Hypertensive disorders of pregnancy, including preeclampsia, are among the most common causes of obstetric-related morbidity and mortality worldwide.1 Preeclampsia occurs in 2% to 7% of pregnancies, but its specific etiology is unknown.2 Studies have found an association between preeclampsia and poor early placentation, unfavorable immune response, and maternal inflammatory responses to circulating trophoblast debris.3,4 Understanding the etiology of preeclampsia may help physicians and scientists develop and target interventions to identify, counsel, and care for women at increased risk for the disease.
Earlier studies that implicated the maternal immune response in the development of hypertensive disorders of pregnancy reported higher rates of preeclampsia in women who were exposed to “less familiar” paternal antigens as compared with women with prolonged duration of sexual cohabitation with their partner.5–10 Similarly, the incidence of preeclampsia is higher in parous women who change partners within a short time interval before subsequent pregnancies.11 Conversely, nulliparous women who had a previous aborted pregnancy with the same partner demonstrated a lower risk of preeclampsia in subsequent pregnancies than nulliparous women who had no previous pregnancy with the same partner.12 In assisted reproduction, a similar immunologic phenomenon has been reported, suggesting that women undergoing in vitro fertilization (IVF) are at an increased risk for adverse perinatal complications, such as preterm delivery, low birth weight, and preeclampsia.13,14 Initial reports in IVF cycles using embryos derived from donor oocytes documented a high frequency of preeclampsia and gestational hypertension, ranging from 23% to 51%.15–18 These studies suggest that familiar fetal antigenicity may protect against the development of preeclampsia. Previous studies comparing ovum donor recipients with women undergoing IVF have reported conflicting findings and are limited by small sample size and difficulty finding a satisfactory control group. These studies have compared cohorts with significantly different ages and proportions of women with multiple gestations, both of which are established risk factors for preeclampsia and gestational hypertension.
We sought to test the hypothesis that women who conceived with embryos derived from donated oocytes are at higher risk for gestational hypertension and preeclampsia, given the foreign antigenicity of the developing fetuses and trophoblastic tissue.
MATERIALS AND METHODS
We selected our study population from donor oocyte recipient pregnancies (singletons and twins) that resulted in live births between 1998 and 2005. Donor oocyte recipients required oocyte donation for inadequate ovarian response to previous stimulation, markedly abnormal ovarian reserve testing, or ovarian failure. Women in the study were selected at random from an IVF database maintained at the Weill Cornell medical school in New York, New York, and were matched one-to-one on the basis of age and plurality (singleton or twin) to controls who delivered after IVF using autologous oocytes during the same year. Although data on ethnicity were not routinely recorded, the study population was drawn from a practice population that is predominantly non-Hispanic white. The investigators were blinded to the obstetric outcomes of the women during random selection of participants.
Obstetricians of each participant were contacted and asked to provide data or allow access to their records to report specifically on whether the pregnancy was complicated by gestational hypertension or preeclampsia. Data on gestational age and birth weight of each delivery were also obtained. Gestational hypertension was defined as two elevated blood pressures more than 140 mm Hg systolic or more than 90 mm Hg diastolic, separated by 6 hours, and with or without proteinuria. This definition included women with preeclampsia, which was diagnosed as gestational hypertension with proteinuria. Proteinuria was characterized as more than 300 mg on a 24-hour urine collection or more than or equal to 1+ protein on a catheter-collected urine specimen, as suggested by the American College of Obstetricians and Gynecologists.19
Primary outcomes were the incidence of preeclampsia or gestational hypertension (with and without proteinuria) in the third trimester. Secondary outcomes included gestational age and birth weight. Dichotomous outcomes of gestational hypertension and preeclampsia, as well as preterm delivery before 37 weeks and birth weights of less than 2,500 g were analyzed using χ2 and Student t tests. Because of the lack of independence between twins for low birth weight, this outcome was statistically examined only in singletons. Results were considered statistically significant with P<.05. Multivariable logistic regression analysis was performed to evaluate for the effect of embryonic origin, age, parity, and multiple gestation.
Pregnancies resulting from the transfer of both fresh and cryopreserved embryos were included in the analysis. Women were excluded if they had monozygotic twins or if outcome data were not reported by the obstetrical provider. All women consented to the release of medical information on the obstetric outcomes in their ensuing pregnancies. The study was reviewed and approved by the institutional review boards at the University of California, San Francisco, and Weill Cornell Medical College.
Obstetric providers responded to questionnaires or provided records on pregnancies from 77 donor oocyte recipients and 81 autologous IVF pregnancies, representing a 79% response rate. There were no significant differences in patient characteristics between the two cohorts (Table 1).
Nineteen (25%) pregnancies from donor oocyte recipients and six (7%) pregnancies from autologous IVF cycles had gestational hypertension (P<.02) (Table 2). Thirteen (17%) donor oocyte recipient pregnancies had preeclampsia and four (5%) autologous IVF pregnancies had preeclampsia (P=.02). These differences remained statistically significant after multivariable logistic regression, which controlled for frozen embryos, multiple gestations, parity, and maternal age (Table 3). Pregnancies in donor oocyte recipients were more likely than controls to have gestational hypertension (adjusted odds ratio [OR] 4.2, 95% confidence interval [CI] 1.5–11.9) and preeclampsia (adjusted OR 4.0, 95% CI 1.2–13.8). Although the lowest incidence of preeclampsia was seen in multiparous women using their own oocytes (5%), the increased incidence of gestational hypertension seen in women using donated oocytes was observed in both nulliparous (23%) and multiparous (31%) women.
Although there was no difference in mean gestational age, the incidence of preterm delivery was slightly increased in donor oocyte recipients (34%) when compared with women undergoing autologous IVF (19%, P=.03). This difference was statistically significant after controlling for maternal age and multiple gestation (OR 2.6, 95% CI 1.04–6.3). All pregnancies were carried until at least 31 weeks of gestation; however, 26 (34%) of the donor oocyte recipient cycles delivered before 37 weeks of gestation compared with 15 (19%) women undergoing autologous IVF (Table 2). After controlling for gestational age, there were no differences in mean birth weight or the incidence of low birth weight singleton neonates between groups. There was no difference in live birth per gestational sac (86% compared with 88%, P=.62) between autologous and donor recipient groups, respectively. Pregnancies resulting from transfer of frozen–thawed embryos had a higher rate of gestational hypertension and preeclampsia than pregnancies from fresh embryos: 25% compared with 15% and 19% compared with 10%, respectively. After controlling for multiple variables, use of cryopreserved and thawed embryos was an independent risk factor for the development of gestational hypertension (OR 5.0, 95% CI 1.2–20.5) and preeclampsia (OR 5.7, 95% CI 1.2–28.4). As expected, twin gestations were more likely to have gestational hypertension (OR 5.0, 95% CI 1.8–14.2) and preeclampsia (OR 5.8, 95% CI 1.8–19.1). Twin gestations showed a strong association with prematurity and low birth weight.
We found a higher incidence of gestational hypertension and preeclampsia among donor oocyte recipients in a population that was matched for age and singleton or twin gestation. Our findings are consistent with those of other investigators16,17,20–22 who reported similarly high rates of gestational hypertension and support the hypothesis that ovum donor recipients are at increased risk for hypertensive disorders of pregnancy. Multiparous women usually have lower rates of preeclampsia than nulliparous women, which is a trend that was observed in our population using autologous oocytes. Loss of this trend in women conceiving with donor oocytes supports a hypothesis of immune tolerance in the etiology of preeclampsia.
Although the study was not specifically designed to measure the effect of cryopreservation on these outcomes, we did find an association between cryopreservation and hypertensive disorders of pregnancy, which has not been previously reported. Our cohort is not large enough to differentiate between various methods of cryopreservation. In contrast to some earlier studies, we found that donor oocyte recipients may be at higher risk for preterm delivery.
A possible explanation for the increased risk of preeclampsia is that foreign antigens on the trophoblastic tissue are more likely to elicit an alloimmune response from the mother, leading to an increase in circulating antigen–antibody complexes and triggering the preeclampsia endothelial cascade. Another immune-related mechanism is that embryonic human leukocyte antigen-C ligands involved in receptivity of host cells to trophoblast may not function as well in the absence of the recipient's own genotypic ligands.4 Alternatively, embryos might not be the causal factor, but instead the recipient herself could be predisposed to preeclampsia, independent of embryonic factors. It is conceivable that women with diminished ovarian reserve and diminished ovarian steroid production may have undergone vascular or immunologic changes that make them more susceptible to gestational hypertension and preeclampsia.23 We further recognize that the etiology of preeclampsia may be different in IVF pregnancies, as is suggested by higher risks in cryopreserved cycles; however, we believe that IVF offers a compelling model to study the role of fetal antigenicity in the development of preeclampsia.
We also report a novel finding that frozen embryos are independently associated with a risk of both gestational hypertension and preeclampsia. A possible explanation is that cryopreservation may induce changes in gene expression in the developing embryo and trophoblast, thus predisposing the patient to preeclampsia. This finding was identified in a post hoc analysis and needs to be confirmed in larger, prospective studies.
Several earlier studies have reported conflicting findings. Negative studies were limited by a lack of power or by noncomparability between control participants and ovum donor recipients who were older and more likely to have multiple gestations.24,25 Subsequent controlled studies have reported a similarly higher incidence of new-onset hypertensive disorders of pregnancy in women using donated oocytes; however, these studies were limited by smaller sample sizes, inability to control for gestational age and multiple gestation, as well as use of nonvalidated surveys to report cases of preeclampsia (Table 4).20–22
The strength of our study is that both cohorts were similar with regard to age, parity, and gestational number. The incidence of pregnancy-associated hypertensive disorders among women using autologous oocytes in our study is commensurate with the expected risk in women with infertility, and the increased incidence of such disorders in our subpopulation with twins is similar to reported rates in this population, suggesting that our data are consistent with known outcomes and risk factors.2,26 This report should stimulate discourse and further research on gestational hypertension and the obstetric consequences of assisted reproduction.
Our study is retrospective and subject to the associated limitations of data follow-up. Of course, our study is nonrandomized and subject to confounding bias. However, we did match on several key predictors and attempted to control for other potential confounders. Further, because of the nature of this subject, a randomized trial is not feasible. We recognize that the etiology of preeclampsia may be different in IVF pregnancies, as is suggested by higher risks in cryopreserved cycles; however, we believe that IVF offers a compelling model to study the role of fetal antigenicity in the development of preeclampsia. Another limitation is that our findings with regard to the effect of cryopreservation are based on a small subgroup of women. Although we were also unable to obtain data on race and ethnicity retrospectively, the majority of women in the population from which the study participants were drawn were non-Hispanic white, potentially limiting the generalizability of the study to this population.
A prospective study should enroll age-matched women receiving fresh and cryopreserved embryos from both autologous and donor cycles, as well as gestational carriers to evaluate the potential additive effect of paternal antigens. To achieve 80% power to detect a threefold increase in the risk of preeclampsia (assuming a baseline risk of 5% in this population with an alpha of 0.025), each cohort would need 169 women with even numbers of fresh and cryopreserved cycles. If we hypothesize that gestational surrogates would have an even higher rate of preeclampsia, such as fourfold higher than baseline, then we would need to compare 75 gestational surrogates to age-matched controls. Ideally, in a prospective study, multiple gestations would be excluded or at least evenly distributed between cohorts.
Despite these limitations, our findings are significant and should generate informed discussions with women and providers regarding the risk of gestational hypertension and preeclampsia in women carrying pregnancies conceived from nonautologous or cryopreserved embryos. Obstetric providers should be aware that pregnancies in donor oocyte recipients or subsequent to cryopreservation and thawing of embryos may be at increased risk and merit closer surveillance for preeclampsia and gestational hypertension. Providers caring for these women may decide to monitor these pregnancies more carefully for the development of hypertensive diseases of pregnancy.
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