Abstract
In this single-center matched-cohort study, women who underwent IVF/ICSI with donor oocytes between 2007 and 2014 (n = 259) were compared to women undergoing autologous cycles during the same time period (n = 515). The matching (1:2) took into consideration the women’s age, type of treatment (IVF/ICSI), and year of embryo transfer. All women were healthy and below 40 years of age at the time of IVF/ICSI, and the treatments were performed using a strict policy of single embryo transfer. Multiple logistic regression analysis, adjusted for body mass index (BMI), smoking, and parity, showed a four times increased risk of gestational hypertensive disorders (adjusted odds ratio, AOR 4.25; 95% confidence interval (CI), 2.61–6.92) and pre-eclampsia (AOR 3.99; 95% CI 2.27–7.00) in pregnancies achieved with donor oocytes. There was also a higher rate of cesarean section in women who gave birth after oocyte donation (AOR 1.69; 95% CI 1.22–2.35) and a higher risk of postpartum hemorrhage >1000 mL (AOR 1.59; 95% CI, 1.11–2.27). After further adjustment for preeclampsia in the logistic regression analysis, no additional increased perinatal risks were found. The incidence of preterm delivery, low weight at birth, need of neonatal intensive care, Apgar scores, and incidence of perinatal death were also similar between the groups.
摘要：
在这项单中心配对队列研究中, 我们将2007年至2014年期间接受IVF/ICSI供卵的女性(n= 259)与同一时期接受自体周期的女性(n= 515)进行了比较。匹配(1:2)考虑了女性的年龄、治疗类型(IVF/ICSI)和胚胎移植的年份。所有接受IVF/ICSI治疗的女性均健康且年龄在40岁以下, 并且采用严格的单胚胎移植政策进行治疗。针对体重指数(BMI)、吸烟和胎次调整后的多元逻辑回归分析显示, 用供体卵母细胞实现妊娠的妊娠期高血压疾病(调整后的比值比, AOR 4.25;95%置信区间(CI), 2.61-6.92)以及前先兆子痫(AOR 3.99;95% CI 2.27-7.00)的风险增加了4倍。卵母细胞捐赠后分娩的妇女剖宫产率也较高(AOR 1.69;95% CI 1.22-2.35), 产后出血>1000 mL(AOR 1.59;95%可信区间,1.11-2.27)的风险较高。进一步对先兆子痫进行logistic回归分析后, 未发现额外增加的围产期风险。两组之间的早产发生率、低出生体重、新生儿重症监护需求、Apgar评分和围产期死亡发生率也相似。
The Chinese abstracts are translated by Prof. Dr. Xiangyan Ruan and her team: Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China.
Introduction
Oocyte donation (OD) has gained widespread utilization in assisted reproductive technologies (ART) with a broadened range of indications additional to premature ovarian insufficiency, such as advanced female reproductive age and gestational surrogacy [Citation1,Citation2]. Rapidly increasing numbers of OD in cross-border reproductive health care [Citation3–5] and lack of homogeneity amongst treatment policies have been reported [Citation6].
Data from studies comparing OD pregnancies to natural conceptions have consistently reported a higher prevalence of preeclampsia, explanatory of a poorer perinatal outcome in OD pregnancies [Citation7–10]. However, studies comparing OD versus in-vitro fertilization (IVF) using autologous oocytes have been conflicting [Citation9–15].
A limited sample size and power might explain part of the discrepancies, as well as lack of adjustment for confounders, differences between the populations studied, a high prevalence of women >40 years of age undergoing OD-treatments and multiple births [Citation7,Citation16].
In Sweden, ART treatments are offered within the tax-funded healthcare system to couples with primary infertility, female age <39 years and male partner <56 years. Since 2003, OD has also been available, albeit restricted only to university hospital-based clinics. The selection of couples for OD follows a strict process including psychosocial evaluation. Both potential parents should display good health, but particularly the oocyte recipient should not present with obvious or known major increased risks to pregnancy complications. There is a strict policy of a single embryo for transfer in OD treatments, as well as in a clear majority of IVF treatments using autologous oocytes [Citation17], aiming to reduce maternal and perinatal complications associated with multiple conceptions [Citation18].
The aim of our study was to assess if pregnancies achieved by OD in a well-characterized population of young and healthy women, presented with increased maternal and perinatal risks when compared to matched pairs undergoing IVF with autologous oocytes.
Material and methods
This study was a prospective, single-center matched cohort study of women who achieved pregnancies and live births using donor oocytes after IVF with or without intra-cytoplasmic sperm injection (ICSI) and compared 1:2 to control women undergoing IVF/ICSI with autologous oocytes. All ART treatments were performed at the Reproductive Medicine Unit, Karolinska University Hospital between January 1 2007 and December 31 2014 with a strict policy of single embryo transfer. All recipient couples underwent selection process at the center. All oocyte donors, also underwent psychosocial and health investigations at the center, were <36 years, in good physical and mental health, had no family history of hereditary diseases and had a wish to donate oocytes by altruistic reasons to unrelated couples, with no economic reward interests.
The matching (1:2) took into consideration the women’s age at time of embryo transfer, type of treatment (IVF/ICSI), and year of embryo transfer. Treatments using supernumerary frozen-thawed embryos were also included, to allow separate subanalyses.
Data collection
Prospectively collected data on IVF/ICSI treatments using OD or autologous oocytes were obtained from the Reproductive Medicine’s electronic database (LinneFiler®, Fertsoft AB, Uppsala, Sweden), implemented since 1997. After the child’s delivery, a specific report is updated, with a ≥95% completeness of data.
The Swedish maternal healthcare is standardized and also free of charge and pregnancy, and delivery data are prospectively entered in a medical registry database, Obstetrix® (Cerner Sweden AB, Stockholm) [Citation19]. By using the unique personal identity number assigned to Swedish citizens, linking between the registries and detailed obstetric outcome data pertaining to the female study cohort could be retrieved.
This study was approved by the Regional Ethics Committee (Dnr 2011/1758-31/2, Amendment 2014/470-32).
Variables and outcome measures
Demographic variables including woman’s age, smoking habits, body mass index (BMI), and partner’s age were collected, as well as treatment data indicating if IVF or ICSI were applied, if OD or autologous oocytes were used, the date of embryo transfer and if the embryo used was derived from a fresh or frozen cycle. Gestational length was calculated using the date of embryo transfer and the date of delivery. Obstetric outcome variables were extracted through their ICD-10.
Statistical analyses
For group comparisons, differences in continuous variables were tested using T-tests, as data distribution was normal. Categorical variables were analyzed using Chi-square or Fischer’s exact test. Logistic regression analysis was used to estimate crude and adjusted odds ratios (AOR) with 95% confidence intervals (CI). Women who underwent IVF/ICSI with autologous oocytes were used as the reference group in the regression models. Multivariate logistic regression was used to adjust for potential confounding factors including BMI, smoking, and parity. Adjusted odds ratios AOR and 95% CI were estimated in the models using only observations with complete information (complete case analysis). All analyses were performed using SPSS software version 23 (IBM). The level of significance was set at p < .05, two-sided.
Results
During the study period, 259 women achieved pregnancies after OD, and data on 515 women that used autologous oocytes in IVF/ICSI treatments (IVF/ICSI group) matched by age, IVF or ICSI, and year of transfer were obtained. Demographic data are summarized in . The groups were comparable in regards to women’s and male partner’s age, smoking habits, and parity. A higher proportion of women with obesity (BMI >30) was observed in the IVF/ICSI group. A few women in the cohort had medical conditions such as diabetes or essential hypertension, without significant differences between the groups (). The proportion of women who achieved pregnancies after fresh embryo transfer was higher in the IVF/ICSI group and conversely, pregnancies obtained after frozen embryo transfer were more frequent after OD.
Table 1. Demographic data of patients who achieved pregnancies after IVF/ICSI using donor oocytes or autologous oocytes.
A significantly higher rate of maternal complications was observed in OD pregnancies (), where 44.7% presented with one or several complications combined, compared to 30.6% of women treated using autologous oocytes (p < .001). A significantly higher prevalence of hypertensive disorders (OR 3.96; 95% CI, 2.45–6.40), including gestational hypertension (3.21; 95% CI, 1.37–7.51) and pre-eclampsia (3.92; 95% CI, 2.24–6.85) was found after OD, with a higher risk of severe pre-eclampsia and HELLP. These differences between the groups remained significant after adjustments for BMI >25, nulliparity, and smoking (see ). No significant differences were found as regards to gestational diabetes, placental abruption, placenta previa, pPROM, or chorioamnionitis.
Table 2. Obstetric outcomeTable Footnotea of pregnancies achieved by IVF/ICSI using donor oocytes or autologous oocytes.
A high prevalence of PPH was noted in both cohorts but the risk was significantly higher in pregnancies obtained after OD both in the unadjusted and adjusted analysis (OR 1.54; 95% CI, 1.09–2.19 and AOR 1.59; 95% CI, 1.11–2.27, respectively, and . In subset analysis of fresh cycles (), a significantly higher prevalence of hypertensive complications and pre-eclampsia were found after OD when compared to IVF/ICSI controls. Additionally, but notably only in the group of frozen embryos, a significantly higher proportion of OD pregnancies presented with PPH, when compared to IVF/ICSI (34.5% vs 20%, respectively), OR 2.11; 95% CI 1.18–3.78 ().
Table 3. Obstetric outcome of pregnancies achieved by IVF/ICSI using donor oocytes or autologous oocytes dichotomized using subanalysis of pregnancies obtained after transfer of fresh or frozen-thawed embryos.
The prevalence of delivery by cesarean section was high in both groups but most frequent in OD pregnancies with a rate of 45.9% vs 32.9%, OR 1.73; CI 1.27–2.35 and AOR 1.69; 95% CI 1.22–2.35.
Perinatal outcomes are summarized in . Notably, no significant differences were seen between the two groups related to preterm birth, low birth weight, or any other of the studied perinatal outcomes. While subanalysis of crude OR’s between the groups of fresh versus frozen-thawed embryos indicated a significantly higher prevalence of preterm birth and low birth weight in OD pregnancies after transfer of frozen-thawed embryos only (), such a difference could not be validated in the adjusted analysis ().
Table 4. Perinatal outcome of children born after IVF/ICSI using donor oocytes or autologous oocytes.
Table 5. Perinatal outcome of pregnancies achieved by IVF/ICSI using donor oocytes or autologous oocytes.
Table 6. Logistic regression models adjusted for several confounders for analysis of obstetric and perinatal outcome of pregnancies achieved by IVF/ICSI using donor oocytes or autologous oocytes.
Discussion
The main findings of our study indicate a substantial and significant increase of pregnancy complications including a four-fold increased risk of gestational hypertensive disorders and preeclampsia and increased risks of PPH, in a well-characterized population of young and healthy women who received a single embryo in their OD treatments giving rise to singleton births. In an earlier metaanalysis [Citation7], an increased risk of PPH in OD pregnancies was noted. However, in the present study this could only be seen in the subgroup of patients with pregnancies obtained by froze-thaw embryos. The association between OD treatment and pregnancy complications remained significant also after adjustment for earlier established confounding factors.
To our knowledge, this is the largest single-center matched cohort study using double as many controls as cases and examining the effect of OD on obstetric and perinatal outcomes when compared to IVF/ICSI with autologous oocytes in singleton pregnancies. Our findings may have implications for practice and indicate that women with OD might benefit from prophylaxis with aspirin in early pregnancy [Citation21]. The increasing numbers of OD treatments worldwide and the rapid spreading of OD as cross-border reproductive care [Citation3–5] allow women who are older than the women of our study or with comorbidities to undergo such treatments. Our data give credence to the earlier suggested strict recommendation of single embryo transfer in OD treatments and its application to be applied as a rule, as even in this very healthy and young population of women in our study, increased pregnancy risks were observed in pregnancies obtained by OD.
A major strength of our study is the use of prospectively collected data into standardized healthcare databases and follow-up in a standardized maternal care setting that was offered to 100% of our women study population and with a completeness of nearly 100% of the medical record and registry data for the obstetrical outcomes of interest in the study [Citation22]. No maternal deaths were observed in these cohorts and a very low frequency of perinatal deaths which did not differ between the groups.
As several earlier studies have clearly pointed out, infertility in itself may be a cause of adverse obstetrical and perinatal outcomes [Citation22] and the use of donor oocytes from infertile women, such as in previous studies may also partially explain the higher obstetrical risks in OD pregnancies [Citation9]. In our study, oocyte donors were all young women in good health and the majority had proven fertility. Our results are also in agreement with a recent meta-analysis reporting on studies performed between 1991 and 2012 on hypertensive disorders and preeclampsia in OD pregnancies [Citation23]. However, young women comparable to our study population have been a minority across previous studies, and multiple births have been frequently associated with the increased risks [Citation24]. Further in agreement with our findings, two additional meta-analyses had concluded that the increased risk of hypertensive disorders in OD pregnancies was independent of maternal age and multiple gestations [Citation7,Citation25].
Limitations of our study include the lack of a group of natural pregnancies as a control group under the study period and heterogeneous infertility causes in woman with OD. In contrast with previous studies [Citation7,Citation13–16], preterm delivery and low birth weight in our study were only significantly increased in unadjusted analysis of OD pregnancies after transfer of frozen-thawed embryos when compared to pregnancies obtained with autologous oocytes. On the other hand, our adjusted analysis support that the high rate of preeclampsia and gestational hypertension occurring in OD pregnancies explain most of the differences regarding preterm delivery and low birth weight, as the differences between the groups did not remain after adjusting for preeclampsia and gestational hypertension, and also possibly, are explanatory for the increased rate of cesareans and NICU treatment, which were higher than the reported rates of 20% and 10%, respectively, in Sweden [Citation26].
In conclusion, our data hence support that OD is itself an independent risk factor for the development of gestational hypertensive disorders and preeclampsia, also in recipient women that are generally young, lean, nonsmoking, and in good health condition, even within OD programs with a strict single embryo transfer policy. Pregnancies obtained after OD confer a four-fold increase in the likelihood of developing gestational hypertension and preeclampsia, and also a higher risk of cesarean delivery and PPH when compared to pregnancies obtained by IVF/ICSI using autologous oocytes. Reassuringly, no additional perinatal complications were evidenced, possibly due to a high quality and standardized maternal and delivery care. However, reproductive medicine and fetomaternal specialists and the women undergoing such treatments should be aware of these increased risks to enable implement preventive measures and early diagnosis of preeclampsia.
Acknowledgments
The authors wish to thank Lena Hyberg and Karin Persdotter-Eberg, RM, for administrative support, and Margareta Fridström, MD PhD and Per-Olof Karlström, MD PhD, for their continuous efforts in developing of a high-quality program for oocyte donor treatments at our center.
Disclosure statement
No potential conflict of interest was reported by the authors.
Additional information
Funding
References
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