2–25.9
⬍.001
................................................................................................................................................................................................................................................................................................................................................................................
Gestational age at delivery (wk)
.......................................................................................................................................................................................................................................................................................................................................................................
Range
23.0–43.0
Mean (SD)
38.7 (1.8)
21.7–42.9
.......................................................................................................................................................................................................................................................................................................................................................................
38.6–38.8
39.0 (1.9)
38.9–39.1
.72
................................................................................................................................................................................................................................................................................................................................................................................
Birthweight (g)
.......................................................................................................................................................................................................................................................................................................................................................................
Range
500–5028
Mean (SD)
3402 (516)
307–4718
.......................................................................................................................................................................................................................................................................................................................................................................
3376–3429
3336 (536)
3300–3372
.38
................................................................................................................................................................................................................................................................................................................................................................................
* Student t test.
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PCOG Papers
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TABLE 3
Prevalence of hypertensive disorders
All hypertensive disorders
CVS group n ⴝ 1540 (%)
Control group n ⴝ 840 (%)
RR
P value*
76 (4.9)
37 (4.4)
1.11
.312
..............................................................................................................................................................................................................................................
Gestational hypertension
7 (0.5)
4 (0.5)
1.00
.66
Mild preeclampsia
28 (1.8)
24 (2.9)
0.62
.96
Severe preeclampsia
28 (1.8)
9 (1.1)
1.64
.11
6 (0.4)
0 (0)
—
.07
7 (0.5)
0 (0)
—
.06
9 (1.1%)
2.48
.02
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Eclampsia
..............................................................................................................................................................................................................................................
HELLP syndrome
..............................................................................................................................................................................................................................................
All severe disorders
41 (2.7%)
..............................................................................................................................................................................................................................................
* . 2
delivery outcomes for each group are shown in Table 2. The mean maternal age and delivery BMI in the CVS group were significantly greater than those of the control group (P ⬍ .001). The differences in birthweight and gestational age at delivery between the groups were not statistically significant. The incidence of prematurity was 8.4% (129/1540 subjects) in the CVS group and 8.6% (73/ 840 subjects) in the control group. This difference was not significant. The incidence of intrauterine growth restriction (IUGR) was 6.5% (100/1540 subjects) in the CVS group and 6.2% (52/840 subjects) in the control group. Again, this difference was not significant. The prevalence of hypertensive disorders in each group is shown in Table 3. The difference in prevalence of all hypertensive disorders of pregnancy between the CVS and control groups was not significant. The power of this study to detect a 50% increase (RR ⫽ 1.5) in the prevalence of all hypertensive disorders in the CVS group was 0.62. The prevalence of severe preeclampsia, eclampsia, and HELLP syndrome appeared to be
higher in the CVS group. However, these differences alone did not reach statistical significance. In contrast, when all severe disorders were combined, the RR was 2.48. This difference was statistically significant (P ⫽ .02). The incidence of severe hypertensive disorders of pregnancy stratified by gestational age at the time of CVS is shown in Table 4. The differences in frequency of severe hypertensive disorders between the gestational age ranges were not statistically significant.
C OMMENT Preeclampsia is a multisystem and multifactorial syndrome unique to human pregnancy. It is characterized by onset of hypertension and proteinuria after the 20th week of pregnancy. Clinical manifestations of preeclampsia include visual disturbances, headache, epigastric pain, platelet disturbances, liver dysfunction, and convulsions. As such, it is a leading cause of maternal and fetal mortality.14,15
The incidence of preeclampsia is estimated at about 5-8% of all pregnancies in the United States. Other conditions leading to endothelial damage, including diabetes, obesity, chronic renal disease, antiphospholipid antibody syndrome, autoimmune or rheumatologic diseases, and advanced maternal age, also predispose patients to development of preeclampsia.15,16 The pathogenesis of preeclampsia is unknown, although current proposed causes involve alterations in early placentation. It has been suggested that placental disruption may lead to impaired placental vasculature and endothelial dysfunction, with resultant placental ischemia. Invasion of endothelium and tunica media of maternal spiral arteries by cytotrophoblasts in early placentation leads to formation of large-capacitance low-resistance vessels in normal pregnancies. These vessels normally form in the late first trimester, and are completed by 18-20 weeks. They allow for increased blood flow to the uteroplacental unit.17 In preeclampsia, the cytotrophoblasts infiltrate only the decidual portion of the spiral arteries, without the second wave of penetration into the myometrium. The retained musculoelastic vessels of the uterus induce hypoperfusion when contracted, resulting in placental changes consistent with ischemia, including atherosis, fibrinoid necrosis, thrombosis, sclerotic narrowing of arterioles, and infarction.18 The process of angiogenesis plays a central role in placentation. Many studies have identified placental growth factor (PlGF), vascular endothelial growth factor (VEGF), and the VEGF antagonist, soluble fms-like tyrosine kinase 1 (sFlt-1), as being factors involved in pla-
TABLE 4
Severity of hypertensive disorder by week of gestation Week of gestation
Severe preeclampsia
Eclampsia
HELLP syndrome
All aevere disorders
P value*
10.0–10.9 (n ⫽ 17)
9 (52.9%)
1 (5.9%)
0
10 (58.9%)
ns
11.0–11.9 (n ⫽ 35)
13 (37.1%)
2 (5.7%)
3 (8.6%)
18 (55.1%)
ns
12.0–12.9 (n ⫽ 18)
4 (2.2%)
1 (5.6%)
3 (16.7%)
8 (44.4%)
ns
13.0–13.9 (n ⫽ 6)
2 (33.3%)
2 (33.3%)
1 (16.7%)
5 (83.3%)
ns
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
* 2.
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PCOG Papers cental ischemia. A disturbance in the balance of proangiogenic VEGF and antiangiogenic sFlt-1 may result in abnormal vascular development and contribute to the development of preeclampsia.19 Damage induced by CVS in early placentation is theorized to induce inflammation and focal hemorrhage, resulting in reduced placental perfusion.12 Maternal immune response to paternally derived fetal antigens may also contribute to endothelial dysfunction.20 It can be hypothesized that this anatomic disruption will alter biochemical levels of PlGF, VEGF, and sFlt-1, and possibly predispose patients to preeclampsia developing later in the pregnancy. Although, our study did not demonstrate an association between CVS and hypertensive disorders, we believe that the analysis of angiogenic factors in combination with placental disruption at the time of CVS may provide useful information. Although Silver et al12 noted a relationship between between transabdominal CVS in the late first trimester and preeclampsia/gestational hypertension, our findings did not demonstrate an association between CVS at 10-13 weeks’ gestational age and hypertensive disorders of pregnancy, as a whole. However, we observed a greater severity of preeclampsia in women exposed to CVS in the first trimester than in the controls who did not undergo an invasive procedure (Table 3). One limitation of this study is that number of controls was substantially less than the number of CVS subjects. Because it was not feasible to obtain complete obstetric and neonatal medical records for the women and infants who delivered at more than 30 other institutions in the metropolitan area, it was necessary to restrict our observations to the patients who delivered at our institution. This resulted in a substantial reduction in the number of subjects who were eligible for inclusion in the study. As a result, the power of our study was reduced. Because the difference between the prevalence of eclampsia and HELLP syndrome approached significance, it is possible that we failed to find a difference when a difference truly existed. To exclude a type II statistical error at a power 591.e6
www.AJOG.org of 80% for severe preeclampsia, it would require a sample size of 4500 subjects in each group. For eclampsia and HELLP syndrome, 3915 subjects would be required given the same parameters. Another limitation of the study is that the subjects in the CVS group had a significantly greater mean maternal age and BMI than did the controls. These factors are associated with increased risk for hypertension and thus could have contributed to a higher rate of severe hypertensive disorders in the CVS group. The strength of this study centers around the fact that standardized definitions of hypertensive disorders were used and each case was categorized systematically based on widely accepted criteria. Also, there are no published studies to date that have examined the relationship between hypertensive disorders and CVS, with the use of standard diagnostic criteria. Additional factors that should be evaluated in future studies include increasing the number of study and control subjects, controlling for maternal age, the number of device insertions and the quantity of villi removed per procedure, placental location, and the presence or absence of conception by advanced reproductive technology. Each of these factors could play a role in development of hypertensive disorders in pregnancy. f REFERENCES 1. Canadian Collaborative CVS-Amniocentesis Clinical Trial Group. Multicentre randomized clinical trial of chorion villus sampling and amniocentesis. Lancet 1989;i:1-6. 2. Smidt-Jensen S, Permin M, Philip J, et al. Randomised comparison of amniocentesis and transabdominal and transcervical chorionic villus sampling. Lancet 1992;340:1237-44. 3. Rhoads, GG, Jackson LG, Schlesselman SE, et al. The safety and efficacy of chorionic villus sampling for early prenatal diagnosis of cytogenetic abnormalities. N Engl J Med 1989;320:609-17. 4. Jackson LG, Zachary JM, Fowler SE, et al. A randomized comparison of transcervical and transabdominal chorionic-villus sampling. The U.S. National Institute of Child Health and Human Development Chorionic-Villus Sampling and Amniocentesis Study Group. N Engl J Med 1992;327:594-8. 5. Snijders RJ, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age
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and fetal nuchal-translucency thickness at 10-14 weeks of gestation. Fetal Medicine Foundation First Trimester Screening Group. Lancet 1998;352:343-6. 6. Spencer K, Spencer CE, Power M, Dawson C, Nicolaides KH. Screening for chromosomal abnormalities in the first trimester using ultrasound and maternal serum biochemistry in a one-stop clinic: a review of three years prospective experience. BJOG 2003;110: 281-6. 7. Wapner R, Thom E, Simpson JL, et al. Firsttrimester screening for trisomies 21 and 18. N Engl J Med 2003;349:1405-13. 8. Lippman A, Tomkins DJ, Shime J, Hamerton, JL. Canadian multicentre randomized clinical trial of chorion villus sampling and amniocentesis: final report. Prenat Diagn 1992;12:385-408. 9. Smidt-Jensen S, Permin M, Phillip J, et al. Randomised comparison of amniocentesis and transabdominal and transcervical chorionic villus sampling. Lancet 1992;340:1237-44. 10. Schaap AH, van der Pol HG, Boer K, Leschot LJ, Wolf H. Long-term follow-up of infants after transcervical chorionic villus sampling and after amniocentesis to compare congenital abnormalities and health status. Prenat Diagn 2002;22:598-604. 11. Holmes LB. Report of National Institute of Child Health and Human Development Workshop on Chorionic Sampling and Limb and Other Defects, October 20, 1992. Teratology 1993;48:7-13. 12. Silver RK, Wilson RD, Philip J, et al. Late first-trimester placental disruption and subsequent gestational hypertension/preeclampsia. Obstet Gynecol 2005;105:587-92. 13. Report of the National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000;183:S1-S22. 14. American College of Obstetricians and Gynecologists. Diagnosis and management of preeclampsia and eclampsia. Washington, DC: The College; 2002. ACOG practice bulletin no. 33. 15. Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. Lancet 2001;357:53-6. 16. Dekker GA. Risk factors for preeclampsia. Clin Obstet Gynecol 1999;42:422-35. 17. Zhou Y, Damsky CH, Fisher SJ. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype: one cause of defective endovascular invasion in this syndrome? J Clin Invest 1997;99:2152-64. 18. Brosens IA. Morphological changes in the uteroplacental bed in pregnancy hypertension. Clin Obstet Gynaecol 1977;4:573-93. 19. McKeeman GC, Ardill JE, Caldwell CM, Hunter AJ, McClure N. Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop. Am J Obstet Gynecol 2004;191:1240-6.
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www.AJOG.org 20. Wilson ML, Goodwin TM, Pan VL, Ingles SA. Molecular epidemiology of preeclampsia. Obstet Gynecol Surv 2003;58:39-66.
D ISCUSSION Dena Towner, MD. Adusumalli et al should be lauded for such an ambitious study. It was no small feat to have reviewed more than 2000 charts for pregnancy outcomes. He chose to evaluate a biologically plausible effect of CVS— hypertensive disorders of pregnancy that in large part are thought to be secondary to placentation abnormalities. Early placental implantation is critical for fetal growth and development and obstetric outcomes. Disruption of this process could in theory lead to abnormal implantation and secondary fetal and maternal effects. Certain medical disorders, including hypertension, vascular disease, systemic lupus erythematocus, antiphospholipid syndrome, are associated with poor implantation and an increased risk of preeclampsia. In early pregnancy, the trophoblast invades into the spiral arterioles and transforms these vessels into low-resistance vessels, which open into the maternal sinuses of the placenta. Thus, it is biologically plausible that CVS
could cause disruption of the normal implantation process. The effect may not be limited locally to the site sampled. An inflammatory response invoked by healing could lead to a widespread effect on implantation. The impetus for this study was a report in 2005 by Silver et al1 identifying an increased risk of hypertensive diseases in women having CVS in gestational week 13-14. A limitation to this study was that it was not designed to directly study hypertensive outcomes in pregnancy. Surrogate markers for severe preeclampsia were used, including growth restriction of the neonate based on birthweight less than fifth percentile and delivery less than 37 weeks. The odds ratio (OR) for severe preeclampsia was 2.49 comparing CVS with early amniocentesis. This study clearly suggested that CVS could be associated with severe preeclampsia later in pregnancy. Fortunately, rates of preeclampsia were still in what is considered an expected range, thus of questionable clinical significance. In the study by Adusumalli et al, they identified a large population of women undergoing CVS and compare them
with a group without invasive testing. They reviewed the medical records after delivery to determine whether there was an association with hypertensive diseases, excluding women at increased risk for hypertensive diseases of pregnancy. They identified significant differences in several maternal characteristics, including age, parity, BMI, and ethnicity, all of which have association with preeclampsia risks. Overall, they found no significant difference for the prevalence of hypertensive diseases of pregnancy between the groups. However, when breaking down the severity of disease, they identified near significance for eclampsia and HELLP syndrome as separate entities. When they looked at all forms of severe disease as a group, there appeared to be a significant increase in severe diseases (2.7% vs 1.1%, RR 2.48), compared to the control group. This RR is nearly identical to that found by Silver et al.1 REFERENCE 1. Silver RK, Wilson RD, Philip J, et al. Late firsttrimester placental disruption and subsequent gestational hypertension/preeclampsia. Obstet Gynecol 2005;105:587-92.
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Chorionic villus sampling and risk for hypertensive disorders of pregnancy Jasvant Adusumalli, MD; Christina S. Han, MD; Stephen Beckham, BS; Marguerite L. Bartholomew, MD; John Williams III, MD OBJECTIVE: This study was undertakin to evaluate the relationship between chorionic villus sampling at 10-13 weeks’ gestational age and hypertensive disorders of pregnancy. STUDY DESIGN: The prevalence of hypertensive disorders of pregnancy in women with singleton gestations, undergoing transcervical or transabdominal chorionic villus sampling between 10 weeks 0 days’ and 13 weeks 6 days’ gestational age was compared with that of control women with singleton gestations having first-trimester screening with nuchal translucency and biochemistry between 11 weeks 0 days’ and 13 weeks 6 days’ gestational age. Patients having invasive prenatal diagnosis (chorionic villus sampling or amniocentesis) were excluded from the control group. All patients delivered at Cedars-Sinai Medical Center.
RESULTS: There were 1540 women who had chorionic villus sampling and 840 controls. Hypertensive disorders of pregnancy were diagnosed in 76 (4.9%) patients in the chorionic villus sampling group and in 37 (4.4%) of the controls (2 ⫽ 0.34, P ⫽ .31). CONCLUSION: Chorionic villus sampling at 10 to 13 weeks’ gestational age does not appear to increase the overall risk for hypertensive disorders of pregnancy. However, there appears to be an association between chorionic villus sampling and severe hypertensive disorders including severe preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelet count syndrome.
Key words: chorionic villus sampling, gestational hypertension, preeclampsia, pregnancy
Cite this article as: Adusumalli J, Han CS, Beckham S, Bartholomew ML, Williams J III. Chorionic villus sampling and risk for hypertensive disorders of pregnancy. Am J Obstet Gynecol 2007;196:591.e1-591.e7.
C
horionic villus sampling (CVS) provides first-trimester prenatal diagnosis of genetic disorders. The procedure may be performed by either the transabdominal or transcervical route, involving sampling of the placenta between 10 weeks 0 days and 13 weeks 6 days of gestation. When compared with second-trimester genetic amniocentesis, the availability of CVS in the first trimester provides earlier results for patients, aiding in patient privacy and safer pregnancy termination. Both genetic amniocentesis and CVS provide diagnostic ac-
curacy of 99% for the diagnosis of chromosomal abnormalities. Risks include the mild discomfort of an invasive procedure, a 0.5-1% risk of pregnancy loss after amniocentesis, and a 1-2% risk of pregnancy loss after CVS.1-4 In the late 1990s, the introduction of First Trimester Aneuploidy Screening (FTAS) provided an alternative to invasive diagnostic testing. First-trimester ultrasound measurement of the fetal nuchal translucency (NT) and biochemical evaluation of pregnancy-associated plasma protein A (PAPP-A) and free
From the Division of Maternal-Fetal Medicine (Drs Adusumalli, Bartholomew, and Williams) and the Department of Obstetrics and Gynecology (Dr Han), Cedars-Sinai Medical Center, Los Angeles, CA; the David Geffen School of Medicine, University of California, Los Angeles, CA (Mr Beckham); and the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI (Dr Bartholomew). Presented at the 73rd Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Sun Valley, ID, Oct. 4-8, 2006. Received Aug. 31, 2006; revised Nov. 30, 2006; accepted March 2, 2007. Reprints: Jasvant Adusumalli, MD, Department of Obstetrics/Gynecology, Division of MaternalFetal Medicine, 8635 W. 3rd St, Suite 160W, Los Angeles, CA 90048; [email protected] 0002-9378/$32.00 © 2007 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2007.03.015
beta subunit of human chorionic gonadotropin (free beta-HCG), used separately or together, predict with acceptable sensitivity the risk of fetal aneuploidy, particularly trisomy 21. When measured, the NT (in combination with maternal age) has a 77% detection rate for trisomy 21.5 When maternal age, NT, PAPP-A, and free beta-HCG are used in combination there is a 90% detection rate for trisomy 21.6,7 By using screening methods, only those whose results place them at increased risk would be offered invasive testing in the form of CVS or amniocentesis. The risks of CVS are not limited to fetal loss and procedural discomfort. Premature rupture of membranes, fetomaternal hemorrhage, and infection are all rare risks encountered with CVS.8,9 Long-term outcome studies of CVS performed after 10 weeks have found no increase in rates of congenital malformations, neonatal morbidity, pediatric morbidity, functional disturbance, or delayed physical growth.10 CVS performed before 10 weeks has been associated with an increased risk of limb reduction defects.11
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PCOG Papers In 2005, Silver et al12 suggested a relationship between placental disruption during transabdominal CVS in late first trimester (13-14 weeks) and an increased risk of hypertension and preeclampsia later in pregnancy. In their study, a retrospective database review of 3698 cytogenetically normal pregnancies was performed and a higher rate of hypertension and preeclampsia in the late CVS group (5.4%) compared with early amniocentesis group (3.5%) was noted. However, the study was limited by nonstandard definitions of preeclampsia and a control group that potentially had the placenta traversed during the procedure. Referring physician diagnoses were used to identify gestational hypertension and preeclampsia, without categorization of severity. Severe preeclampsia was then defined by preterm delivery (⬍37 weeks) or presence of fetal growth restriction (⬍5th percentile). To date, there have been no other published studies examining the relationship between CVS and subsequent development of hypertensive disorders of pregnancy. The aim of our study was to compare the rates of hypertensive disorders of pregnancy in patients who underwent CVS (with or without preceding FTAS), with those who did not undergo any invasive procedures (FTAS only) and to determine whether CVS increases the risk of developing hypertensive disorders.
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FIGURE 1
Process in patient selection
CVS Patient Selection CVS Patients N = 7042
Multiple Gestation
Singletons
N = 628
N = 6414
Fetal Abnormality
No Abnormality
N = 196
N = 6218
Elective Ab N = 41 Spontaneous Ab N = 118
Continuing Pregnancy N = 6059
Delivered Elsewhere
Delivered at CSMC
N = 4212
N = 1847
M ATERIALS AND M ETHODS The study involved a single-site retrospective medical record review located at the Cedars-Sinai Medical Center, a tertiary care teaching hospital. Study subjects were identified with databases from the Cedars-Sinai Prenatal Diagnosis Center (PDC). The PDC CVS database was used to identify subjects who had undergone CVS. The FTAS database was used to identify subjects who had FTAS. Those subjects that had FTAS without subsequent CVS or amniocentesis served as the control group. The 2 groups were compared with regard to development of preeclampsia: a study group (CVS with or without FTAS) and a control group, (FTAS only). CVS was performed either 591.e2
Medical Complications* N=26
Complete Records
Incomplete Records N = 281
N = 1540
Ab, abortion; CSMC, Cedars-Sinai Medical Center. *Chronic hypertension (n ⫽ 9), systemic lupus erythematosus (n ⫽ 5), pregestational diabetes mellitus (n ⫽ 5), antiphospholipid syndrome (n ⫽ 4), chronic renal disease (n ⫽ 2), inherited thrombophilia (n ⫽ 1).
transcervically or transabdominally by primarily 1 operator (J.W.). Transcervical CVS was performed by using a 16gauge catheter and transabdominal CVS
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was performed by using a 20-gauge needle, both under direct ultrasound guidance. A maximum of 2 device insertions was allowed per procedure.
PCOG Papers
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FIGURE 2
Process in selection of control subjects
Control Patient Selection 1st Trimester Screening Patients N = 2197
Multiple Gestation
Singletons
N = 65
N = 2132
CVS N = 384
No Procedure
Amnio N = 191
N = 1557
Elective Ab N = 6 Spontaneous Ab N = 26
Continuing Pregnancy N = 1525
Delivered Elsewhere
Delivered at CSMC
N = 538
N = 987
Medical Complications* N = 14
Complete Records
Incomplete Records N = 133
N = 840
Ab, abortion; CSMC, Cedars-Sinai Medical Center *Chronic hypertension (n ⫽ 3), systemic lupus erythematosus (n ⫽ 2), pregestational diabetes mellitus (n ⫽ 4), antiphospholipid syndrome (n ⫽ 2), chronic renal disease (n ⫽ 2), inherited thrombophilia (n ⫽ 1).
Patient data were collected from outpatient, inpatient, and newborn records. The nature of the data included nonidentifying demographics, medical his-
tory, ultrasound, CVS, amniocentesis, laboratory, delivery, preeclampsia, and birth outcome-related information. Intrapartum vital signs, medical records,
and laboratory information were all thoroughly examined for each subject with potential hypertensive disorders. Inclusion criteria included subjects who underwent either CVS or FTAS at the Cedars-Sinai Prenatal Diagnosis Center from 1999-2005, delivered at Cedars-Sinai Medical Center and had singleton intrauterine pregnancies. Exclusion criteria included pregnancies with the following: multiple gestation (including cotwin demise, vanishing twin, or multifetal reduction), known congenital anomalies, known chromosomal abnormalities, and suspected confined placental mosaicism. Additional exclusion criteria included subjects with the following medical conditions: pregestational diabetes mellitus, pregestational or chronic hypertension, sickle cell anemia, chronic renal disease, autoimmune/rheumatologic disorders, inherited thrombophilias, and antiphospholipid antibody syndrome. The study was approved by the Cedars-Sinai Medical Center Institutional Review Board. Preeclampsia was defined according to standard American College of Obstetrics and Gynecology guidelines. Hypertensive conditions were defined by criteria set forth by the National High Blood Pressure Education Working Group Report. Mild preeclampsia was defined using the following criteria: (1) blood pressure greater than 140/90 that occurs after 20 weeks of gestation in a woman with previously normal blood pressure and (2) proteinuria of at least 300 mg in a 24-hour specimen or 1⫹ on urine dipstick.13 Severe preeclampsia was defined with the use of the following criteria: (1) blood pressure of 160/110 measured on 2 occasions at least 6 hours apart with the patient at bed rest, (2) proteinuria of at least 5 g in a 24-hour collection or 3⫹ or greater by dipstick on 2 random urine samples collected 4 hours apart, (3) oliguria of less than 500 mL in 24 hours, (4) thrombocytopenia, (5) elevated hepatic enzymes or impaired liver function, (6) persistent headache or other cerebral or visual disturbances, (7) persistent epigastric pain or right upper-quadrant pain, and (8) fetal growth restriction.14
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www.AJOG.org ery, gestational age at delivery, and birthweight. Statistical analyses were performed by using Analyse-it, (Analyse-it Software Ltd, Leeds, United Kingdom).
TABLE 1
Ethnicity of CVS and control patients CVS group n ⴝ 1540
Control group n ⴝ 840
1320 (85.7%)
688 (82.0%)
.08
125 (8.1%)
45 (5.2%)
.19
Hispanic
20 (1.3%)
35 (4.2%)
⬍.001
Asian
74 (4.8%)
71 (8.6%)
⬍.001
White
P value*
..............................................................................................................................................................................................................................................
African American
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Other
1 (0.06%)
Eclampsia was defined as the presence of preeclampsia and seizures not attributable to any other cause.13 Additional disease entities in the spectrum of hypertensive disorders of pregnancy are chronic hypertension, gestational hypertension, and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Gestational hypertension was defined as blood pressure elevation detected for the first time after midpregnancy without proteinuria.13 Chronic hypertension was defined as hypertension that is present and observable before the 20th week of gestation.13 HELLP syndrome was identified by those subjects exhibiting hemolysis, elevated liver enzymes, and low platelet counts.
1 (0.12%)
.15
Sample size calculation The sample size needed to detect a difference between a 5% prevalence of preeclampsia in the control group and a 7.5% prevalence in the CVS group (relative risk [RR] ⫽ 1.5) with 80% power was calculated to be 1471 patients in each group.
Statistical analysis Differences in continuous variables between the study and control groups were analyzed by using the Student t test, and categorical variables were evaluated by using 2y when appropriate. The variables analyzed included maternal age, parity, body mass index (BMI) at deliv-
R ESULTS From January 1999 to December 2005, 7042 women underwent CVS at CedarsSinai Medical Center. Of these women, 5502 were excluded from the study that was based on the flow-diagram shown in Figure 1. There were 1540 subjects who met inclusion criteria and had complete records. During the same time period, FTAS was performed on 2197 women. Of these women, there were 840 subjects who met the same inclusion criteria as shown in Figure 2. There were 384 women in the CVS group who also had FTAS. The ethnic backgrounds of the patients in the CVS and control groups are shown in Table 1. The percentage of white and African American patients was similar between the CVS and the control groups. There were significantly fewer Hispanic women in the CVS group compared with the controls, and there were significantly fewer Asian women in the control group compared with the CVS group. The maternal characteristics and
TABLE 2
Maternal characteristics and delivery outcomes CVS group (n ⴝ 1540)
95% CI
Control group (n ⴝ 840)
95% CI
P value*
Maternal age (y)
.......................................................................................................................................................................................................................................................................................................................................................................
Range
22–49
19–48
.......................................................................................................................................................................................................................................................................................................................................................................
Mean (SD)
38.6 (3.1)
38.4–38.7
33.6 (4.3)
33.3–33.9
⬍.001
................................................................................................................................................................................................................................................................................................................................................................................
Parity
.......................................................................................................................................................................................................................................................................................................................................................................
Range
0–9
0–8
.......................................................................................................................................................................................................................................................................................................................................................................
Mean (SD)
0.81 (0.9)
0.8–0.9
0.63 (0.87)
0.6–0.7
⬍.001
................................................................................................................................................................................................................................................................................................................................................................................ 2
Maternal BMI at delivery (kg/m )
.......................................................................................................................................................................................................................................................................................................................................................................
Range
19.2–62.0
Mean (SD)
29.3 (5.5)
16.3–53.6
.......................................................................................................................................................................................................................................................................................................................................................................
28.8–29.4
25.5 (5.0)
25.2–25.9
⬍.001
................................................................................................................................................................................................................................................................................................................................................................................
Gestational age at delivery (wk)
.......................................................................................................................................................................................................................................................................................................................................................................
Range
23.0–43.0
Mean (SD)
38.7 (1.8)
21.7–42.9
.......................................................................................................................................................................................................................................................................................................................................................................
38.6–38.8
39.0 (1.9)
38.9–39.1
.72
................................................................................................................................................................................................................................................................................................................................................................................
Birthweight (g)
.......................................................................................................................................................................................................................................................................................................................................................................
Range
500–5028
Mean (SD)
3402 (516)
307–4718
.......................................................................................................................................................................................................................................................................................................................................................................
3376–3429
3336 (536)
3300–3372
.38
................................................................................................................................................................................................................................................................................................................................................................................
* Student t test.
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TABLE 3
Prevalence of hypertensive disorders
All hypertensive disorders
CVS group n ⴝ 1540 (%)
Control group n ⴝ 840 (%)
RR
P value*
76 (4.9)
37 (4.4)
1.11
.312
..............................................................................................................................................................................................................................................
Gestational hypertension
7 (0.5)
4 (0.5)
1.00
.66
Mild preeclampsia
28 (1.8)
24 (2.9)
0.62
.96
Severe preeclampsia
28 (1.8)
9 (1.1)
1.64
.11
6 (0.4)
0 (0)
—
.07
7 (0.5)
0 (0)
—
.06
9 (1.1%)
2.48
.02
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Eclampsia
..............................................................................................................................................................................................................................................
HELLP syndrome
..............................................................................................................................................................................................................................................
All severe disorders
41 (2.7%)
..............................................................................................................................................................................................................................................
* . 2
delivery outcomes for each group are shown in Table 2. The mean maternal age and delivery BMI in the CVS group were significantly greater than those of the control group (P ⬍ .001). The differences in birthweight and gestational age at delivery between the groups were not statistically significant. The incidence of prematurity was 8.4% (129/1540 subjects) in the CVS group and 8.6% (73/ 840 subjects) in the control group. This difference was not significant. The incidence of intrauterine growth restriction (IUGR) was 6.5% (100/1540 subjects) in the CVS group and 6.2% (52/840 subjects) in the control group. Again, this difference was not significant. The prevalence of hypertensive disorders in each group is shown in Table 3. The difference in prevalence of all hypertensive disorders of pregnancy between the CVS and control groups was not significant. The power of this study to detect a 50% increase (RR ⫽ 1.5) in the prevalence of all hypertensive disorders in the CVS group was 0.62. The prevalence of severe preeclampsia, eclampsia, and HELLP syndrome appeared to be
higher in the CVS group. However, these differences alone did not reach statistical significance. In contrast, when all severe disorders were combined, the RR was 2.48. This difference was statistically significant (P ⫽ .02). The incidence of severe hypertensive disorders of pregnancy stratified by gestational age at the time of CVS is shown in Table 4. The differences in frequency of severe hypertensive disorders between the gestational age ranges were not statistically significant.
C OMMENT Preeclampsia is a multisystem and multifactorial syndrome unique to human pregnancy. It is characterized by onset of hypertension and proteinuria after the 20th week of pregnancy. Clinical manifestations of preeclampsia include visual disturbances, headache, epigastric pain, platelet disturbances, liver dysfunction, and convulsions. As such, it is a leading cause of maternal and fetal mortality.14,15
The incidence of preeclampsia is estimated at about 5-8% of all pregnancies in the United States. Other conditions leading to endothelial damage, including diabetes, obesity, chronic renal disease, antiphospholipid antibody syndrome, autoimmune or rheumatologic diseases, and advanced maternal age, also predispose patients to development of preeclampsia.15,16 The pathogenesis of preeclampsia is unknown, although current proposed causes involve alterations in early placentation. It has been suggested that placental disruption may lead to impaired placental vasculature and endothelial dysfunction, with resultant placental ischemia. Invasion of endothelium and tunica media of maternal spiral arteries by cytotrophoblasts in early placentation leads to formation of large-capacitance low-resistance vessels in normal pregnancies. These vessels normally form in the late first trimester, and are completed by 18-20 weeks. They allow for increased blood flow to the uteroplacental unit.17 In preeclampsia, the cytotrophoblasts infiltrate only the decidual portion of the spiral arteries, without the second wave of penetration into the myometrium. The retained musculoelastic vessels of the uterus induce hypoperfusion when contracted, resulting in placental changes consistent with ischemia, including atherosis, fibrinoid necrosis, thrombosis, sclerotic narrowing of arterioles, and infarction.18 The process of angiogenesis plays a central role in placentation. Many studies have identified placental growth factor (PlGF), vascular endothelial growth factor (VEGF), and the VEGF antagonist, soluble fms-like tyrosine kinase 1 (sFlt-1), as being factors involved in pla-
TABLE 4
Severity of hypertensive disorder by week of gestation Week of gestation
Severe preeclampsia
Eclampsia
HELLP syndrome
All aevere disorders
P value*
10.0–10.9 (n ⫽ 17)
9 (52.9%)
1 (5.9%)
0
10 (58.9%)
ns
11.0–11.9 (n ⫽ 35)
13 (37.1%)
2 (5.7%)
3 (8.6%)
18 (55.1%)
ns
12.0–12.9 (n ⫽ 18)
4 (2.2%)
1 (5.6%)
3 (16.7%)
8 (44.4%)
ns
13.0–13.9 (n ⫽ 6)
2 (33.3%)
2 (33.3%)
1 (16.7%)
5 (83.3%)
ns
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
* 2.
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PCOG Papers cental ischemia. A disturbance in the balance of proangiogenic VEGF and antiangiogenic sFlt-1 may result in abnormal vascular development and contribute to the development of preeclampsia.19 Damage induced by CVS in early placentation is theorized to induce inflammation and focal hemorrhage, resulting in reduced placental perfusion.12 Maternal immune response to paternally derived fetal antigens may also contribute to endothelial dysfunction.20 It can be hypothesized that this anatomic disruption will alter biochemical levels of PlGF, VEGF, and sFlt-1, and possibly predispose patients to preeclampsia developing later in the pregnancy. Although, our study did not demonstrate an association between CVS and hypertensive disorders, we believe that the analysis of angiogenic factors in combination with placental disruption at the time of CVS may provide useful information. Although Silver et al12 noted a relationship between between transabdominal CVS in the late first trimester and preeclampsia/gestational hypertension, our findings did not demonstrate an association between CVS at 10-13 weeks’ gestational age and hypertensive disorders of pregnancy, as a whole. However, we observed a greater severity of preeclampsia in women exposed to CVS in the first trimester than in the controls who did not undergo an invasive procedure (Table 3). One limitation of this study is that number of controls was substantially less than the number of CVS subjects. Because it was not feasible to obtain complete obstetric and neonatal medical records for the women and infants who delivered at more than 30 other institutions in the metropolitan area, it was necessary to restrict our observations to the patients who delivered at our institution. This resulted in a substantial reduction in the number of subjects who were eligible for inclusion in the study. As a result, the power of our study was reduced. Because the difference between the prevalence of eclampsia and HELLP syndrome approached significance, it is possible that we failed to find a difference when a difference truly existed. To exclude a type II statistical error at a power 591.e6
www.AJOG.org of 80% for severe preeclampsia, it would require a sample size of 4500 subjects in each group. For eclampsia and HELLP syndrome, 3915 subjects would be required given the same parameters. Another limitation of the study is that the subjects in the CVS group had a significantly greater mean maternal age and BMI than did the controls. These factors are associated with increased risk for hypertension and thus could have contributed to a higher rate of severe hypertensive disorders in the CVS group. The strength of this study centers around the fact that standardized definitions of hypertensive disorders were used and each case was categorized systematically based on widely accepted criteria. Also, there are no published studies to date that have examined the relationship between hypertensive disorders and CVS, with the use of standard diagnostic criteria. Additional factors that should be evaluated in future studies include increasing the number of study and control subjects, controlling for maternal age, the number of device insertions and the quantity of villi removed per procedure, placental location, and the presence or absence of conception by advanced reproductive technology. Each of these factors could play a role in development of hypertensive disorders in pregnancy. f REFERENCES 1. Canadian Collaborative CVS-Amniocentesis Clinical Trial Group. Multicentre randomized clinical trial of chorion villus sampling and amniocentesis. Lancet 1989;i:1-6. 2. Smidt-Jensen S, Permin M, Philip J, et al. Randomised comparison of amniocentesis and transabdominal and transcervical chorionic villus sampling. Lancet 1992;340:1237-44. 3. Rhoads, GG, Jackson LG, Schlesselman SE, et al. The safety and efficacy of chorionic villus sampling for early prenatal diagnosis of cytogenetic abnormalities. N Engl J Med 1989;320:609-17. 4. Jackson LG, Zachary JM, Fowler SE, et al. A randomized comparison of transcervical and transabdominal chorionic-villus sampling. The U.S. National Institute of Child Health and Human Development Chorionic-Villus Sampling and Amniocentesis Study Group. N Engl J Med 1992;327:594-8. 5. Snijders RJ, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age
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and fetal nuchal-translucency thickness at 10-14 weeks of gestation. Fetal Medicine Foundation First Trimester Screening Group. Lancet 1998;352:343-6. 6. Spencer K, Spencer CE, Power M, Dawson C, Nicolaides KH. Screening for chromosomal abnormalities in the first trimester using ultrasound and maternal serum biochemistry in a one-stop clinic: a review of three years prospective experience. BJOG 2003;110: 281-6. 7. Wapner R, Thom E, Simpson JL, et al. Firsttrimester screening for trisomies 21 and 18. N Engl J Med 2003;349:1405-13. 8. Lippman A, Tomkins DJ, Shime J, Hamerton, JL. Canadian multicentre randomized clinical trial of chorion villus sampling and amniocentesis: final report. Prenat Diagn 1992;12:385-408. 9. Smidt-Jensen S, Permin M, Phillip J, et al. Randomised comparison of amniocentesis and transabdominal and transcervical chorionic villus sampling. Lancet 1992;340:1237-44. 10. Schaap AH, van der Pol HG, Boer K, Leschot LJ, Wolf H. Long-term follow-up of infants after transcervical chorionic villus sampling and after amniocentesis to compare congenital abnormalities and health status. Prenat Diagn 2002;22:598-604. 11. Holmes LB. Report of National Institute of Child Health and Human Development Workshop on Chorionic Sampling and Limb and Other Defects, October 20, 1992. Teratology 1993;48:7-13. 12. Silver RK, Wilson RD, Philip J, et al. Late first-trimester placental disruption and subsequent gestational hypertension/preeclampsia. Obstet Gynecol 2005;105:587-92. 13. Report of the National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000;183:S1-S22. 14. American College of Obstetricians and Gynecologists. Diagnosis and management of preeclampsia and eclampsia. Washington, DC: The College; 2002. ACOG practice bulletin no. 33. 15. Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. Lancet 2001;357:53-6. 16. Dekker GA. Risk factors for preeclampsia. Clin Obstet Gynecol 1999;42:422-35. 17. Zhou Y, Damsky CH, Fisher SJ. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype: one cause of defective endovascular invasion in this syndrome? J Clin Invest 1997;99:2152-64. 18. Brosens IA. Morphological changes in the uteroplacental bed in pregnancy hypertension. Clin Obstet Gynaecol 1977;4:573-93. 19. McKeeman GC, Ardill JE, Caldwell CM, Hunter AJ, McClure N. Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop. Am J Obstet Gynecol 2004;191:1240-6.
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www.AJOG.org 20. Wilson ML, Goodwin TM, Pan VL, Ingles SA. Molecular epidemiology of preeclampsia. Obstet Gynecol Surv 2003;58:39-66.
D ISCUSSION Dena Towner, MD. Adusumalli et al should be lauded for such an ambitious study. It was no small feat to have reviewed more than 2000 charts for pregnancy outcomes. He chose to evaluate a biologically plausible effect of CVS— hypertensive disorders of pregnancy that in large part are thought to be secondary to placentation abnormalities. Early placental implantation is critical for fetal growth and development and obstetric outcomes. Disruption of this process could in theory lead to abnormal implantation and secondary fetal and maternal effects. Certain medical disorders, including hypertension, vascular disease, systemic lupus erythematocus, antiphospholipid syndrome, are associated with poor implantation and an increased risk of preeclampsia. In early pregnancy, the trophoblast invades into the spiral arterioles and transforms these vessels into low-resistance vessels, which open into the maternal sinuses of the placenta. Thus, it is biologically plausible that CVS
could cause disruption of the normal implantation process. The effect may not be limited locally to the site sampled. An inflammatory response invoked by healing could lead to a widespread effect on implantation. The impetus for this study was a report in 2005 by Silver et al1 identifying an increased risk of hypertensive diseases in women having CVS in gestational week 13-14. A limitation to this study was that it was not designed to directly study hypertensive outcomes in pregnancy. Surrogate markers for severe preeclampsia were used, including growth restriction of the neonate based on birthweight less than fifth percentile and delivery less than 37 weeks. The odds ratio (OR) for severe preeclampsia was 2.49 comparing CVS with early amniocentesis. This study clearly suggested that CVS could be associated with severe preeclampsia later in pregnancy. Fortunately, rates of preeclampsia were still in what is considered an expected range, thus of questionable clinical significance. In the study by Adusumalli et al, they identified a large population of women undergoing CVS and compare them
with a group without invasive testing. They reviewed the medical records after delivery to determine whether there was an association with hypertensive diseases, excluding women at increased risk for hypertensive diseases of pregnancy. They identified significant differences in several maternal characteristics, including age, parity, BMI, and ethnicity, all of which have association with preeclampsia risks. Overall, they found no significant difference for the prevalence of hypertensive diseases of pregnancy between the groups. However, when breaking down the severity of disease, they identified near significance for eclampsia and HELLP syndrome as separate entities. When they looked at all forms of severe disease as a group, there appeared to be a significant increase in severe diseases (2.7% vs 1.1%, RR 2.48), compared to the control group. This RR is nearly identical to that found by Silver et al.1 REFERENCE 1. Silver RK, Wilson RD, Philip J, et al. Late firsttrimester placental disruption and subsequent gestational hypertension/preeclampsia. Obstet Gynecol 2005;105:587-92.
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