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ORIGINAL RESEARCH |
From the 1 Division of Epidemiology and Biostatistics and 2 Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey; and 3 Department of Maternal and Child Health, University of Alabama at Birmingham, Birmingham, Alabama.
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ABSTRACT |
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METHODS: A retrospective cohort study entailing a case–crossover analysis was performed based on women who had two consecutive singleton live births (n=154,810) between 1989 and 1997 in Missouri. Small for gestational age was defined as infants with birth weight below the 10th centile for gestational age. Risk and recurrence of ischemic placental disease was assessed from fitting logistic regression models after adjusting for several confounders.
RESULTS: Preeclampsia in the first pregnancy was associated with significantly increased risk of preeclampsia (odds ratio 7.03, 95% confidence interval 6.51, 7.59), SGA (odds ratio 1.16, 95% confidence interval 1.06, 1.27), and placental abruption (odds ratio 1.90, 95% confidence interval 1.51, 2.38) in the second pregnancy. Similarly, women with SGA and abruption in the first pregnancy were associated with increased risks of all other conditions in the second pregnancy.
CONCLUSION: Women with preeclampsia, SGA, and placental abruption in their first pregnancy—conditions that constitute ischemic placental disease—are at substantially increased risk of recurrence of any or all these conditions in their second pregnancy. Although causes of these conditions remain largely speculative, these entities may manifest through a common pathway of ischemic placental disease with significant risk of recurrence.
LEVEL OF EVIDENCE: II
We recently showed that, among medically indicated preterm births, the chief conditions that necessitated medical interventions included, in order of decreasing frequency, preeclampsia, small for gestational age, fetal distress, and placental abruption.4 These conditions were implicated in approximately 54% of all medically indicated preterm births. As with preterm birth,5 each of these conditions has a significant rate of recurrence.
Because patients may present with more than one of these clinical manifestations, we hypothesized that these clinical conditions may share similar underlying causes, and that ischemic placental disease may be the common pathway through which these conditions may manifest. We tested this hypothesis by designing a case–crossover analysis of singleton live births in a large, population-based data source of successive pregnancies.
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MATERIALS AND METHODS |
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We previously reported, using this same data source, the recurrence of preterm birth5 and the risks of ischemic placental disease conditions.4 In this article we examine recurrence of ischemic placental disease. Gestational age in these data files are largely based on menstrual dating (approximately 95% of records) and in a small fraction was based on a clinical estimate (also contained on the data files). The clinical estimate of gestation was used when the menstrual estimate was grossly inconsistent with birthweight (ie, extremely low birthweight at term gestation). Preeclampsia was diagnosed based on clinical criteria and included women with eclampsia or chronic hypertension with superimposed preeclampsia. Small for gestational age was defined as birthweight below the 10th centile for gestational age, and the standard used for defining the norms was based on all live births in Missouri between 1989 and 1997 (ie, internal standards).
We designed a case–crossover analysis11 and estimated the risks of preeclampsia, small for gestational age, and placental abruption in the first and second pregnancies, as well as the recurrence of these conditions. The extent to which these conditions recurred in the second pregnancy was estimated based on the relative risk. This study, by design, can be viewed as a case–crossover analysis because women with an ischemic placental disease condition (eg, preeclampsia) in the second pregnancy may have been normotensive in the first pregnancy (ie, a crossover phenomenon). This enables subjects as being their own "control," thereby enabling the analysis as one of a case–crossover design.11,12 An advantage of this design is the implicit control for confounders that may otherwise be difficult to adjust. The case–crossover study design is particularly useful when the exposure is intermittent, the effect of risk is immediate and transient, and the outcome is abrupt.
Analyses were adjusted for several potential confounding factors in the second births through logistic regression models; these included period of birth (1989 through 1997), maternal age (categorized as less than 20, 20 to 24, 25 to 29, 30 to 34 and 35 or more years), maternal race or ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, and other race or ethnicity), maternal education (number of years of completed schooling, categorized as less than 8, 8 to 11, 12, and 13 or more years), marital status (single or married), smoking during pregnancy (yes or no), prepregnancy maternal body mass index, defined as weight (in kilograms) to height squared (in meters), and categorized as less than 18.5, 18.5 to 24.9, 25.0 to 29.9, and 30 or more. Finally, all models were adjusted for interpregnancy interval (categorized as less than 1, 1 to 1.4, 1.5 to 1.9, 2.0 to 2.4, 2.5 to 2.9, 3.0 to 3.4, 3.5 to 3.9, and 4 or more years) between the first birth and the start of the second pregnancy. The ethics review committee of the Institutional Review Board of UMDNJ-Robert Wood Johnson Medical School, NJ, approved the study.
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RESULTS |
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The rates of preeclampsia, small for gestational age, and placental abruption in the second pregnancy in relation to the presence of these conditions in the first pregnancy are shown in Table 2.
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The association of ischemic placental disease between the first and second pregnancies is shown in Table 3 and Figure 1. If women had their first pregnancy complicated by preeclampsia, then they had the highest risk of recurrence of preeclampsia in their second pregnancy; however, they were also at increased risk for small for gestational age birth and placental abruption in their second pregnancy. This pattern of increased recurrence risks was seen for all of the ischemic placental disease conditions. Of note is that the odds ratios were highest for the recurrence of each condition (ie, preeclampsia–preeclampsia, small for gestational age–small for gestational age, and abruption–abruption between the first and second pregnancies, respectively).
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DISCUSSION |
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The classification of preeclampsia, small for gestational age, and placental abruption under the rubric of ischemic placental disease4 is well supported through studies on placental histologic findings. Lesions characteristic of placental ischemia such as hemosiderin deposition, necrosis, and atherosis, are commonly found in placentas of pregnancies complicated by preeclampsia,18,19 small for gestational age, and placental abruption.22 Rasmussen and colleagues2 showed that a history of placental dysfunction (defined as fetal growth restriction, preterm birth, and pregnancy-induced hypertension) is strongly associated with increased risk of placental abruption in the subsequent pregnancy. They speculated that these conditions may either share similar causative processes or represent different clinical expressions of recurring placental dysfunction.2 Although informative, their study was restricted to women who developed placental abruption in the subsequent pregnancy. Our findings extend beyond those of Rasmussen et al2 in that we not only show the increased risk of recurrence for each of preeclampsia, small for gestational age, and abruption, but also that any one of these disease states confers increased risk of any other conditions. This finding supports our general hypothesis that ischemic placental disease states may be one unified pathway through which these conditions manifest.
The increased risk of recurrence of ischemic placental disease in the second pregnancy for each condition, as well as the increased risk for other conditions, suggests that genetic factors may help shape these risks. In particular, the highest risk of recurrence was for preeclampsia and, to a lesser extent, to small for gestational age births. Both these conditions have strong genetic predispositions, as well as environmental influences.1,26 It is possible that environmental exposures may modify the genetic links to favor some subtypes than others.
Our findings warrant caution in interpretation due to the potential influence of certain unmeasured confounders. Studies have documented a role for change in paternity in shaping disease risks, most notably, preeclampsia. Preeclampsia is characterized as a disease of the first pregnancy, with its incidence almost halving in the second pregnancy.30,31 However, women changing partners between their pregnancies have risks similar to those seen in their first pregnancy, suggesting a role for an immune maladaptation.28 Our data do not carry any information on changes in paternity. Furthermore, although placental ischemia may be a common finding for all of the four clinical conditions of ischemic placental disease, other conditions (eg, large for gestational age) may also be associated with them.
While national- and state-level vital statistics data provide a valuable resource for population-based research,32 these data must be used judiciously and interpreted with care.33,34 Numerous researchers have validated clinical data entities from birth certificates compared with hospital chart records. A comparison of findings from several larger studies suggests the following: the sensitivity of birth certificates for preeclampsia (referred to as pregnancy-associated hypertension on the birth certificate) ranges from 42% to 60% and 78% to 90% for abruption. The positive predictive values for these two conditions range from 78% to 90% and 92% to 100%, respectively. Despite the fact that sensitivities for reporting of preeclampsia and placental abruption are lower than the levels desired for screening tests, given the good concordance demonstrated by their positive predictive values, we are confident that any bias from underreporting of these variables will result in a bias toward the null. We also note that, although there are no validation studies of vital statistics data quality in maternally linked data sets, with continuity of perinatal care across pregnancies, it is likely that the data quality in our study population exceeds that found in the extant literature, none of which was conducted in Missouri.
Our study employs the case–crossover study design.11,12 This design allows cases of a disease to serve as their own controls in an earlier time window. In this study, we conducted a prospective cohort analysis to assess the risk of ischemic placental disease in the subsequent pregnancy. This case–crossover analysis ensures that misclassification of ischemic placental disease states, if any, are minimized. Although our data do not include this information, it is likely that most of our study subjects received prenatal care from the same clinician or group practice, thereby limiting the likelihood of diagnostic misclassification of ischemic placental disease in the second pregnancy.
We have shown that women with pregnancies complicated by preeclampsia, small for gestational age, and placental abruption—conditions that constitute ischemic placental disease—are at increased risk of recurrence of these conditions in their second pregnancy. The tendency of each condition in the syndrome of ischemic placental disease to be associated with increased risks for other complications in the syndrome suggests some commonality to underlying causative mechanisms. These findings may have implications for patient counseling as well as for directions for future research pursuits. Previous work by our group4 suggests that if we find ways to prevent ischemic placental disease, we may be able to prevent over one half of all indicated preterm births.
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Footnotes |
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Corresponding author: Cande V. Ananth, PhD, MPH, Division of Epidemiology and Biostatistics, Department of Obstetrics, Gynecology, and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, 125 Paterson Street, New Brunswick NJ 08901-1977; e-mail: cande.ananth{at}umdnj.edu.
Financial Disclosure The authors have no potential conflicts of interest to disclose.
doi:10.1097/01.AOG.0000266983.77458.71
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REFERENCES |
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