Obstetrics & Gynecology:
Late First-Trimester Placental Disruption and Subsequent Gestational Hypertension/Preeclampsia
Silver, Richard K. MD*; Wilson, R Douglas MD†; Philip, John MD‡; Thom, Elizabeth A. PhD§; Zachary, Julia M.§; Mohide, Patrick MD¶; Mahoney, Maurice J. MD∥; Simpson, Joe L. MD**; Platt, Larry D. MD††; Pergament, Eugene MD‡‡; Hershey, Douglas MD§§; Filkins, Karen MD¶¶; Johnson, Anthony DO∥∥; Wapner, Ronald J. MD***; Jackson, Laird G. MD***; for the NICHD EATA Trial Group
*From Evanston Hospital of Northwestern University Medical School, Evanston, Illinois; †British Columbia Women's Hospital, Vancouver, British Columbia, Canada; ‡Rigshospitalet, Copenhagen, Denmark; §The Biostatistics Center, George Washington University, Rockville, Maryland; ¶McMaster University Medical Centre, Hamilton, Ontario, Canada; ∥Yale University, New Haven, Connecticut; **Baylor College of Medicine, Houston, Texas; ††Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California; ‡‡Department of Obstetrics and Gynecology, Northwestern University Medical School, Chicago, Illinois; §§Prenatal Diagnosis of Northern California Medical Group, Sacramento, California; ¶¶UCLA Center for the Health Sciences, Los Angeles, California; ∥∥Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan; and ***Drexel University College of Medicine, Philadelphia, Pennsylvania.
*The other members of the EATA Trial Group are listed in the Appendix.
Supported by grants R01 HD31991 and HD32109 from the National Institute of Child Health and Human Development and by the Danish Centre for Evaluation and Health Technology Assessment, National Board of Health, Denmark.
Address reprint requests to: Richard K. Silver, MD, Evanston Northwestern Healthcare, Department of Obstetrics and Gynecology, 2650 Ridge Avenue, Suite 118, Evanston, IL 60201; e-mail: firstname.lastname@example.org.
Received August 20, 2004. Received in revised form October 29, 2004. Accepted November 4, 2004.
OBJECTIVE: To evaluate the potential relationship between placental disruption in weeks 13 and 14 and the subsequent development of gestational hypertension or preeclampsia.
METHODS: Using subjects recruited during a randomized trial funded by the National Institute of Child Health and Human Development, which compared early amniocentesis and late transabdominal chorionic villus sampling (CVS) in weeks 13 and 14, rates of gestational hypertension and preeclampsia were compared between cases with varying degrees of placental disruption.
RESULTS: A total of 3,698 of 3,775 randomized subjects had cytogenetically normal pregnancies and were analyzed. A significantly higher rate of hypertension/preeclampsia was observed in the late CVS group (5.4%, n = 1,878) compared with the early amniocentesis cohort (3.5%, n = 1,820; P = .005). This difference persisted after controlling for maternal age, body mass index, parity, previous preterm delivery, smoking, and fetal gender. Early amniocentesis cases were further stratified on the basis of whether the placenta had been penetrated (n = 460) or not (n = 1,360). Risk of hypertensive complications was lowest if the placenta was not traversed (3.4%), greater with placental penetration (3.9%), and highest when the placenta was directly sampled during CVS (5.4%, P = .02).
CONCLUSION: We hypothesize that focal disruption of the placenta at 13–14 weeks may increase the risk of hypertension/preeclampsia. These findings provide support for the theory that disturbances in early placentation lead subsequently to maternal hypertension.
LEVEL OF EVIDENCE: II-1
Preeclampsia continues to be a serious obstetric complication in contemporary practice. Despite a concerted effort to understand its underlying pathophysiology, no single unifying theory as to its cause has been confirmed. That gestational hypertension and preeclampsia are unique conditions of pregnancy is indisputable as is the resolution of these conditions after delivery of the fetus and placenta. Among the plausible theories for this clinical syndrome is the possibility that abnormal placentation in early pregnancy contributes to hypertensive complications in the third trimester. We set out to explore this theory by evaluating maternal outcomes subsequent to prenatal diagnosis, during which focal placental disruption occurred coincident with the procedures being performed. This opportunity presented itself as part of a large National Institutes of Health–funded randomized clinical trial comparing 2 procedures between 13 and 14 weeks of gestation, namely, late chorionic villus sampling (CVS) and early amniocentesis. Specifically, we asked whether the degree of placental disruption accompanying these prenatal diagnostic procedures could be correlated with the occurrence of hypertensive complications later in pregnancy.
MATERIALS AND METHODS
Detailed methodology for the trial sponsored by the National Institute of Child Health and Human Development has previously been reported in detail.1 Pertinent to this analysis is a brief description of the randomized population, the prenatal diagnostic techniques used and the methods of data collection. Fourteen participating centers received institutional review board approval for the randomized trial and provided certified operators, each of whom had performed at least 25 amniocenteses and 25 chorionic villus samplings within the gestational window of 11–14 weeks and were also performing contemporaneous prenatal diagnostic procedures on nonstudy patients. Women were eligible if 34 years or older at enrollment, if they had a previous trisomy, or if they were screen-positive (ie, equivalent risk to age 35 at delivery) after first-trimester assessment. As explained elsewhere1 initial gestational age range of eligibility (77–104 days) was subsequently restricted to the 13th and 14th weeks after reports indicated an increased fetal risk from amniocentesis during the earlier gestational age range.2,3 Thus, more than 90% of procedures were performed in weeks 13–14 of gestation (91–104 days).
Before randomization, eligible patients underwent ultrasound evaluation to determine that early amniocentesis and late transabdominal CVS were both feasible, based on uterine and placental position and amniotic fluid volume. Using a central automated phone system and computer-generated randomization sequences, consenting subjects were assigned (stratified by center) to 1 of the 2 study procedures. Continuous transabdominal ultrasound guidance was used for each procedure. Two sampling passes were allowed, and a second procedure, if needed, could only be performed 7 days after the initial attempt. Early amniocentesis was performed with a 22-gauge spinal needle, and late CVS was performed with either a single spinal needle (19 or 20 gauge) or double-needle technique (18, 20 gauge), with the larger guide needle introduced to the placental margin, after which the sample needle was inserted into the chorionic villus.
Baseline demography was obtained before randomization. Procedure-related variables were recorded by the operator immediately after each procedure. Maternal outcomes were obtained from obstetricians’ offices by chart review and were confirmed through telephone contact between the study site coordinators and the patients within 4 months of delivery, using a structured questionnaire. Gestational hypertension and preeclampsia were coded if identified by the referring physician who cared for the patient, but detailed data to characterize severity were not collected. We therefore used preterm delivery (< 37 weeks) or the presence of fetal growth restriction (birth weight < fifth percentile) as surrogate findings for “severe preeclampsia.” In so doing, we reviewed the frequency with which preterm labor or premature membrane rupture were the primary diagnoses associated with preterm birth to estimate the potential for misclassification of severe preeclampsia cases. Data on maternal complications were not available for 42 cases of early spontaneous loss or termination of cytogenetically normal pregnancies and missing in 15 patients who delivered liveborn infants. These 57 cases were coded as not having the outcome variable: hypertension/preeclampsia.
For the present study, 3 cohorts were compared: late CVS in which the placenta was directly sampled (group A) and early amniocentesis in which the placenta was either traversed (group B) or not traversed (group C). Continuous variables were evaluated between groups using the Kruskal-Wallis test, whereas categorical variables were compared by Fisher exact or χ2 tests, as appropriate. Logistic regression was performed, with “any reported gestational hypertension or preeclampsia” and “severe hypertension/preeclampsia” as the variable and procedure type or degree of placental disruption (groups A, B, and C) as independent variables. Considered as potential confounding factors, maternal age (in years), maternal body mass index, parity, smoking status (yes or no), previous preterm delivery, and fetal gender were included in the logistic regression model. Statistical analyses were performed with SAS 8.0 (SAS Institute, Cary, NC).
Figure 1 summarizes the 3 cohorts compared, as derived from the original study design. In 6 cases a nonassigned procedure was performed (3 crossovers in each randomized group); 5 of those were chromosomally normal and were included in this analysis. None of these 5 women developed gestational hypertension or preeclampsia. Placental disruption was hypothesized to be greatest for late CVS (group A, n = 1,878) because a villus sample was actually removed. Placental disruption was deemed logically to be less in early amniocentesis procedures in which the placenta was traversed to enter the amnion (group B, n = 460) and least for early amniocentesis in which the placenta was not traversed (group C, n = 1360). Notably, the majority of early amniocenteses (groups B and C) did not involve placental penetration (75%), and anterior placental location was significantly more common in group B compared with group C procedures (84.3% versus 36.6%, respectively, P < .001).
The clinical diagnosis of gestational hypertension or preeclampsia was made in 166 women (4.5%). A significantly higher rate of gestational hypertension or preeclampsia was observed in women undergoing late CVS (group A) when compared with the 2 early amniocentesis groups, B and C (5.4% versus 3.5%, P = .005).1 Comparison of cases by degree of placental disruption revealed that only maternal body mass index was significantly different between groups, and this was greatest in group B (Table 1). In Table 2, a stepwise difference in risk of hypertensive complications is shown: least in group C (3.4%), greater in group B (3.9%), and highest in group A (5.4%, P = .02). This same relationship held when the analysis was restricted to severe preeclampsia (0.5% versus 1.3% versus 1.7%, respectively; P = .01). The overlap between severe preeclampsia cases and other associations with preterm delivery (premature membrane rupture in 2 cases and preterm labor in no cases) was minimal and, excluding those 2 cases, did not alter the findings reported above.
Multivariable logistic regression took into account the variables potentially related to the risk of hypertensive complications in pregnancy (maternal age, body mass index, parity, previous preterm delivery, smoking, and fetal gender). In these models, membership in group A (compared with groups B and C) remained predictive of hypertensive complications, as did the categorical variable that stratified cases by degree of placental disruption in each of the 3 groups (Table 3). This analysis was unchanged after controlling for gestational age at prenatal diagnosis and the volume of cases performed by each operator.
We considered needle size and single- versus double-needle sampling for group A (CVS) and the effect of multiple sampling attempts in all groups (Table 4). No differences were observed with respect to subsequent gestational hypertension or preeclampsia, except for the higher risk in group A cases associated with the 19-gauge (ie, intermediate size) sampling needle, the larger of the 2 needles used in the single-needle method of sampling. The significance of this finding is unclear because of the small sample size in this cell.
Our study found a potential relationship between the degree of placental disruption during the late first trimester and the subsequent manifestation of maternal hypertensive complications. A greater likelihood of gestational hypertension or preeclampsia was noted as the degree of placental disruption increased. These observations are intriguing because placental dysfunction is a credible precondition among women who develop hypertensive disorders in pregnancy. Pertinent to the current study are the theoretic antecedents of preeclampsia, which include abnormalities in placental penetration of the uterine decidua followed by incomplete spiral artery proliferation. Because spiral artery remodeling occurs during the “second wave” of trophoblast invasion (at 14–16 weeks of gestation), the narrow window during which prenatal diagnosis was performed in this trial (13–14 weeks) makes plausible at least a temporal relationship to these theories.4
An aberrant maternal immune response to fetal antigens has also been implicated as an alternative mechanism that may contribute to the development of preeclampsia.4 To the extent that an abnormal maternal immune response to paternally derived antigens might play a role in the etiology of preeclampsia, placental disruption at 13–14 weeks could certainly release fetal material into the maternal circulation. Studies showing increased maternal serum alpha-fetoprotein levels after prenatal diagnosis indicate the possibility of increased fetal-maternal transfer following certain procedures.5,6
Reduced uterine blood flow and placental ischemia have also been proposed as elements of preeclampsia pathophysiology. Disruption of the placenta during prenatal diagnosis, with focal hemorrhage and subsequent inflammation, could theoretically inhibit the spiral arteriolar widening, contributing to reduced placental perfusion and initiating a cascade of additional effects that include oxidative stress and endothelial cell dysfunction.4 Various animal models of preeclampsia have intentionally employed early perturbations of placental or uterine perfusion to provoke preeclampsia-like conditions. This has been accomplished in rats by creating an imbalance in vasoactive mediators responsible for placental perfusion or by directly reducing uterine blood flow with secondary reduction of placental and fetal growth.7,8
Despite the novelty of the association reported herein, we are mindful of significant limitations related to our analysis. Misclassification could have occurred, given that the original trial was not designed to explore gestational hypertension/preeclampsia as a primary endpoint, and diagnoses were not confirmed by chart review. The approximate doubling of the incidence of hypertensive complications noted in group A still resulted in an absolute rate that was low (< 6%) and within an expected range for similar populations of pregnant women. Thus, the immediate clinical significance of our finding, even if confirmed, may be limited. Our observations cannot be extrapolated to either CVS or amniocentesis performed in their usual time frames of 10–12 and 15–21 weeks, respectively. Nor has preeclampsia been linked to CVS or amniocentesis in prior trials for which maternal data were provided.2,9,10 However, a clinically relevant question that our analysis does prompt is the advisability of transplacental sampling when the alternative of not traversing the placenta exists. Some authors have empirically recommended avoiding the placenta during amniocentesis to minimize the risk of fetal complications.11,12 Although this strategy would seem intuitive, clear support for this practice cannot be found.13–19 In fact, it has been alternatively suggested that traversing the placenta to obtain amniotic fluid may actually reduce the procedure-related risk of miscarriage by limiting the likelihood of postprocedure leaking, especially during early midtrimester procedures.19 In support are data from the current study (Table 2), with lower rates of amniotic fluid leakage being observed in group B versus group C cases. Defining both maternal and fetal risks is of interest because the demand for prenatal diagnosis at 13–14 weeks is likely to increase in response to proliferation of first-trimester screening using nuchal translucency and serum analytes.20
In conclusion, our results support a potential relationship between late first-trimester placental disruption and subsequent gestational hypertension/preeclampsia. It is pivotal in pursuing this idea to broaden the scope and definition of placental disruption to include additional causes unrelated to prenatal diagnosis, such as occult or overt placental trauma, ischemia, or inflammation.
1. Philip J, Silver RK, Wilson RD, Thom EA, Zachary JM, Mohide P, et al. Late first-trimester invasive prenatal diagnosis: results of an international randomized trial. Obstet Gynecol 2004;103:1164–73.
2. Sundberg K, Bang J, Smidt-Jensen S, Brocks V, Lundsteen C, Parner J, et al. Randomised study of the risk of fetal loss related to early amniocentesis versus chorionic villus sampling. Lancet 1997;350:697–703.
3. Canadian Early and Mid-Trimester Amniocentesis Trial (CEMAT) Group. Randomised trial to assess safety and fetal outcome of early and midtrimester amniocentesis. Lancet 1998;351:242–7.
4. Wilson ML, Goodwin TM, Pan VL, Ingles SA. Molecular epidemiology of preeclampsia. Obstet Gynecol Surv 2003;58:39–66.
5. Thomsen SG, Isager-Sally L, Lange AP, Saurbrey N, Gronvall S, Schioler V. Elevated maternal serum alpha-fetoprotein caused by midtrimester amniocentesis: a prognostic factor. Obstet Gynecol 1983;62:297–300.
6. Shulman LP, Meyers CM, Simpson JL, Andersen RN, Tolley EA, Elias S. Fetomaternal transfusion depends on the amount of chorionic villi aspirated but not on method of chorionic villus sampling. Am J Obstet Gynecol 1990;162:1185–8.
7. Yallampalli C, Garfield RE. Inhibition of nitric oxide synthesis in rats during pregnancy produces signs similar to those of preeclampsia. Am J Obstet Gynecol 1993;169:1316–20.
8. Neerhof MG, Silver RK, Caplan MS, Thaete LG. Endothelin-1-induced placental and fetal growth restriction in the rat. J Matern Fetal Med 1997;6:125–8.
9. Smidt-Jensen S, Permin M, Philip J, Lundsteen C, Zachary JM, Fowler SE, et al. Randomised comparison of amniocentesis and transabdominal and transcervical chorionic villus sampling. Lancet 1992;340:1237–44.
10. Jackson LG, Zachary JM, Fowler SE, Desnick RJ, Golbus MS, Ledbetter DH, et al. A randomized comparison of transcervical and transabdominal chorionic villus sampling. N Engl J Med 1992;327:594–8.
11. Porreco RP, Young PE, Resnick R, Cousins L, Jones OW, Richards T, et al. Reproductive outcome following genetic amniocentesis for genetic indications. Am J Obstet Gynecol 1982;143:653–60.
12. Tabor A, Philip J, Madsen M, Bang J, Obel EB, Norgaard-Pedersen B. Randomized controlled trial of genetic amniocentesis in 4,606 low-risk women. Lancet 1986;1:1287–93.
13. Crane JP, Kopta MM. Genetic amniocentesis: impact of placental position upon the risk of pregnancy loss. Am J Obstet Gynecol 1984;150:813–16.
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20. Wapner R, Thom E, Simpson JL, Pergament E, Silver R, Filkins K, et al, for the BUN Study Group. First trimester screening for trisomies 21 and 18. N Engl J Med 2003;349:1405–13.
Besides the authors, the members of The Randomized Trial of Early Amniocentesis and Transabdominal CVS (EATA) investigative group are as follows: Rigshospitalet, Genetic Center: J. Bang, W. Keller, A. Meyer, M. Vad, B. Binzer, A. G. Sidenius, S. Lindstrøm, S. Flint, K. Sundberg, and L. Sperling; Chromosome Laboratory: C. Lundsteen and A. M. Lind; Hvidovre Hospital: S. Smidt-Jensen; Drexel University College of Medicine: G. Davis, M. DiVito, and M. McGee; Baylor College of Medicine: R. Carpenter, J. Dungan, and A. Burke; Northwestern University Medical School: N. A. Ginsberg, C. Dougherty, and K. DeMarco; Fetal Diagnostic Center, Evanston Hospital of Northwestern University Medical School: S. MacGregor, K. Blum, E. Leeth, and J. Weimer; Cedars-Sinai Medical Center: D. E. Carlson (deceased), J. Williams, D. Krakow, C. A. Walla, W. Herbert, K. Wendt, and N. Greene; Magee-Women's Hospital: W. A Hogge, E. Smith, and K. Ventura; UCLA Center for the Health Sciences: S. Beverly; University of Tennessee, Memphis: L. Shulman, S. Elias, O. Phillips, L. Seely, and P. King; Wayne State University: M. Evans, D. Duquette, E. Krivchenia, and P. Devers; Yale University: J. Copel, R. Bahado-Singh, M. DiMaio, and S. Turk; McMaster University Medical Center: J. Smith, M. L. Beecroft, G. White, N. Brown, M. Huggins, and V. Freeman; BC Women's Hospital: D. Shaw and S. Soanes; Prenatal Diagnosis of Northern California Medical Group: K. Kahl and M. Palmer; University of Maryland, Baltimore: K. Frayer; Mt Sinai School of Medicine, New York: R. Desnick, K. Eddleman, J. Stone, R. Zinberg, and J. Robinowitz; The George Washington University Biostatistics Center: B. Fisher, K. Poydence, P. Van, and N. Boone; The National Institute of Child Health and Human Development: F. de la Cruz and J. Hanson; Danish Centre for Evaluation and Health Technology Assessment, National Board of Health, Denmark: F. Børlum Kristensen. Cited Here...
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