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Oocyte donation pregnancies and the risk of preeclampsia or gestational hypertension: a systematic review and metaanalysis

American Journal of Obstetrics and Gynecology, Volume 214, Issue 3, March 2016, Pages 328 - 339

The purpose of this study was to determine whether pregnancies that were achieved via oocyte donation, compared with pregnancies achieved via other assisted reproductive technology methods or natural conception, demonstrate increased risk of preeclampsia or gestational hypertension. Comparative studies of pregnancies that were achieved with oocyte donation vs other methods of assisted reproductive technology or natural conception with preeclampsia or gestational hypertension were included as 1 of the measured outcomes. Abstracts and unpublished studies were excluded. Two reviewers independently selected studies, which were assessed for quality with the use of methodological index for non-randomized studies, and extracted the data. Statistical analysis was conducted. Of the 523 studies that were reviewed initially, 19 comparative studies met the predefined inclusion and exclusion criteria and were included in the metaanalysis, which allowed for analysis of a total of 86,515 pregnancies. Our pooled data demonstrated that the risk of preeclampsia is higher in oocyte-donation pregnancies compared with other methods of assisted reproductive technology (odds ratio, 2.54; 95% confidence interval, 1.98–3.24; P < .0001) or natural conception (odds ratio, 4.34; 95% confidence interval, 3.10–6.06; P < .0001). The risk of gestational hypertension was also increased significantly in oocyte donation pregnancies in comparison with other methods of assisted reproductive technology (odds ratio, 3.00; 95% confidence interval, 2.44–3.70; P < .0001) or natural conception (odds ratio, 7.94; 95% confidence interval, 1.73–36.36; P = .008). Subgroup analysis that was conducted for singleton and multiple gestations demonstrated a similar risk for preeclampsia and gestational hypertension in both singleton and multiple gestations. This metaanalysis provides further evidence that supports that egg donation increases the risk of preeclampsia and gestational hypertension compared with other assisted reproductive technology methods or natural conception.

Key words: gestational hypertension, oocyte donation, preeclampsia.

Introduced for the first time in the early 1980s, oocyte donation enables women with diminished ovarian reserve, premature ovarian failure, genetic disorders, and surgical menopause to become pregnant.1, 2, and 3 In 2012, there were approximately 20,000 attempts at pregnancy with the use of oocyte donation in the United States.4 This number has been increasing over the past decade.5 However, several adverse pregnancy outcomes have been correlated with pregnancies that were achieved after successful oocyte transfer compared with other conception methods, such as first-trimester bleeding, preterm birth, low birthweight, and intrauterine growth restriction.6, 7, 8, and 9 Hypertensive disorders, such as preeclampsia and gestational hypertension, are other important examples of such complications that usually occur after the 20 weeks of gestation.7, 8, and 9

Hypertensive disorders during pregnancy affect 5–10% of all pregnancies in the United States10; gestational hypertension is the most common cause of hypertension in pregnancy. Approximately 15% of gestational hypertension cases proceed to chronic hypertension after pregnancy,11 and 10–50% of patients who initially are diagnosed with gestational hypertension will be diagnosed with preeclampsia in 1–5 weeks after the diagnosis.12 and 13 Pregnancy outcomes of mild gestational hypertension are similar to those of the general obstetrics population.13 and 14 However, severe gestational hypertension and preeclampsia are significant causes of maternal deaths each year, along with significant fetal morbidities worldwide.15, 16, and 17

Observations of gestational hypertensive complications among oocyte donation pregnancies were first reported in the late 1980s.18 However, conclusive evidence for association remains a challenge to substantiate because of intrinsic confounding variables within this patient population. Gestational hypertensive disorders are associated independently with inherent characteristics of the recipients of oocyte donation, such as advanced maternal age, primiparity, primary cause of infertility (eg, maternal obesity), and ensuing multiple gestations.19, 20, 21, 22, 23, 24, and 25 This is especially a concern when several comparative studies have made little attempt to match for these variables across study populations or adjust for them in their subsequent analysis.

A previous metaanalysis was done to encompass studies that were published before 2010 without any subgroup analyses to control for the confounders.26 In the past 5 years, there have been many more published studies that investigate the occurrence of hypertensive disorders in oocyte donation pregnancies. Therefore, our objective was to conduct a systematic review and metaanalysis of the existing literature to determine whether the risk of preeclampsia or gestational hypertension was increased in pregnancies that were achieved via oocyte donation, compared with other assisted reproductive technology (ART) methods or natural conception.

Methods

This metaanalysis was conducted according to the Metaanalysis of Observational Studies in Epidemiology guidelines.27

A literature search was done by the investigators in PubMed, MEDLINE, Embase, and CENTRAL from January 1989 to July 15, 2015. In addition, Google, Google Scholar, and references of selected articles were used to identify other studies. We used the following keywords: preeclampsia, pregnancy-induced hypertension, gestational hypertension, pregnancy complication, egg, oocyte, ovum, donation, and donor.

Eligibility criteria

We included comparative studies that described pregnancies that were achieved through oocyte donation with the subsequent generation of preeclampsia or gestational hypertension as an outcome and compared them with pregnancies that were achieved through other methods of ART or natural conception. Gestational hypertension is defined as a new-onset elevated blood pressure (mild, ≥140/90 mm Hg; severe, ≥160/110 mm Hg) after 20 weeks of gestation without proteinuria or end-organ failure.28 Before 2013, preeclampsia was diagnosed when gestational hypertension was accompanied by proteinuria (≥0.3 g/24 h).29 In 2013, the American College of Obstetricians and Gynecologists (ACOG) replaced proteinuria as a necessary criterion for preeclampsia diagnosis with signs and symptoms of end-organ injuries.28 The definitions of preeclampsia and gestational hypertension that were used for inclusion were based on the regional standards and guidelines in place at the time of each study.

Comorbidities (such as, gestational diabetes mellitus, HELLP (hemolysis, elevated liver enzymes, and low platelet count syndrome), morbid obesity, preterm labor, and multiple gestations) were not exclusion criteria. Abstracts, reviews, case studies, editorials, and noncomparative primary studies were excluded. The studies that had nonspecific “hypertensive disorders” as their outcome were also excluded. No language restrictions were applied.

Quality assessment

The Methodological Index for Non-Randomized Studies (MINORS)30 was used to assess the quality of nonrandomized studies. This framework consists of 12 items that evaluate a study’s validity, methods, and completeness of reporting elements. In the MINORS criteria, a comparative study is assigned a score of 0–2 for each of the 12 items included, for a maximum score of 24. Higher scores are indicative of greater methodologic quality.

Two investigators assessed each study independently and compared their scores afterwards to reach a consensus. If an agreement could not be reached, a third investigator was consulted.

Data extraction

The data from oocyte donation pregnancies, which lasted at least until week 20 of gestation, along with the control group, were extracted in a 2 × 2 contingency table. The data for nonoocyte donation ART (such as, in vitro fertilization, intracytoplasmic sperm injection, and insemination) were collected under the ART label. The data on spontaneous conception groups who did not use any type of assisted reproduction were collected separately under the natural conception label. Another investigator confirmed the extracted data independently. Disagreements were resolved by consulting a third investigator.

Data synthesis

Studies were classified into 4 groups based on their outcomes and control groups: (1) preeclampsia as the outcome and other methods of ART as the control, (2) preeclampsia as the outcome and natural conception as the control, (3) gestational hypertension as the outcome and other ART methods as the control, and (4) gestational hypertension as the outcome and natural conception as the control. It was possible for a study to be assigned to >1 group depending on whether they included both preeclampsia and gestational hypertension as the outcome or both ART and natural conception as the control.

Metaanalysis was performed with Review Manager software (version 5.3; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). The Mantel-Haenszel model was used to analyze the dichotomous variables to produce an odds ratio (OR) for each outcome with a 95% confidence interval (CI). For each outcome, the heterogeneity of the study was assessed with the use of Chi2 test and I2 statistics. When no degree of heterogeneity was detected (I2 = 0%), we used a fixed-effects model. When some degree of heterogeneity was present (I2 > 0%), we used a random-effects model. Funnel plot analysis was used to assess publication bias by plotting ORs against standard errors.

Results

Study characteristics

The conducted search identified 523 studies for initial review, of which 19 were deemed to meet preidentified inclusion and exclusion criteria (Figure 1).7, 8, 9, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, and 46 There were no randomized control trials found. From the 19 selected studies, 6 were case-control,32, 33, 35, 40, 41, 44, and 45 and 13 were retrospective cohort studies.7, 8, 9, 31, 34, 36, 37, 38, 39, 42, 43, and 46 Thirteen studies had other methods of ART as their only comparison8, 9, 31, 32, 33, 35, 36, 37, 39, 42, 43, 44, and 45; 3 studies had natural conception as their only comparison,34, 40, and 46 and 3 studies included both comparison groups.7, 40, and 41 In regards to outcomes, 5 studies included only preeclampsia32, 34, 37, 38, and 40; 4 studies included only gestational hypertension,31, 33, 35, and 46 and 10 studies included both outcomes.7, 8, 9, 36, 39, 41, 42, 43, 44, and 45 Ten of the included studies originated from the United States8, 32, 33, 34, 35, 36, 37, 40, 45, and 46; 8 originated from Europe,7, 9, 31, 38, 41, 42, 43, and 44 and 1 originated from Israel.39 A total of 86,515 pregnant women were included and observed during their pregnancies. The characteristics of the patients in the studies are listed in Table 1. The range of maternal age in the oocyte donation, other methods of ART, and natural conception groups were 33.5-46.2, 33-44, and 30.7-44.1, respectively. One study included only singleton pregnancies39; 2 studies that only included twin or multiple pregnancies,8 and 32 and 16 studies that did not have such restrictions.7, 9, 31, 33, 34, 35, 36, 37, 38, 40, 41, 42, 43, 44, 45, and 46 Of the 16 studies, 6 studies provided separate data for singleton and multiple subgroups.7, 31, 42, 43, 44, and 45

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Figure 1 Electronic search strategy and resultsFlow diagram for inclusion of the studies examining the association between oocyte donation and gestational hypertensive disorders.ART, assisted reproductive technology; GH, gestational hypertension; NC, natural conception; PE, preeclampsia.Masoudian. Risk of gestational hypertensive disorders in oocyte donation. Am J Obstet Gynecol 2016.

Table 1 Characteristics of the studies that were included in the metaanalysis

Study Country Design Study period Inclusion criteria Exclusion criteria Control group Mean maternal age, yr Parity
Cobo et al,32 2014 Spain RC 2007-2012 Live birth or stillbirth ≥24 weeks of gestation; IVF with own oocyte or donated oocyte Pregnancy loss at <24 weeks of gestation IVF OD, 41.2; ART, 35.7 N/A
Fox et al,33 2014 United States RCC 2005-2012 Twin, >20 weeks of gestation Monochorionic monoamniotic placentation, previous diagnosis of hypertension IVF N/A N/A
Gundogan et al,34 2010 United States RCC 2004-2006 Placental deliveries with OD <24 weeks of gestation IVF OD, 43;
ART, 37.3
N/A
Henne et al,35 2007 United States RC 1997-2002 OD pregnancies N/A NC OD, 42.3;
NC, 36.8
OD, 0.59;
NC, 1.22
Keegan et al,36 2007 United States RCC 1999-2003 OD/IVF patients <35 or ≥40 years old Triplet pregnancies, frozen embryo transfers, monitored at program satellite offices IVF OD, 42.6; ART, 35.1 N/A
Klatsky et al,37 2010 United States RC 1998-2005 OD pregnancies N/A IVF OD, 40.2;
ART, 39.8
OD, 0.27;
ART, 0.24
Krieg et al,38 2008 United States RC 2001-2005 OD pregnancies at >38 years old N/A IVF OD, 42.7;
ART, 41.3
OD, 0.32;
ART, 0.35
Le Ray et al,39 2012 France RC 2008-2010 Women who gave birth at >43 years old N/A IVF, NC OD, 46.2;
ART, 44.0;
NC, 44.1
OD, 0.3;
ART, 0.9;
NC, 1.4
Levron et al,40 2014 Israel RC 2005-2011 OD pregnancies beyond first trimester; singleton Congenital anomalies and chromosomal abnormality IVF OD, 45;
ART, 41
Nulliparous:
OD, 51%;
ART, 44%
Malchau et al,7 2013 Denmark RC 1995-2010 OD pregnancies resulted in birth N/A IVF, ICSI, NC OD, 37.1;ART, 33.4;
NC, 30.7
OD, 1.3;
ART, 1.39;
NC, 1.85
Porreco et al,41 2005 United States RCC 1998-2004 OD pregnancies at >45 years old N/A NC N/A N/A
Salha et al,42 1999 UK RCC 1992-1997 Pregnancies with gamete donation delivered at ≥24 weeks of gestation N/A Insemination, embryo donation, NC OD, 38.1;
ART, 31.9;
NC, 37.2
Primigravida:
OD, 85%;
ART, 89%;
NC, 82%
Sekhon et al,8 2014 United States RC 2005-2013 Twin, at >24 weeks of gestation Monochorionic monoamniotic placentation IVF OD, 43;
ART, 41.9
Nulliparous:
OD, 71.1%;
ART, 73.1%
Söderstörm et al,43 1998 Finland RC 1991-1996 OD pregnancies with birth at ≥24 weeks of gestation or ≥500-g newborn infant N/A IVF OD, 33.5;
ART, 33.4
Primipara:
OD, 84%;
ART, 69%
Stoop et al,44 2012 Belgium RC 1999-2008 OD pregnancies with birth at >20 weeks of gestation Pregnancies after preimplantation genetic diagnosis, testicular sperm extraction, or use of donor sperm IVF OD, 36;
ART, 36
OD, 0.23;
ART, 0.23
Tranquilli et al,9 2013 Italy RC not specified 26 cases of ICSI embryo transfer with OD N/A ICSI OD, 42.7;
ART, 37.5
N/A
Van Dorp et al,45 2014 Netherland RCC 1992-2009 OD pregnancies with birth at >24 weeks of gestation Cycles without embryo transfer IVF OD, 36.4;
ART, 36.7
Nulliparous:
OD, 78%;
ART, 64%
Wiggins and Main,46 2005 United States RCC 1999-2004 OD pregnancies N/A IVF OD, 41.9;
ART, 37.7
Nulliparous:
OD, 70%;
ART, 74%
Wolff et al,47 1997 United States RC 1992-1995 OD pregnancies N/A NC OD, 41.5;
NC, 42.7
Nulliparous:
OD, 70%;
NC, 39%

ART, assisted reproduction therapy; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; N/A, not available; NC, natural conception; OD, oocyte donation; RC, retrospective cohort; RCC, retrospective case-control.

Masoudian. Risk of gestational hypertensive disorders in oocyte donation. Am J Obstet Gynecol 2016.

Risk of bias in included studies

All 19 studies were assessed for methodologic quality with the use of MINORS criteria (Table 2). There was high concordance between the 2 reviewers; as a result, a third reviewer was involved in only a few instances. Criteria that received a low score in the majority of studies that were assessed included “prospective collection of data” (0% of studies included this), “unbiased assessment of the study endpoint” (5% of studies included this), and “prospective calculation of study size” (5% of studies included this). The remaining 9 criteria were reported by most studies with various degrees of adequacy. Overall, the total MINORS scores of the studies were similar, ranging from 14–20, with a median score of 17.

Table 2 Methodological Index for Non-Randomized Studies score of the studies that were included in the metaanalysis

Study Methodological Index for Non-Randomized Studies score
Cobo et al,32 2014 18
Fox et al,33 2014 17
Gundogan et al,34 2010 14
Henne et al,35 2007 18
Keegan et al,36 2007 15
Klatsky et al,37 2010 20
Krieg et al,38 2008 15
Le Ray et al,39 2012 18
Levron et al,40 2014 17
Malchau et al,7 2013 16
Porreco et al,41 2005 17
Salha et al,42 1999 17
Sekhon et al,8 2014 20
Söderstörm et al,43 1998 18
Stoop et al,44 2012 19
Tranquilli et al,9 2013 15
Van Dorp et al,45 2014 17
Wiggins and Main,46 2005 18
Wolff et al,47 1997 16

Masoudian. Risk of gestational hypertensive disorders in oocyte donation. Am J Obstet Gynecol 2016.

To identify evidence of publication bias, we generated funnel plots of the studies that used other methods of ART as the comparison group (Figure 2). All included studies fell within the 95% confidence interval lines. Both graphs look symmetric, which indicates no publication bias. Funnel plots for studies with natural conception as comparison group were not generated because of the low number of studies.

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Figure 2 Funnel plot of included studies with other methods of assisted reproductive technologyStudies with other methods as the comparison group and A, preeclampsia or B, gestational hypertension as the outcome.OR, odds ratio; SE, standard error.Masoudian. Risk of gestational hypertensive disorders in oocyte donation. Am J Obstet Gynecol 2016.

Outcome analysis: preeclampsia

There were 15 studies that reported preeclampsia as their outcomes in comparison with in vitro fertilization or intracytoplasmic sperm injection. After pooling the data for metaanalysis, we found that oocyte donation significantly increases the risk of preeclampsia compared with the other methods of ART comparison group (OR, 2.54; 95% CI, 1.98–3.24; P < .0001; Figure 3, A). Analysis of the 5 studies that included natural conception as their comparison group also found an increased risk of development of preeclampsia in the oocyte donation patients (OR, 4.34; 95% CI, 3.10–6.06; P < .0001; Figure 3, B). A subgroup analysis was performed to examine the effects of singleton vs multiple gestations in the oocyte transfer pregnancies with the use of other methods of ART as the comparison. The risk of the development of preeclampsia after oocyte donation was higher in both singleton (OR, 2.24; 95% CI, 1.42–3.53; P = .0005; Figure 4, A) and multiple (OR, 2.56; 95% CI, 1.84–3.58; P < .0001; Figure 4, B) gestation groups. A sensitivity analysis was done for studies with ART as a comparison, which scored >18; our results were robust (OR, 2.75; 95% CI, 1.93–3.90; P < .0001).

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Figure 3 Forest plot that compares the risk of preeclampsia outcome in oocyte donation pregnanciesThe risk of preeclampsia outcome with A, other methods of assisted reproductive technology or B, natural conception.ART, assisted reproductive technology; CI, confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel; NC, natural conception; OD, oocyte donation.Masoudian. Risk of gestational hypertensive disorders in oocyte donation. Am J Obstet Gynecol 2016.

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Figure 4 Subgroup forest plot analysis that compares the risk of preeclampsia outcomeThe risk of preeclampsia outcome in A, singleton or B, multiple gestations after oocyte donation compared with singleton or multiple gestations after other methods of assisted reproductive technology.ART, assisted reproductive technology; CI, confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel; NC, natural conception; OD, oocyte donation.Masoudian. Risk of gestational hypertensive disorders in oocyte donation. Am J Obstet Gynecol 2016.

Outcome analysis: gestational hypertension

In 13 studies, ART was the comparison group, and gestational hypertension was the outcome. The metaanalysis indicated that oocyte donation pregnancies are at higher risk of gestational hypertension compared with other methods of ART pregnancies (OR, 3.00; 95% CI, 2.44–3.70; P < .0001; Figure 5, A). Only 2 studies with gestational hypertension as an outcome had a comparison group that consisted of women with natural conception pregnancies. However, the risk of gestational hypertension was also shown to be higher in the oocyte-donation pregnancies compared with the natural conception group (OR, 7.94; 95% CI, 1.73–36.36; P = .008; Figure 5, B). A subgroup analysis of singleton and multiple pregnancies with other methods of ART as the comparison group was conducted. The risk of the development of gestational hypertension was higher in both singleton (OR, 2.86; 95% CI, 2.10–3.90; P < .0001; Figure 6, A) and multiple (OR, 3.08; 95% CI, 1.95–4.87; P < .0001; Figure 6, B) gestation groups. A sensitivity analysis was done for studies with ART as comparison, which scored >18; our results were robust (OR, 1.93; 95% CI, 2.35-4.33; P < .0001).

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Figure 5 Forest plot that compares the risk of gestational hypertension outcomeThe risk of gestational hypertension outcome in oocyte donation pregnancies compared with A, other methods of assisted reproductive technology or B, natural conception.ART, assisted reproductive technology; CI, confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel; NC, natural conception; OD, oocyte donation.Masoudian. Risk of gestational hypertensive disorders in oocyte donation. Am J Obstet Gynecol 2016.

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Figure 6 Subgroup forest plot analysis that compares the risk of gestational hypertension outcomeThe risk of gestational hypertension outcome in A, singleton or B, multiple gestations after oocyte donation compared with singleton or multiple gestations after other methods of assisted reproductive technology.ART, assisted reproductive technology; CI, confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel; OD, oocyte donation.Masoudian. Risk of gestational hypertensive disorders in oocyte donation. Am J Obstet Gynecol 2016.

Comment

Main findings

The main findings of this study indicate that pregnancies that are achieved via oocyte donation have higher risk of the development of preeclampsia and gestational hypertension compared with pregnancies that are achieved through other methods of ART and natural conception. Subgroup analysis of singleton and nonsingleton gestations was in accordance with the main findings because the risk of the development of preeclampsia and gestational hypertension was still significantly higher than the comparison ART group.

The only systematic review and metaanalysis that has been done to evaluate hypertensive complications in oocyte donation pregnancies was done by Pecks et al.26 It included 11 observational studies that were published from 1997 to early 2010, 9 of which are also included in our current metaanalysis. Of the 2 studies that were not included, 1 was an abstract,47 and the other did not differentiate between different kinds of hypertensive disorders.48 Although the previous metaanalysis included separate analyses for the 2 comparator groups (other methods of ART and natural conception), it did not differentiate between the hypertensive outcomes (gestational hypertension and preeclampsia). Pecks et al also found an association between oocyte donation and hypertensive disorders (OR, 3.87; 95% CI, 2.61–5.74). However, the method of study selection could have been more elaborate, and more parameters could have been included in the description of the study characteristics (such as sample size, parity, and multiple gestations). Further, there was no of risk of bias assessment of the selected studies included in this publication.

To conclusively identify the independent risk of hypertensive disorders of pregnancy originating from oocyte donation, consideration of the important confounders in this patient population to this outcome must be identified and appropriately accounted for. Pecks et al26 performed a qualitative assessment of the included studies and concluded that the increased risk of hypertensive disorders in patients with oocyte donation was independent of maternal age and multiple gestations. The quantitative subgroup analysis that was presented in the current analysis supports this conclusion in relation to the number of fetuses being carried in a given pregnancy, whereas insufficient data were available to perform a similar subgroup analysis on maternal age. However, the additional 10 studies7, 8, 9, 31, 32, 36, 38, 39, 43, and 44 (2010–2014) that were included in the current analysis used appropriate study designs that matched for potential confounders (such as maternal age, parity, and multiple gestations); in cases where this was not possible, the effect of these confounding variables were accounted for with the use of adjusted OR analysis. Although alterations in hormonal milieu could also contribute to the increased risk of preeclampsia and gestational hypertension, the comparison between ART that used autologous oocytes and donor oocytes provides evidence that the introduction of a foreign egg is a major contributing factor. As such, the cumulative data collected to date may support oocyte donation as an independent risk factor for development of preeclampsia and gestational hypertension.

Biologic plausibility

From a biologic standpoint, it is certainly plausible that oocyte donation in and of itself may be an independent risk factor for the development of gestational hypertensive disorders, particularly preeclampsia. The introduction of a foreign egg into the uterus may cause heightened immunologic responses within the recipient and impair the process of placentation.49, 50, 51, and 52 Although the cause of preeclampsia is not understood entirely, it is clear that the placenta plays a central role in development of this disorder. In the widely described “2-stage” model of disease, it is believed that placental damage and dysfunction early in pregnancy (<20 weeks of gestation) results in the release of antiangiogenic and proinflammatory mediators from the placenta into the maternal circulation.53 This translates a placental disease into the maternal compartment, where it can lead to heightened maternal inflammatory responses and endothelial dysfunction that result in increased peripheral vascular resistance.54

The proposed “immunologic theory” of preeclampsia additionally is supported by evidence of increased preeclampsia risk in pregnancies after sperm donation or previous barrier method contraception use. Similar to the hypothesis provided earlier, in these studies it is postulated that a lack of maternal immune tolerance to paternal sperm antigens generates a heightened immune response at the maternal-fetal interface, which results in placental dysfunction and subsequent preeclampsia.55, 56, 57, and 58 Although they are recognized as 2 different diseases, preeclampsia and gestational hypertension have many placental pathologic features in common.59 Hence, the heightened immune response potentially could play a role in the development of gestational hypertension as well. Considering the evidence presented in this metaanalysis on the risk of preeclampsia and gestational hypertension in these pregnancies, further prospective studies must be conducted to investigate clues and markers of preeclampsia during early pregnancy to provide better opportunities for therapeutic interventions and prevent progression to further stages of the disease.

Strengths and limitations

The strengths of this study include (1) rigorous methodologic systematic review in accordance with Metaanalysis of Observational Studies in Epidemiology guidelines27; (2) a comprehensive search of various databases with no language restrictions; (3) the inclusion of a large number of studies with a total of 86,515 pregnant women; (4) a quality assessment of included studies with MINORS criteria to evaluate the risk of study bias30; (5) separation of preeclampsia and gestational hypertension as 2 different outcomes because of the difference in pathophysiology, complications, prognosis, and management; (6) separation of other methods of ART and natural conception as 2 different comparison groups, which accounted for the potential difference in the baseline patient characteristics and potential risks of the development of complications; (7) the completion of a subgroup analysis of singleton and nonsingleton pregnancies that did not alter the conclusion; (8) a low degree of heterogeneity that allowed more reliable pooled data; and (9) a lack of publication bias because of the symmetry of the funnel plot.

This study also has some potential limitations. First, all included studies were either retrospective cohort or case control studies. There were no prospective studies or randomized control trials available. This resulted in lower quality assessment scores with the use of the MINORS checklist, which is indicative of a higher risk of bias inherent in the included studies. The lack of prospective studies in this metaanalysis may be the product of restricted key terms that were searched looking for studies that specifically investigated oocyte-donation pregnancies. Therefore, it limited the capture of larger prospective studies with substantial subsets of oocyte-donation pregnancies. One of the initiatives going forward would provide opportunities for future studies to perform a secondary analysis of such potential subsets.

Second, in 2013, ACOG changed the diagnostic criteria for preeclampsia.28 In the new criteria, the presence of proteinuria can be replaced by new onset of 1 of the following 5 events: thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or cerebral or visual symptoms. Because the cohorts of patients that were studied in most of the studies gave birth before 2013, the diagnostic definition of preeclampsia that was used in the identification of these patients is entirely reflective of the older diagnostic criteria of de novo hypertension in the presence of proteinuria. Also, there was some regional variability among the studies that provided a definition for preeclampsia. The definition of preeclampsia based on various regional and international guidelines has been outlined in the systematic review by Gillon et al.60 Despite the variability, proteinuria remains a consistent feature among the guidelines. In the studies that were included in our metaanalysis, there are small differences in cut-off value for proteinuria (500 mg/24 h rather than 300 mg/24 h). Even for current practices, the new guidelines by ACOG are not adopted universally into clinical practices, and reaching consensus is difficult. As such, diagnosis of patients would be more challenging, and the applicability of these findings to certain patients who were diagnosed with preeclampsia would become more limited. Nonetheless, a similar risk was observed for gestational hypertension that indicated that these changes to diagnostic criteria might have a minimal impact on the risks that are associated with oocyte donation in relation to the development of hypertension in pregnancy.

Third, the presence of few studies for which natural conception was used as a comparator group prevented us from conducting any subgroup analysis with these patients. However, this was justifiable because of the fact that other methods of ART serve as a better control than natural conception because of similarity in patient demographics that may result in higher baseline risk of adverse pregnancy outcomes.

Fourth, there were some parameters that were not considered or adjusted for by many studies. Therefore, the applicability of the results was limited to a certain degree by the confounders. For example, gestational diabetes mellitus and a history of hypertensive disorders in previous pregnancies are established risk factors for hypertensive disorders during pregnancies that were not matched or adjusted for in most of the studies.

Some of the following parameters were included in a few studies: cryopreservation,31, 36, and 42 maternal smoking,31, 40, 42, 43, and 46 maternal body mass index,8, 31, 32, and 42 ethnicity,8, 9, 31, 36, 40, 43, 44, and 46 paternal age,8 and 43 pregnancy with donor sperm,31 and 38 cause of infertility,31, 42, and 45 and age of the egg donor.31, 40, 43, 44, and 45 One study found an increased incidence of preeclampsia in oocytes that were cryopreserved, compared with fresh egg donations.36 However, a later study by Cobo et al31 investigated the effect of cryopreservation as its primary objective and concluded that it is not associated with any major obstetric or perinatal harm. Body mass index is an established risk factor for hypertension in pregnancy.61, 62, and 63 On the other hand, smoking is known to reduce the risk of preeclampsia.64, 65, 66, and 67 The studies that mentioned the ethnicity of the subjects had predominantly white participants. The role of paternal age, pregnancy with donor sperm, and age of egg donor is still unclear and could be the subject of further investigations in the future. Although it is important that the confounders be accounted for in the forthcoming studies, the consistency in effect direction and size in this study provides strong evidence that the overall conclusion would most likely remain the same.

Conclusions and implications

This metaanalysis suggests that oocyte donation increases the risk of preeclampsia and gestational hypertension, compared with other methods of ART or natural conception. This risk factor should be considered during preconception counseling to ensure that an informed decision is made. Women who become pregnant after oocyte donation should be under closer surveillance after the 20 weeks of gestation for the development of hypertensive disorders.

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Footnotes

a Department of Pediatric Pathology, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

b Department of Pediatric Surgery, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

c Department of Obstetrics and Gynecology, The Ottawa Hospital, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

d Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada

Corresponding author: Dina El Demellawy MD PhD FRCPC.

The authors report no conflict of interest.