Impaired placental function has various manifestations during pregnancy, primarily fetal growth restriction or small for gestational age (SGA), hypertensive disease, and placental abruption. These complications affect more than 5% of pregnancies, resulting in maternal and perinatal morbidity and mortality.1 Placental villitis, the suspected basis for adverse outcomes, is estimated to reoccur in 25–50% of pregnancies.2 The tendency for uteroplacental insufficiency to reoccur is evidenced by the fact that the birth of an SGA neonate in the first pregnancy increases the risk of recurrence by more than sevenfold.3–5 Moreover, placental disease may present itself differently in subsequent pregnancies.6
The association of prior pregnancy outcome with future pregnancy outcome is also evidenced by the fact that a history of placental abruption is the leading risk factor for recurrence.7 With a history of two repeated placental abruptions, the risk continues to rise.8,9 As for hypertensive disease, an overall recurrence rate of 20.7% had been reported.10
Most of the literature examined the risk of reappearance of placenta-mediated adverse outcomes, primarily the one succeeding the affected gestation. However, little is known regarding the risk of recurrence in the third successive pregnancy and how obstetric history of specific placenta-mediated complications can moderate that risk. Thus, we aimed to estimate the risk of recurrent placenta-mediated complications in women in their third delivery according to their obstetric history.
MATERIALS AND METHODS
We conducted a retrospective cohort study of all women with singleton pregnancies who delivered their first three consecutive deliveries (24 weeks of gestation or greater) in a single university-affiliated tertiary medical center over a 20-year period (1994–2013). In an attempt to better isolate placenta-mediated adverse events, we excluded women with multiple gestations and fetal structural or chromosomal anomalies in either pregnancy from the analysis. Because the records regarding stillbirth were not complete, we excluded women with stillbirth in any of their first three pregnancies as well. In addition, deliveries of unknown gestational age in any one of the first three deliveries or women who did not deliver all three first consecutive deliveries in our medical center were excluded as well.
We obtained data from our departmental electronic medical records. During the study period, three different electronic medical records were used. Notwithstanding their extraction from different resources, all relevant data were filled during and immediately after delivery by either the attending physician or midwife. Furthermore, the data used in the current study were primarily discrete fields and as such less prone to error. Lastly, in terms of data quality assurance, internal consistency crosschecks are performed at regular time intervals by medical staff. The following demographic and obstetric variables were recorded: maternal age, gravidity, parity, gestational age at delivery, obstetric comorbidities such as diabetes mellitus, hypertensive disorders (gestational hypertension or preeclampsia), placental abruption, SGA, or severe SGA. These were defined as birth weight less than the 10th or less than the 3rd percentile, respectively, according to local birth weight curves adjusted for gestational age at delivery and neonatal gender.11 The definition of SGA was based solely on the calculation of birth weight centile according to the local birthweight curves11 and not on the presence or absence of such a diagnosis on the medical records.
Gestational hypertension was defined as systolic blood pressure of 140 mm Hg or higher or diastolic blood pressure 90 or higher that occurred after 20 weeks of gestation.12 Prepregnancy hypertension or hypertension occurring before 20 weeks of gestation was considered chronic hypertension. Preeclampsia was defined as hypertension accompanied by proteinuria of 300 mg or greater in 24 hours or the presence of eclampsia.
Gestational age at delivery was determined by the last menstrual period and was verified by first-trimester ultrasonography when available. In cases of in vitro fertilization, gestational age was determined according to the date of embryo transfer.
Placenta-mediated complications were defined as complications resulting in placental disease, including at least one of the following: hypertensive disorders (gestational hypertension or preeclampsia), placental abruption, or SGA less than the 10th percentile. The risk of placenta-mediated complications in the third delivery was assessed according to the presence (marked as [+]) or absence (marked as [–]) of complications in previous deliveries.
The study population was divided into four cohorts: 1) women with placenta-mediated complications in both the first and second deliveries; 2) women with placenta-mediated complications in the first delivery but not in the second delivery; 3) women with placenta-mediated complications in the second delivery but not in the first delivery; and 4) women with no placenta-mediated complications in either their first or second deliveries. This latter cohort was selected as the reference population.
Rabin Medical Center review board (institutional review board) approval was obtained.
Data analysis was performed with SPSS 21.0. Normality was evaluated using Shapiro-Wilk test. Standard χ2 test and analysis of variance test were used to compare categorical and continuous variables, respectively. Multivariable logistic regression analysis was used to adjust the risk of placenta-mediated complications in the third delivery for potential confounders. Additionally, we further evaluated the influence of the number of prior pregnancies complicated with placenta-mediated complications on the risk of placenta-mediated complications in the third delivery. Variables that were found to be different between the groups (P<.05) in the bivariate analysis were entered to the multivariable logistic regression model. The model was tested for goodness of fit. Differences were considered significant when the P value was <.05.
Of 49,259 women (121,728 deliveries) during the study period, 4,615 women (13,845 deliveries) delivered their first three consecutive deliveries in our medical center with 4,472 women (13,416 deliveries) meeting inclusion criteria (Fig. 1; Table 1). Maternal mean age during the third delivery was 32.5±4.2 years. In terms of gravidity, the median gravidity of the third delivery was three and an interquartile interval of three to four. Among our study population, 64.2% (2,869/4,472) had only three pregnancies, and 89.3% had no more than one additional early fetal demise. Only 3.1% of all patients had more than two spontaneous miscarriages. The overall rate of placenta-mediated complications peaked at first delivery (14.4%) and reached its nadir at the third delivery to 5.9% (Table 1).
The distribution of our study population, exhibiting placenta-mediated complications in the third delivery, according to the rate of placenta-mediated complications in the first two deliveries was as follows: 111 women (2.5%) had placenta-mediated complications in both the first and second deliveries, 532 women (11.9%) had placenta-mediated complications in the first delivery but not in the second delivery, 179 women (4.0%) had placenta-mediated complications in the second delivery but not in the first delivery, and 3,650 women (81.6%) had no placenta-mediated complications in either the first or second deliveries (reference group).
The rate of preterm delivery (less than 37 weeks of gestation) was 6%, 4.8%, and 4.9% in the first, second, and third deliveries, respectively. In multivariate logistic regression adjusted for maternal age, chronic hypertension, diabetes complicating pregnancy, and gestational age at delivery, the adjusted odds ratio (OR) for placenta-mediated complications in the third delivery increased significantly with a greater number of prior pregnancies with placenta-mediated complications (Table 2). Furthermore, to delineate the influence of the number of prior pregnancies complicated with placenta-mediated complications, we performed another multivariate logistic regression controlling for maternal age, chronic hypertension, diabetes complicating pregnancy, and gestational age at delivery, comparing all subsets of patients. The adjusted OR for placenta-mediated complications in the third pregnancy increased as the number of prior pregnancies with placenta-mediated complication increased in a dose-dependent manner; 4.35 (confidence interval [CI] 3.03–6.24, P<.001) for a single previous pregnancy with placenta-mediated complications in comparison with no obstetric history of such complications and adjusted OR 1.95 (CI 1.16–3.27, P=.01) for previous two pregnancies with placenta-mediated complications in comparison with only a single prior pregnancy with placenta-mediated complications.
Likewise, in multivariate logistic regression adjusted for maternal age, chronic hypertension, diabetes complicating pregnancy, and gestational age at delivery, the adjusted OR for SGA (both less than the 10th and less than the third centiles) in the third delivery increased significantly with a greater number of prior pregnancies with placenta-mediated complications. The risk of a specific placenta-mediated complication (ie, placental abruption, hypertensive disorder, or SGA less than the 10th percentile) in the third delivery as a function of a history of any placenta-mediated complications in prior deliveries is presented in Figure 2. In all groups, the most prevalent placenta-mediated complication was SGA and the risk of each complication was greater the higher the incidence of placenta-mediated complications in prior pregnancies; women with placenta-mediated complications in all previous deliveries had the highest risk of recurrence of any placenta-mediated complication (27.6%), whereas those with no placenta-mediated complications in previous deliveries had the lowest risk (3.7%) (Fig. 2).
Because SGA was found to be the main placenta-mediated complication in our cohort, we further analyzed the risk of placenta-mediated complications stratified by obstetric history of SGA (less than the 10th percentile; Fig. 3A) and severe SGA (less than the 3rd percentile; Fig. 3B). The risk of subsequent SGA and placenta-mediated complications in the third delivery rose as the number of prior deliveries with SGA increased, and it declined with each prior birth uncomplicated by SGA. A history of severe SGA was associated with a greater risk of SGA (either less than the 10th or less than the 3rd percentile) or any placenta-mediated complications in the third delivery as compared with a history of SGA less than the 10th percentile (Fig. 3) (P<.001).
In the current study we aimed to explore the effect of placenta-mediated complications in the first two deliveries and the risk of recurrence in the third delivery. Our main findings were: 1) the overall rate of placenta-mediated complications was highest in nulliparous women and decreased to a rate of 5.9% in the third delivery; 2) recurrence of placenta-mediated complications increased the risk of reappearance in a dose-dependent manner, that is, women with a history of two affected pregnancies were at greater risk of recurrence than women with a history of only one such pregnancy; and 3) SGA in previous deliveries was significantly associated not only with the recurrence of SGA, but also with additional placenta-mediated complications.
There is ample evidence in the literature supporting the relationship between outcomes of prior pregnancies and future pregnancies.13,14 Our findings that nulliparous women are at greater risk of placenta-mediated complications, including preeclampsia and low birth weights, are in accordance with previous findings in the literature.15,16 The finding of a decrease in the incidence of such adverse outcomes with subsequent pregnancies is likely explained by pathogenesis that is linked to primiparity such as in preeclampsia by increased physician awareness and, possibly, by pharmacologic prophylaxis with aspirin.17 It is also possible that women who experienced severe pregnancy complications refrain from additional future pregnancies.
The most common adverse placenta-mediated complication in our study was the birth of an SGA neonate. Because this outcome, by definition, affects 10% of all fetuses, this finding is not surprising. Nonetheless, according to our results, this complication was also associated with other future placenta-mediated complications, including severe SGA, placental abruption, and preeclampsia. This observation, complying with previous reports, can be explained by the existence of a common pathophysiology, resulting in any or all forms of placental insufficiency.6
Strengths of our study include the large cohort of patients with consecutive deliveries managed in a single center for more than 19 years. Additionally, use of our own electronic medical records, as opposed to birth certificates or patient recall, increases accuracy and diminishes recall bias. Exclusion of fetuses with a chromosomal or structural anomaly, findings that could cause nonplacenta-mediated SGA, allows for a better estimation of recurrence of adverse placenta-mediated complications.
Our study is limited by its retrospective design. Nonetheless, pregnancy history is not amendable to randomization. Still there is possible selection bias, originating from the fact that certain women may choose to have more children than others or return to the same hospital where they previously delivered, whereas others might go elsewhere. Because we relied on our retrospective comprehensive computerized files (dating back to 1994), we do not have data pertaining to additional risk factors that could be significant confounders in assessing placenta-mediated complications such as ethnicity, pregestational body mass index, and smoking. However, because our population is composed mainly of Caucasian women, we believe that the effect of ethnicity to bias our results is minimal, yet the problem of generalizability of our results arises. Additionally, the rate of smoking during pregnancy in our population is reported to be approximately 6%,18 which is considered relatively low; therefore, we think it unlikely that it differentially biased our results. Lastly, we did not have complete information pertaining to early fetal demise, a parameter that by itself could be attributed to placental insufficiency. Nonetheless, the median gravidity of our cohort was three with an interquartile range of three to four, so even if there were repeated abortions in our cohort, their influence on the results was, most likely, minimal.
In conclusion, our study shows that a history of placenta-mediated complications in the first or second pregnancy is associated with recurrence in the third pregnancy. Therefore, the subsequent pregnancy necessitates close follow-up. In cases of two prior affected pregnancies, this risk increases even more.
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© 2017 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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