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




Methods


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


Literature search


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. Before 2013, preeclampsia was diagnosed when gestational hypertension was accompanied by proteinuria (≥0.3 g/24 h). 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. 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) 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 Chi 2 test and I 2 statistics. When no degree of heterogeneity was detected (I 2 = 0%), we used a fixed-effects model. When some degree of heterogeneity was present (I 2 > 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 ). There were no randomized control trials found. From the 19 selected studies, 6 were case-control, and 13 were retrospective cohort studies. Thirteen studies had other methods of ART as their only comparison ; 3 studies had natural conception as their only comparison, and 3 studies included both comparison groups. In regards to outcomes, 5 studies included only preeclampsia ; 4 studies included only gestational hypertension, and 10 studies included both outcomes. Ten of the included studies originated from the United States ; 8 originated from Europe, and 1 originated from Israel. 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 pregnancies ; 2 studies that only included twin or multiple pregnancies, and 16 studies that did not have such restrictions. Of the 16 studies, 6 studies provided separate data for singleton and multiple subgroups.




Figure 1


Electronic search strategy and results

Flow 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 2005 United States RCC 1998-2004 OD pregnancies at >45 years old N/A NC N/A N/A
Salha et al, 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, 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, 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, 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, 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, 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, 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, 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, 2014 18
Fox et al, 2014 17
Gundogan et al, 2010 14
Henne et al, 2007 18
Keegan et al, 2007 15
Klatsky et al, 2010 20
Krieg et al, 2008 15
Le Ray et al, 2012 18
Levron et al, 2014 17
Malchau et al, 2013 16
Porreco et al, 2005 17
Salha et al, 1999 17
Sekhon et al, 2014 20
Söderstörm et al, 1998 18
Stoop et al, 2012 19
Tranquilli et al, 2013 15
Van Dorp et al, 2014 17
Wiggins and Main, 2005 18
Wolff et al, 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.




Figure 2


Funnel plot of included studies with other methods of assisted reproductive technology

Studies 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).




Figure 3


Forest plot that compares the risk of preeclampsia outcome in oocyte donation pregnancies

The 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 .



Figure 4


Subgroup forest plot analysis that compares the risk of preeclampsia outcome

The 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).




Figure 5


Forest plot that compares the risk of gestational hypertension outcome

The 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 .



Figure 6


Subgroup forest plot analysis that compares the risk of gestational hypertension outcome

The 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 .




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 ). There were no randomized control trials found. From the 19 selected studies, 6 were case-control, and 13 were retrospective cohort studies. Thirteen studies had other methods of ART as their only comparison ; 3 studies had natural conception as their only comparison, and 3 studies included both comparison groups. In regards to outcomes, 5 studies included only preeclampsia ; 4 studies included only gestational hypertension, and 10 studies included both outcomes. Ten of the included studies originated from the United States ; 8 originated from Europe, and 1 originated from Israel. 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 pregnancies ; 2 studies that only included twin or multiple pregnancies, and 16 studies that did not have such restrictions. Of the 16 studies, 6 studies provided separate data for singleton and multiple subgroups.


May 4, 2017 | Posted by in GYNECOLOGY | Comments Off on Oocyte donation pregnancies and the risk of preeclampsia or gestational hypertension: a systematic review and metaanalysis
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