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Peak serum estradiol level during controlled ovarian hyperstimulation is associated with increased risk of small for gestational age and preeclampsia in singleton pregnancies after in vitro fertilization
Peak serum estradiol level during controlled ovarian hyperstimulation is associated with increased risk of small for gestational age and preeclampsia in singleton pregnancies after in vitro fertilization Anthony N. Imudia, M.D.,a Awoniyi O. Awonuga, M.D.,b Joseph O. Doyle, M.D.,a Anjali J. Kaimal, M.D.,c Diane L. Wright, Ph.D.,a Thomas L. Toth, M.D.,a and Aaron K. Styer, M.D.a a
Massachusetts General Hospital Fertility Center, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; b Division of Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, Michigan; and c Division of Maternal Fetal Medicine, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Objective: To assess the impact of elevated peak serum E2 levels (EPE2; defined as levels >90th percentile) on the day of hCG administration during controlled ovarian hyperstimulation (COH) for IVF on the likelihood for small for gestational age (SGA), preeclampsia (PreE), and preterm delivery (PTD) in singleton pregnancies. Design: Retrospective cohort study. Setting: Tertiary-care academic medical center. Patient(s): Singleton live-birth pregnancies conceived after fresh IVF-ET. Intervention(s): None. Main Outcome Measure(s): The delivery rate of SGA infants and the development of PreE and PTD in patients with and without EPE2. Result(s): Patients with EPE2 during COH were more likely to deliver SGA infants (7 [26.9%] vs. 10 [3.8%]; odds ratio [OR], 95% confidence interval [CI] {9.40, 3.22–27.46}) and develop PreE (5 [18.5%] vs. 12 [4.5%]; adjusted OR, 95% CI {4.79, 1.55–14.84}). No association was found between EPE2 and the likelihood for delivery before 37 weeks, 35 weeks, or 32 weeks of gestation. Receiver operating characteristic analysis revealed that EPE2 level predicted adverse obstetrical outcome (SGA þ PreE) with 38.5% and 91.7% sensitivity and specificity, respectively. Using a serum peak E2 cutoff value of 3,450 pg/mL (>90th percentile level), the positive predictive value was 37%, while the negative predictive value was 92%. Conclusion(s): EPE2 level (>3,450 pg/mL) on the day of hCG administration during COH is associated with greater odds of developing PreE and delivery of an SGA infant in singleton pregnancies resulting from IVF cycles. (Fertil SterilÒ 2012;97:1374–9. Ó2012 by American Society for Reproductive Medicine.) Key Words: Estradiol, controlled ovarian hyperstimulation, IVF, small for gestational age, preterm delivery, preeclampsia, abnormal placentation
A
ssisted reproductive technology (ART) is an increasingly successful and widely employed modality for the treatment of infertility. In 2008, more than 61,000 infants were born as a result of ART,
making up approximately 1% of all births in the United States (1). It is well recognized that there is a significantly increased risk of multiple gestations (2), chromosomal abnormalities, small for gestational age (SGA)/low
Received January 18, 2012; revised March 14, 2012; accepted March 15, 2012; published online April 10, 2012 A.N.I. has nothing to disclose. A.O.A. has nothing to disclose. J.O.D. has nothing to disclose. A.J.K. has nothing to disclose. D.L.W. has nothing to disclose. T.L.T. has nothing to disclose. A.K.S. has nothing to disclose. Reprint requests: Anthony N. Imudia, M.D., Massachusetts General Hospital, 55 Fruit Street, Yawkey 10A, Boston, Massachusetts 02114-2622 (E-mail: [email protected]). Fertility and Sterility® Vol. 97, No. 6, June 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2012.03.028 1374
birth weight (LBW), preterm delivery (PTD) (3–9), preeclampsia (PreE), placenta previa, cesarean delivery, and perinatal mortality (8–17) in singleton gestations conceived with ART compared with spontaneously conceived pregnancies. The putative mechanism(s) that may increase the risk of these conditions remain uncertain. As a result, it is unclear whether these increased risks are attributable to underlying infertility, intrinsic characteristics of the infertile couple, the endogenous hormonal milieu associated with controlled VOL. 97 NO. 6 / JUNE 2012
Fertility and Sterility® ovarian hyperstimulation (COH) (18), the use of different assisted reproductive techniques (8, 19), or a combination of these factors. Specifically, PreE and SGA have been attributed to aberrant placentation during early pregnancy (20). Although the etiology of these diseases is poorly understood, there is evidence to suggest that abnormal placentation occurs due to decreased trophoblastic invasion of the decidual and myometrial spiral arteries and aberrant cell survival and apoptosis (21–24). The ultimate consequence of this phenomenon is that these arteries retain the ability to respond to vasoactive stimuli, causing incessant vasoconstriction (25, 26). During the course of pregnancy, vasoconstriction may lead to suboptimal blood supply to the growing placenta and subsequent spontaneous abortion, stillbirth, SGA, or PreE (20, 24, 27). Some investigators have reported that elevation of E2 levels during the first trimester in a baboon pregnancy results in the attenuation of extravillous trophoblast invasion of the uterine spiral arteries (28). The mechanism by which this happens has been demonstrated to be impaired angiogenesis in this model (29). It is unclear whether this phenomenon occurs in humans when pregnancies are achieved in the setting of high E2 levels as seen after COH for IVF. However, in the recent landmark study by Kalra et al., higher odds of LBW were seen in singleton gestations after IVF cycles when compared with frozen-thawed cycles (30). In this study, the investigators suggested that gonadotropin-stimulated multifollicular development and production of supraphysiologic levels of sex steroid hormones immediately before embryo implantation may represent an independent mediator contributing to the increased risk of LBW and other disorders of abnormal placentation, such as PreE (30). This implies that the abnormal extravillous trophoblast invasion due to supraphysiologic elevation of sex steroid hormones reported in early baboon pregnancy might be operational in human pregnancy. A discrete and modifiable parameter of routine COH, peak E2, represents a potential compelling upstream factor of ART, which may have downstream implications for aberrant implantation, placentation, and adverse pregnancy outcomes. To this end, the goal of this study was to assess the impact of elevated peak serum E2 levels (EPE)2 on the day of hCG administration during COH and before IVF-ET on the prevalence of SGA, PreE, and PTD in singleton pregnancies.
MATERIALS AND METHODS A retrospective cohort study was conducted after obtaining approval from the Partners Healthcare Institutional Review Board. A total of 1,301 consecutive IVF-ET pregnancies from January 2005 through December 2010 were reviewed. Of these, 637 received their prenatal care and delivered at our institution. An overview of all the inclusion and exclusion criteria is illustrated in Figure 1. The 399 live-birth deliveries resulting from fresh autologous IVF-ET were identified, and 292 met our inclusion criteria for final analysis (singleton conception, i.e., pregnancy starting with single gestational sac and fetal pole on initial ultrasound at 5 weeks, 5 days estimated gestational age). VOL. 97 NO. 6 / JUNE 2012
All patients underwent IVF (with conventional insemination or intracytoplasmic sperm injection [ICSI]) using standard oral contraceptive pills pretreatment with luteal phase GnRH-agonist pituitary downregulation, follicular phase GnRH-agonist flare, or GnRH-antagonist with variable start and exogenous gonadotropins (recombinant FSH and human menopausal gonadotropins) as described in our prior publication (31). Institutional criteria for hCG trigger include a minimum of three follicles with a diameter of R16 mm and a minimum serum E2 concentration of R600 pg/mL. At the time of hCG trigger, patients received hCG (10,000 IU IM) with serum E2 %2,500 pg/mL or (5,000 IU IM) if >2,500 pg/mL, followed by transvaginal ultrasound-guided oocyte retrieval (ER) 35–37 hours later. Patients with a peak serum E2 level >4,500 pg/mL did not have a fresh transfer; they either elected cycle cancellation or cryopreservation of all embryos at the pronuclear stage on day 1 to minimize the risk of ovarian hyperstimulation syndrome (OHSS). Embryos were transferred into the uterine cavity with transabdominal ultrasound guidance 3 or 5 days after ER based upon the morphologic grade of the available embryo cohort and institutional guidelines. Luteal support was provided with IM (50 mg daily) or vaginal (100 mg 3 times a day) P until 10 weeks gestational age plus daily 81 mg of acetylsalicylic acid starting 1 day post-ER and 0.2 mg transdermal E2 every other day (Vivelle, Noven Pharmaceuticals) starting 9 days after ER until pregnancy test. The rates of delivery before 37 weeks (PTD), SGA (defined as birth weight <10th percentile for gestational age using standard curve) (32), and PreE (defined as elevated systolic blood pressure R140 or diastolic blood pressures R90 after 20 weeks' gestation with proteinuria [R1þ in a random clean catch urine analysis or R300 mg/24-hour urine collection]) from the 292 singleton IVF-ET pregnancies were calculated. EPE2 was defined as levels >90th percentile. This threshold was chosen to include only patients with extremely elevated levels in the exposed group, similar to the previously mentioned baboon model (28, 29). Serum E2 levels were measured with Roche cobas immunoassay (Roche Diagnostics). All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS, ver. 19 for Windows). P%.05 was considered statistically significant. The data were expressed as mean SD for continuous variables and number of cases (n) and percentage of occurrence (%) for categorical variables. Differences between groups were analyzed with c2 and Fisher's exact tests for categorical data, and Student's t-test and Wilcoxon rank test for continuous variables, as appropriate. When necessary, the univariate analysis was followed by forward stepwise logistic regression for the risk of SGA, PreE, and PTD. Potential confounders were included in the model if they were considered risk factors for the adverse pregnancy outcomes of interest based on P< .10. Covariates included EPE2 and total gonadotropin dose required for COH. To determine the predictive ability of EPE2, receiver operating characteristic (ROC) curves (a graph of the sensitivity vs. 1-specificity) were used, and the area under the ROC curve (AUC) was determined for the risk of SGA and PreE. 1375
ORIGINAL ARTICLE: EARLY PREGNANCY
FIGURE 1 Consecutive ART Pregnancies (n=1301)
Prenatal Care record linked to ART record (n=637)
Prenatal Care record not linked to ART record (n=664)
Fresh embryo transfer [autologous oocytes, (n=399)]
Cryothaw embryo transfer (n=90), miscarriages (n=82), delivery prior to 24 weeks gestation (n=23), miscellaneous (n=43) [includes vanishing twins, donor cycles etc.]
Singleton live births (n=292)
Peak serum estradiol levels > 90th percentile (n=27)
Multiple live births (n=107)
Peak serum estradiol levels 90th percentile (n=265)
Overview of the inclusion and exclusion criteria. Imudia. Peak E2 level predicts adverse obstetric outcomes. Fertil Steril 2012.
RESULTS There were a total of 20,527 deliveries in our institution during the study period. Approximately 96.7% (19,852) were singleton live births. The prevalence of PTD and PreE in these singleton deliveries was 7.9% (n ¼ 1,569) and 5.0% (n ¼ 994), respectively. Of the 292 singleton IVF deliveries analyzed during the same period, the prevalences of PTD, PreE, and SGA were 6.85% (n ¼ 20), 5.82% (n ¼ 17), and 5.82% (n ¼ 17), respectively. The mean SD serum E2 level on the day of hCG trigger in the study cohort was 2,354 754 pg/mL, while the 90th percentile was 3,450 pg/mL. There was a total of 27 (9.2%) patients with EPE2 (>3,450 pg/mL) on the day of hCG administration during COH. No significant difference was found in maternal age, body mass index (BMI), baseline ovarian reserve measures (antral follicle count, day 3 FSH, and E2), type of stimulation protocol, and total dose of gonadotropin 1376
used for COH among the patients with above and below 90th percentile for the peak serum E2 levels threshold (Table 1). The breakdown of causes of infertility among the two groups was not significantly different. There was no statistical significant difference in the rate of ICSI and assisted hatching between the two groups. Additionally, there was no significant difference in the demographic characteristics such as maternal age, BMI, gravidity and parity, baseline ovarian reserve measures, type of stimulation protocol, causes of infertility, and number and day of ET in patients with and without the different adverse obstetrical outcomes of interest. Patients with EPE2 during COH, compared with those with a lower peak serum E2 threshold, demonstrated a statistically significant higher proportion of SGA infants (7 [26.9%] vs. 10 [3.8%]; odds ratio [OR], 95% confidence interval [CI] {9.40, 3.22–27.46}). This OR was unchanged after performing a forward stepwise logistic regression including maternal age, VOL. 97 NO. 6 / JUNE 2012
Fertility and Sterility®
TABLE 1 Baseline characteristics of patients with and without EPE2 on the day of hCG administration after COH for IVF. Peak serum E2 level Variable
£90th percentile (n [ 265)
>90th percentile (n [ 27)
P value
34.8 4.0 24.2 4.0 13 6 7.6 4.9 45.4 26.7
34.0 3.9 23.3 2.7 12 6 7.1 2.0 39.0 14.7
.31 .13 .28 .60 .22
174 (71.6) 37 (15.2) 32 (13.2) 2,544 1,147
19 (79.2) 3 (12.5) 2 (8.3) 2,516 1,089
.71
Maternal age, y BMI, kg/m2 Antral follicle count Basal FSH, U/L Basal E2 level, pg/mL Stimulation protocol (%) Luteal phase GnRH-agonist Follicular phase GnRH-agonist Follicular phase GnRH-antagonist Total dose of Gn administered, IU
.90
Note: The 90th percentile of peak serum E2 level ¼ 3,450 pg/mL. Data expressed in mean SD and number of cases (percentage). Imudia. Peak E2 level predicts adverse obstetric outcomes. Fertil Steril 2012.
BMI, number of embryos transferred, day of ET, and parity in the model. Both EPE2 and total dose of gonadotropin required for COH were associated with the development of PreE. After adjusting for the total dose of gonadotropin and other known confounders such as maternal age and parity with forward stepwise logistic regression, these patients were still more likely to develop PreE (5 [18.5%] vs. 12 [4.5%]; adjusted OR, 95% CI {4.79, 1.55–14.84}). No association was found between EPE2 level and the likelihood for delivery before 37 weeks, 35 weeks, or 32 weeks of gestation (extreme prematurity). A ROC analysis revealed that EPE2 level was able to predict conditions associated with abnormal placentation and placental insufficiency (SGA þ PreE combined) with 38.5% and 91.7% sensitivity and specificity, respectively. AUC was 0.65 (SE, 0.06; 95% CI, 0.53–0.78; P< .01) for the composite obstetrical outcome, 0.62 (SE, 0.07; 95% CI, 0.49–0.74; P< .05) for SGA, and 0.57 (SE, 0.06; 95% CI, 0.45–0.70; P¼ .22) for PreE. Using a serum peak E2 cutoff value of 3,450 pg/mL, the positive predictive value for these conditions was 37%, while the negative predictive value was 92%.
DISCUSSION In this study, the supraphysiologic peri-implantation maternal hormonal milieu unique to COH during IVF was associated with higher odds for delivery of SGA infants and the development of PreE in singleton conception. Specifically, EPE2 (levels >90th percentile) on the day of hCG administration was associated with these findings. Our findings confirm and support the initial report by Farhi et al. (33) demonstrating a potential upstream impact of elevated preconceptional systemic sex steroid concentrations characteristic of ART on downstream events during human pregnancy. These findings carry both scientific and public health importance and may provide further insight into which facets of ART may be responsible for a potential increased prevalence of maternal and fetal perinatal morbidity after elective fertility therapy. The 7.9% and 5.0% overall rate of preterm delivery and preeclampsia in all singleton live births in our institution is VOL. 97 NO. 6 / JUNE 2012
comparable to the 6.85% and 5.82% seen in deliveries resulting from pregnancies achieved through fresh IVF cycles. While these rates are in contrast to the findings of other studies that have demonstrated an increased risk of these perinatal morbidities (4, 9, 10, 13, 17), these data suggest that IVF may not be the sole significant contributor to these conditions in our institution. In light of our findings in patient cycles with EPE2 and the common practice of avoiding fresh ET in patients with peak serum E2 level >4,500 pg/mL on the day of hCG administration at this institution, the beneficial effect of setting a threshold peak E2 level can in retrospect be appreciated. Patients undergoing COH for IVF with EPE2 clearly demonstrated a higher risk of developing disorders related to abnormal placentation. The odds of delivering SGA infants and developing PreE was nine- and five-fold greater, respectively, in these patients as compared with patients with lower levels (<90th percentile threshold) of serum E2. These findings support the hypothesis generated in the landmark study by Kalra et al. (30) that suggested an elevated risk of LBW after COH and fresh ET. E2 has been shown to play a key role in the morphological and functional differentiation of the villous trophoblast as well as the modulation of uteroplacental blood flow that is critical for optimal fetal growth and development in nonhuman primate pregnancies (34–37). It appears that the low levels of E2 exhibited in early gestation as compared with the later part of pregnancy are required to permit normal progression of uterine spiral artery invasion by cytotrophoblast (28). As suggested by our data, the EPE2 level on the day of hCG trigger was associated with SGA and PreE, which may be due to abnormal remodeling of the spiral artery and trophoblast invasion. This mechanism has been shown to be fully operational in the baboon model (28, 29) and may occur in a similar fashion during human gestation. It is also known that the human placentation process is dependent upon both embryonic substances regulating the adhesive and invasive properties of the trophoblast and maternal uterine and immunologic factors, which play permissive and regulatory roles in modulating trophoblast invasion (38). There is also evidence to suggest that some of these interactions are altered in the setting of COH (39–46). 1377
ORIGINAL ARTICLE: EARLY PREGNANCY To this end, a group of investigators have reported a threefold differential expression of more than 200 endometrial genes during implantation in stimulated cycles compared with natural cycles (47). These changes may alter regulatory processes and modify the entire implantation process and may predispose these pregnancies to higher adverse obstetrical outcomes. The predictive accuracy of conditions associated with abnormal placentation (SGA þ PreE) using the EPE2 level during a fresh IVF cycle as a single marker is modest at best, with a specificity of 92% and sensitivity of 38%. Nevertheless, this study shows that there is an association between EPE2 and the odds of adverse pregnancy outcome such as PreE and SGA. Since reasonable pregnancy and live-birth rates can be achieved in patients without extremes of EPE2 during COH, ART providers should be aware of the possible adverse pregnancy outcome associated with supraphysiological E2 levels on the day of hCG administration. It is important to note also that multiple gestation remains the strongest determinant of perinatal morbidity after any ART therapy and should not be underestimated (48). The risk of PTD, delivery of an SGA infant, and the development of PreE are significantly higher in multiple gestations as compared with in singletons (2, 30, 49). Therefore, continued adoption of conservative ET guidelines, including elective single ET in selected patients, may also serve to reduce the rates of multiple pregnancies and promote the increased use of subsequent frozen ET cycles after fresh IVF (30, 50–52). In both instances, the goal to maintain a consistent reduction in the prevalence of common adverse obstetrical outcomes associated with IVF between fresh and frozen cycles may be achieved. Given that patients with peak serum E2 levels >4,500 pg/mL did not have a fresh transfer in our present cohort, it should be stressed that we reported on patients with a very narrow range of high E2 levels (3,450–4,500) in our exposed group. A follow-up study is underway in our institution to compare the obstetrical outcomes of women who had elective cryopreservation of all embryos due to EPE2 with those who underwent a fresh ET. While the findings of this study are novel, the inherent limitations of a retrospective study, with a small sample size from a single institution, are apparent. Therefore, a larger prospective study from other institutions will be needed to confirm the findings of this study. In the interim, the possible effect of EPE2 on the prevalence of SGA and PreE in IVF singleton deliveries is indeed notable and warrants consideration by the clinician as a potential modifiable factor of COH that may provide a means to impact the ultimate pregnancy outcome.
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Massachusetts General Hospital Fertility Center, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; b Division of Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, Michigan; and c Division of Maternal Fetal Medicine, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Objective: To assess the impact of elevated peak serum E2 levels (EPE2; defined as levels >90th percentile) on the day of hCG administration during controlled ovarian hyperstimulation (COH) for IVF on the likelihood for small for gestational age (SGA), preeclampsia (PreE), and preterm delivery (PTD) in singleton pregnancies. Design: Retrospective cohort study. Setting: Tertiary-care academic medical center. Patient(s): Singleton live-birth pregnancies conceived after fresh IVF-ET. Intervention(s): None. Main Outcome Measure(s): The delivery rate of SGA infants and the development of PreE and PTD in patients with and without EPE2. Result(s): Patients with EPE2 during COH were more likely to deliver SGA infants (7 [26.9%] vs. 10 [3.8%]; odds ratio [OR], 95% confidence interval [CI] {9.40, 3.22–27.46}) and develop PreE (5 [18.5%] vs. 12 [4.5%]; adjusted OR, 95% CI {4.79, 1.55–14.84}). No association was found between EPE2 and the likelihood for delivery before 37 weeks, 35 weeks, or 32 weeks of gestation. Receiver operating characteristic analysis revealed that EPE2 level predicted adverse obstetrical outcome (SGA þ PreE) with 38.5% and 91.7% sensitivity and specificity, respectively. Using a serum peak E2 cutoff value of 3,450 pg/mL (>90th percentile level), the positive predictive value was 37%, while the negative predictive value was 92%. Conclusion(s): EPE2 level (>3,450 pg/mL) on the day of hCG administration during COH is associated with greater odds of developing PreE and delivery of an SGA infant in singleton pregnancies resulting from IVF cycles. (Fertil SterilÒ 2012;97:1374–9. Ó2012 by American Society for Reproductive Medicine.) Key Words: Estradiol, controlled ovarian hyperstimulation, IVF, small for gestational age, preterm delivery, preeclampsia, abnormal placentation
A
ssisted reproductive technology (ART) is an increasingly successful and widely employed modality for the treatment of infertility. In 2008, more than 61,000 infants were born as a result of ART,
making up approximately 1% of all births in the United States (1). It is well recognized that there is a significantly increased risk of multiple gestations (2), chromosomal abnormalities, small for gestational age (SGA)/low
Received January 18, 2012; revised March 14, 2012; accepted March 15, 2012; published online April 10, 2012 A.N.I. has nothing to disclose. A.O.A. has nothing to disclose. J.O.D. has nothing to disclose. A.J.K. has nothing to disclose. D.L.W. has nothing to disclose. T.L.T. has nothing to disclose. A.K.S. has nothing to disclose. Reprint requests: Anthony N. Imudia, M.D., Massachusetts General Hospital, 55 Fruit Street, Yawkey 10A, Boston, Massachusetts 02114-2622 (E-mail: [email protected]). Fertility and Sterility® Vol. 97, No. 6, June 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2012.03.028 1374
birth weight (LBW), preterm delivery (PTD) (3–9), preeclampsia (PreE), placenta previa, cesarean delivery, and perinatal mortality (8–17) in singleton gestations conceived with ART compared with spontaneously conceived pregnancies. The putative mechanism(s) that may increase the risk of these conditions remain uncertain. As a result, it is unclear whether these increased risks are attributable to underlying infertility, intrinsic characteristics of the infertile couple, the endogenous hormonal milieu associated with controlled VOL. 97 NO. 6 / JUNE 2012
Fertility and Sterility® ovarian hyperstimulation (COH) (18), the use of different assisted reproductive techniques (8, 19), or a combination of these factors. Specifically, PreE and SGA have been attributed to aberrant placentation during early pregnancy (20). Although the etiology of these diseases is poorly understood, there is evidence to suggest that abnormal placentation occurs due to decreased trophoblastic invasion of the decidual and myometrial spiral arteries and aberrant cell survival and apoptosis (21–24). The ultimate consequence of this phenomenon is that these arteries retain the ability to respond to vasoactive stimuli, causing incessant vasoconstriction (25, 26). During the course of pregnancy, vasoconstriction may lead to suboptimal blood supply to the growing placenta and subsequent spontaneous abortion, stillbirth, SGA, or PreE (20, 24, 27). Some investigators have reported that elevation of E2 levels during the first trimester in a baboon pregnancy results in the attenuation of extravillous trophoblast invasion of the uterine spiral arteries (28). The mechanism by which this happens has been demonstrated to be impaired angiogenesis in this model (29). It is unclear whether this phenomenon occurs in humans when pregnancies are achieved in the setting of high E2 levels as seen after COH for IVF. However, in the recent landmark study by Kalra et al., higher odds of LBW were seen in singleton gestations after IVF cycles when compared with frozen-thawed cycles (30). In this study, the investigators suggested that gonadotropin-stimulated multifollicular development and production of supraphysiologic levels of sex steroid hormones immediately before embryo implantation may represent an independent mediator contributing to the increased risk of LBW and other disorders of abnormal placentation, such as PreE (30). This implies that the abnormal extravillous trophoblast invasion due to supraphysiologic elevation of sex steroid hormones reported in early baboon pregnancy might be operational in human pregnancy. A discrete and modifiable parameter of routine COH, peak E2, represents a potential compelling upstream factor of ART, which may have downstream implications for aberrant implantation, placentation, and adverse pregnancy outcomes. To this end, the goal of this study was to assess the impact of elevated peak serum E2 levels (EPE)2 on the day of hCG administration during COH and before IVF-ET on the prevalence of SGA, PreE, and PTD in singleton pregnancies.
MATERIALS AND METHODS A retrospective cohort study was conducted after obtaining approval from the Partners Healthcare Institutional Review Board. A total of 1,301 consecutive IVF-ET pregnancies from January 2005 through December 2010 were reviewed. Of these, 637 received their prenatal care and delivered at our institution. An overview of all the inclusion and exclusion criteria is illustrated in Figure 1. The 399 live-birth deliveries resulting from fresh autologous IVF-ET were identified, and 292 met our inclusion criteria for final analysis (singleton conception, i.e., pregnancy starting with single gestational sac and fetal pole on initial ultrasound at 5 weeks, 5 days estimated gestational age). VOL. 97 NO. 6 / JUNE 2012
All patients underwent IVF (with conventional insemination or intracytoplasmic sperm injection [ICSI]) using standard oral contraceptive pills pretreatment with luteal phase GnRH-agonist pituitary downregulation, follicular phase GnRH-agonist flare, or GnRH-antagonist with variable start and exogenous gonadotropins (recombinant FSH and human menopausal gonadotropins) as described in our prior publication (31). Institutional criteria for hCG trigger include a minimum of three follicles with a diameter of R16 mm and a minimum serum E2 concentration of R600 pg/mL. At the time of hCG trigger, patients received hCG (10,000 IU IM) with serum E2 %2,500 pg/mL or (5,000 IU IM) if >2,500 pg/mL, followed by transvaginal ultrasound-guided oocyte retrieval (ER) 35–37 hours later. Patients with a peak serum E2 level >4,500 pg/mL did not have a fresh transfer; they either elected cycle cancellation or cryopreservation of all embryos at the pronuclear stage on day 1 to minimize the risk of ovarian hyperstimulation syndrome (OHSS). Embryos were transferred into the uterine cavity with transabdominal ultrasound guidance 3 or 5 days after ER based upon the morphologic grade of the available embryo cohort and institutional guidelines. Luteal support was provided with IM (50 mg daily) or vaginal (100 mg 3 times a day) P until 10 weeks gestational age plus daily 81 mg of acetylsalicylic acid starting 1 day post-ER and 0.2 mg transdermal E2 every other day (Vivelle, Noven Pharmaceuticals) starting 9 days after ER until pregnancy test. The rates of delivery before 37 weeks (PTD), SGA (defined as birth weight <10th percentile for gestational age using standard curve) (32), and PreE (defined as elevated systolic blood pressure R140 or diastolic blood pressures R90 after 20 weeks' gestation with proteinuria [R1þ in a random clean catch urine analysis or R300 mg/24-hour urine collection]) from the 292 singleton IVF-ET pregnancies were calculated. EPE2 was defined as levels >90th percentile. This threshold was chosen to include only patients with extremely elevated levels in the exposed group, similar to the previously mentioned baboon model (28, 29). Serum E2 levels were measured with Roche cobas immunoassay (Roche Diagnostics). All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS, ver. 19 for Windows). P%.05 was considered statistically significant. The data were expressed as mean SD for continuous variables and number of cases (n) and percentage of occurrence (%) for categorical variables. Differences between groups were analyzed with c2 and Fisher's exact tests for categorical data, and Student's t-test and Wilcoxon rank test for continuous variables, as appropriate. When necessary, the univariate analysis was followed by forward stepwise logistic regression for the risk of SGA, PreE, and PTD. Potential confounders were included in the model if they were considered risk factors for the adverse pregnancy outcomes of interest based on P< .10. Covariates included EPE2 and total gonadotropin dose required for COH. To determine the predictive ability of EPE2, receiver operating characteristic (ROC) curves (a graph of the sensitivity vs. 1-specificity) were used, and the area under the ROC curve (AUC) was determined for the risk of SGA and PreE. 1375
ORIGINAL ARTICLE: EARLY PREGNANCY
FIGURE 1 Consecutive ART Pregnancies (n=1301)
Prenatal Care record linked to ART record (n=637)
Prenatal Care record not linked to ART record (n=664)
Fresh embryo transfer [autologous oocytes, (n=399)]
Cryothaw embryo transfer (n=90), miscarriages (n=82), delivery prior to 24 weeks gestation (n=23), miscellaneous (n=43) [includes vanishing twins, donor cycles etc.]
Singleton live births (n=292)
Peak serum estradiol levels > 90th percentile (n=27)
Multiple live births (n=107)
Peak serum estradiol levels 90th percentile (n=265)
Overview of the inclusion and exclusion criteria. Imudia. Peak E2 level predicts adverse obstetric outcomes. Fertil Steril 2012.
RESULTS There were a total of 20,527 deliveries in our institution during the study period. Approximately 96.7% (19,852) were singleton live births. The prevalence of PTD and PreE in these singleton deliveries was 7.9% (n ¼ 1,569) and 5.0% (n ¼ 994), respectively. Of the 292 singleton IVF deliveries analyzed during the same period, the prevalences of PTD, PreE, and SGA were 6.85% (n ¼ 20), 5.82% (n ¼ 17), and 5.82% (n ¼ 17), respectively. The mean SD serum E2 level on the day of hCG trigger in the study cohort was 2,354 754 pg/mL, while the 90th percentile was 3,450 pg/mL. There was a total of 27 (9.2%) patients with EPE2 (>3,450 pg/mL) on the day of hCG administration during COH. No significant difference was found in maternal age, body mass index (BMI), baseline ovarian reserve measures (antral follicle count, day 3 FSH, and E2), type of stimulation protocol, and total dose of gonadotropin 1376
used for COH among the patients with above and below 90th percentile for the peak serum E2 levels threshold (Table 1). The breakdown of causes of infertility among the two groups was not significantly different. There was no statistical significant difference in the rate of ICSI and assisted hatching between the two groups. Additionally, there was no significant difference in the demographic characteristics such as maternal age, BMI, gravidity and parity, baseline ovarian reserve measures, type of stimulation protocol, causes of infertility, and number and day of ET in patients with and without the different adverse obstetrical outcomes of interest. Patients with EPE2 during COH, compared with those with a lower peak serum E2 threshold, demonstrated a statistically significant higher proportion of SGA infants (7 [26.9%] vs. 10 [3.8%]; odds ratio [OR], 95% confidence interval [CI] {9.40, 3.22–27.46}). This OR was unchanged after performing a forward stepwise logistic regression including maternal age, VOL. 97 NO. 6 / JUNE 2012
Fertility and Sterility®
TABLE 1 Baseline characteristics of patients with and without EPE2 on the day of hCG administration after COH for IVF. Peak serum E2 level Variable
£90th percentile (n [ 265)
>90th percentile (n [ 27)
P value
34.8 4.0 24.2 4.0 13 6 7.6 4.9 45.4 26.7
34.0 3.9 23.3 2.7 12 6 7.1 2.0 39.0 14.7
.31 .13 .28 .60 .22
174 (71.6) 37 (15.2) 32 (13.2) 2,544 1,147
19 (79.2) 3 (12.5) 2 (8.3) 2,516 1,089
.71
Maternal age, y BMI, kg/m2 Antral follicle count Basal FSH, U/L Basal E2 level, pg/mL Stimulation protocol (%) Luteal phase GnRH-agonist Follicular phase GnRH-agonist Follicular phase GnRH-antagonist Total dose of Gn administered, IU
.90
Note: The 90th percentile of peak serum E2 level ¼ 3,450 pg/mL. Data expressed in mean SD and number of cases (percentage). Imudia. Peak E2 level predicts adverse obstetric outcomes. Fertil Steril 2012.
BMI, number of embryos transferred, day of ET, and parity in the model. Both EPE2 and total dose of gonadotropin required for COH were associated with the development of PreE. After adjusting for the total dose of gonadotropin and other known confounders such as maternal age and parity with forward stepwise logistic regression, these patients were still more likely to develop PreE (5 [18.5%] vs. 12 [4.5%]; adjusted OR, 95% CI {4.79, 1.55–14.84}). No association was found between EPE2 level and the likelihood for delivery before 37 weeks, 35 weeks, or 32 weeks of gestation (extreme prematurity). A ROC analysis revealed that EPE2 level was able to predict conditions associated with abnormal placentation and placental insufficiency (SGA þ PreE combined) with 38.5% and 91.7% sensitivity and specificity, respectively. AUC was 0.65 (SE, 0.06; 95% CI, 0.53–0.78; P< .01) for the composite obstetrical outcome, 0.62 (SE, 0.07; 95% CI, 0.49–0.74; P< .05) for SGA, and 0.57 (SE, 0.06; 95% CI, 0.45–0.70; P¼ .22) for PreE. Using a serum peak E2 cutoff value of 3,450 pg/mL, the positive predictive value for these conditions was 37%, while the negative predictive value was 92%.
DISCUSSION In this study, the supraphysiologic peri-implantation maternal hormonal milieu unique to COH during IVF was associated with higher odds for delivery of SGA infants and the development of PreE in singleton conception. Specifically, EPE2 (levels >90th percentile) on the day of hCG administration was associated with these findings. Our findings confirm and support the initial report by Farhi et al. (33) demonstrating a potential upstream impact of elevated preconceptional systemic sex steroid concentrations characteristic of ART on downstream events during human pregnancy. These findings carry both scientific and public health importance and may provide further insight into which facets of ART may be responsible for a potential increased prevalence of maternal and fetal perinatal morbidity after elective fertility therapy. The 7.9% and 5.0% overall rate of preterm delivery and preeclampsia in all singleton live births in our institution is VOL. 97 NO. 6 / JUNE 2012
comparable to the 6.85% and 5.82% seen in deliveries resulting from pregnancies achieved through fresh IVF cycles. While these rates are in contrast to the findings of other studies that have demonstrated an increased risk of these perinatal morbidities (4, 9, 10, 13, 17), these data suggest that IVF may not be the sole significant contributor to these conditions in our institution. In light of our findings in patient cycles with EPE2 and the common practice of avoiding fresh ET in patients with peak serum E2 level >4,500 pg/mL on the day of hCG administration at this institution, the beneficial effect of setting a threshold peak E2 level can in retrospect be appreciated. Patients undergoing COH for IVF with EPE2 clearly demonstrated a higher risk of developing disorders related to abnormal placentation. The odds of delivering SGA infants and developing PreE was nine- and five-fold greater, respectively, in these patients as compared with patients with lower levels (<90th percentile threshold) of serum E2. These findings support the hypothesis generated in the landmark study by Kalra et al. (30) that suggested an elevated risk of LBW after COH and fresh ET. E2 has been shown to play a key role in the morphological and functional differentiation of the villous trophoblast as well as the modulation of uteroplacental blood flow that is critical for optimal fetal growth and development in nonhuman primate pregnancies (34–37). It appears that the low levels of E2 exhibited in early gestation as compared with the later part of pregnancy are required to permit normal progression of uterine spiral artery invasion by cytotrophoblast (28). As suggested by our data, the EPE2 level on the day of hCG trigger was associated with SGA and PreE, which may be due to abnormal remodeling of the spiral artery and trophoblast invasion. This mechanism has been shown to be fully operational in the baboon model (28, 29) and may occur in a similar fashion during human gestation. It is also known that the human placentation process is dependent upon both embryonic substances regulating the adhesive and invasive properties of the trophoblast and maternal uterine and immunologic factors, which play permissive and regulatory roles in modulating trophoblast invasion (38). There is also evidence to suggest that some of these interactions are altered in the setting of COH (39–46). 1377
ORIGINAL ARTICLE: EARLY PREGNANCY To this end, a group of investigators have reported a threefold differential expression of more than 200 endometrial genes during implantation in stimulated cycles compared with natural cycles (47). These changes may alter regulatory processes and modify the entire implantation process and may predispose these pregnancies to higher adverse obstetrical outcomes. The predictive accuracy of conditions associated with abnormal placentation (SGA þ PreE) using the EPE2 level during a fresh IVF cycle as a single marker is modest at best, with a specificity of 92% and sensitivity of 38%. Nevertheless, this study shows that there is an association between EPE2 and the odds of adverse pregnancy outcome such as PreE and SGA. Since reasonable pregnancy and live-birth rates can be achieved in patients without extremes of EPE2 during COH, ART providers should be aware of the possible adverse pregnancy outcome associated with supraphysiological E2 levels on the day of hCG administration. It is important to note also that multiple gestation remains the strongest determinant of perinatal morbidity after any ART therapy and should not be underestimated (48). The risk of PTD, delivery of an SGA infant, and the development of PreE are significantly higher in multiple gestations as compared with in singletons (2, 30, 49). Therefore, continued adoption of conservative ET guidelines, including elective single ET in selected patients, may also serve to reduce the rates of multiple pregnancies and promote the increased use of subsequent frozen ET cycles after fresh IVF (30, 50–52). In both instances, the goal to maintain a consistent reduction in the prevalence of common adverse obstetrical outcomes associated with IVF between fresh and frozen cycles may be achieved. Given that patients with peak serum E2 levels >4,500 pg/mL did not have a fresh transfer in our present cohort, it should be stressed that we reported on patients with a very narrow range of high E2 levels (3,450–4,500) in our exposed group. A follow-up study is underway in our institution to compare the obstetrical outcomes of women who had elective cryopreservation of all embryos due to EPE2 with those who underwent a fresh ET. While the findings of this study are novel, the inherent limitations of a retrospective study, with a small sample size from a single institution, are apparent. Therefore, a larger prospective study from other institutions will be needed to confirm the findings of this study. In the interim, the possible effect of EPE2 on the prevalence of SGA and PreE in IVF singleton deliveries is indeed notable and warrants consideration by the clinician as a potential modifiable factor of COH that may provide a means to impact the ultimate pregnancy outcome.
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