Embryonic synergism may reduce pregnancy loss: a multivariate regression analysis

Embryonic synergism may reduce pregnancy loss: a multivariate regression analysis Demián Glujovsky, M.D.,a Mousa I. Shamonki, M.D.,b and Paul A. Bergh, M.D.b a

Centro de Estudios en Ginecología y Reproducción, Ciudad de Buenos Aires, Argentina, and Associates of New Jersey, Morristown, New Jersey

b

Reproductive Medicine

Objective: To evaluate clinical and assisted reproductive technology (ART) cycle variables related to spontaneous embryo reduction. Design: Observational retrospective cohort study. Setting: Private ART center. Patient(s): A total of 3,467 patients achieving a first-trimester pregnancy after IVF. Intervention(s): None. Main Outcome Measure(s): Rate of any spontaneous embryo reduction and rate of spontaneous single embryo reduction. Result(s): Adjusting for all analyzed variables, only initial gestational sac count, age, and body mass index were associated with the spontaneous embryo reduction rate. Twins had a lower chance of having a spontaneous embryo reduction than singletons (odds ratio 0.6, 95% confidence interval 0.50 – 0.79). When only spontaneous single embryo reduction was assessed, women with two or three initial gestational sacs were less prone to have a spontaneous single embryo reduction than women with one initial gestational sac. Conclusion(s): When spontaneous embryo reduction and spontaneous single embryo reduction were evaluated independently of other clinical and ART cycle variables, they were less frequent in twin pregnancies than in singleton pregnancies. This suggests a role for embryonic synergism in sustaining implantation. (Fertil Steril威 2007;87:509 –14. ©2007 by American Society for Reproductive Medicine.) Key Words: Multiple pregnancy, spontaneous abortion, pregnancy reduction, pregnancy outcome, embryonic synergism, spontaneous fetal reduction, in vitro fertilization

The main goal of any assisted reproductive technology (ART) program is for the consulting couple to achieve a take-home baby. In the quest to provide an increased opportunity for sustained pregnancy, multiple embryo transfer continues to be a common practice in many ART clinics (1). Although clinical pregnancy rates have increased dramatically in the last 20 years, early pregnancy loss in ART pregnancies continues to hamper the efficiency of this treatment and impose an increased financial and psychological burden on the couple. In addition, spontaneous embryo reduction continues to serve as a justification for multiple embryo transfer, defined as the transfer of two or more embryos (2). The rate of pregnancy loss after implantation is high in the general population and has been estimated to be between 25% and 40%, with most occurring in the first 12 weeks (3). Most of the previous reports have shown that the miscarriage rate is inversely related to the number of initially implanted gestational sacs (4 – 6). These reports have limited their analysis to initial sacs, age, and intracytoplasmic sperm injection (ICSI), showing loss rates to be independent of ICSI but directly related to oocyte age. Received January 9, 2006; revised and accepted July 26, 2006. Reprint requests: Paul A. Bergh, M.D., Reproductive Medicine Associates of New Jersey, 111 Madison Avenue, Suite 100, Morristown, New Jersey 07960 (FAX: 973-290-8370; E-mail: [email protected]).

0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.07.1518

Tummers et al. (4) showed that total spontaneous abortion risk was 21.1% for single pregnancies and was 5.1% (complete miscarriage) and 12.1% (partial miscarriage) for twins. Although this study did not take into account embryo quality, when the abortion rate per gestational sac was calculated, the difference was statistically significant between singleton and twin pregnancies (21.1% vs. 11.1%, respectively). Embryo quality can influence implantation rates, as demonstrated by the drive toward reduction of multiple pregnancies with use of single embryo transfers. (7, 8). However, when evaluating similarquality embryos, it is not clear whether the environment of the single embryo transfer is comparable with that created when multiple embryos are replaced. The question of embryos facilitating each other’s ability to sustain implantation was recently addressed by Torsky et al. (9). Using a mathematical model, the investigators calculated the probability of embryonic implantation and found a slightly higher actual than calculated multiple pregnancy rate, and suggested that embryonic synergism may account for this difference (9). Matorras et al. (10) also provided similar data to suggest that embryonic synergism may influence sustained implantation. Recently, La Sala et al. (11) showed a lower spontaneous fetal loss rate in twin vs. singleton gestations in women who received the highestquality embryos.

Fertility and Sterility姞 Vol. 87, No. 3, March 2007 Copyright ©2007 American Society for Reproductive Medicine, Published by Elsevier Inc.

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The goal of our analysis was to determine the rate of spontaneous embryo reduction and spontaneous single embryo reduction in an ART patient cohort while controlling for multiple relevant clinical variables. This report presents factors that contribute to spontaneous early pregnancy loss, thus suggesting that embryonic synergism may play a role in sustaining implantation. MATERIALS AND METHODS Patients The Western Institutional Review Board approved the study protocol and waived consent. A retrospective review was performed on data obtained from 3,467 patients between October 1999 and October 2005 undergoing their first cycle of ART in which a clinical pregnancy was established after a fresh-embryo transfer of autologous oocytes at Reproductive Medicine Associates of New Jersey. Participating patients had an IVF or ICSI procedure and had at least one gestational sac seen during a first-trimester ultrasound. First Trimester Pregnancy Follow-Up Transvaginal oocyte retrieval was performed under ultrasound guidance 36 hours subsequent to hCG administration. Embryo transfer was performed at cleavage (day 3) or blastocyst (day 5 or 6) stage. The number of embryos transferred on day 3 typically ranged from one to four, and depended on the patient’s age and prior IVF history. No more than two blastocysts were transferred on day 5 or 6. The decision to perform a day-3 vs. blastocyst transfer depended on the number of high-quality embryos present on day 3 and on whether preimplantation genetic diagnosis had been performed. Generally, blastocyst transfer was performed if there were at least six high-quality embryos on day 3. Preimplantation genetic diagnosis was performed only on day-3 embryos, with results unavailable until day 5. Blastocysts were graded by the degree of expansion, the cellular number and cohesiveness of the inner cell mass, and the cellularity and cohesiveness of the trophectoderm. For day 5 and 6 transfers, one or two blastocysts of the highest quality were transferred, and any remaining high-quality blastocysts were cryopreserved. The luteal phase for study participants was supported with daily intramuscular administration of 50 mg P in oil, tapered through discharge from the clinic. Serum ␤-hCG was checked 14 days after oocyte retrieval, and a level above 5 IU/L was indicative of pregnancy. Clinical pregnancy was documented by transvaginal ultrasound examination (GE Logiq 400 Pro Series, General Electric Company, Pewaukee, Wisconsin) performed 9 days later. These ultrasound examinations were then performed weekly until a missed abortion was diagnosed or until discharge at 8 weeks pregnancy after serial documentation of progressive fetal growth and fetal heart activity. 510

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Clinical and ART Cycle Features Data on the following variables were collected: patient age, presence of uterine anomaly, history of recurrent miscarriage and polycystic ovary syndrome (PCOS), body mass index (BMI), basal antral follicle count, E2 level and endometrial thickness on day of hCG surge, number of oocytes retrieved, method of fertilization (IVF or ICSI), sperm parameters (sperm count, motility, and morphology), day and number of transferred embryos, number of high-quality embryos on day 3 as a measure of embryo quality (12), and availability of embryos for cryopreservation. Uterine anomaly was diagnosed if any of the following were present: Asherman syndrome, endometrial polyps, submucous fibroids, or uterine malformation. History of both recurrent miscarriage and PCOS was considered. Basal antral follicle count was performed on day 3, counting every follicle between 2 and 10 mm in both ovaries. Embryos were cryopreserved if there were any extra high-quality blastocysts available. End Points Maximal gestational sacs during the first trimester and the number of fetal hearts at the time of pregnancy discharge were documented. Spontaneous embryo reduction was designated whenever there was any difference between these two parameters, and spontaneous single embryo reduction was designated whenever this difference was ⫽ 1. Statistics Data were analyzed using the Student’s t test for continuous variables and Mann-Whitney U test for nonparametric variables. An ␹2 analysis was used for categorical variables. Variables associated with embryo reduction in the univariate analysis (the number of maximal gestational sacs, patient age, BMI, day of embryo transfer, number of transferred embryos, and availability of embryos for freezing) were included in a multivariate analysis. Stepwise multiple logistic regression analysis was used to determine the impact of the relevant clinical features on spontaneous embryo reduction for all patients with a multiple pregnancy. Statistical analysis was performed using Stata Statistical Software Release 9 (StataCorp LP, College Station, TX). RESULTS Data on 3,467 pregnant women were analyzed. Patient age ranged from 20 – 45 years; 2,065 patients had a maximum of one gestational sac, 1,165 had two sacs, 205 had three sacs, 30 had four sacs, and 2 had five sacs. Spontaneous embryo reduction was more frequent in women with singleton vs. multiple pregnancies (23.7% vs. 14.0%, respectively, P⬍.05). Embryo reduction attributable to the loss of a single gestational sac (9.7%) (vs. multiple sac loss [4.3%]) was the most common clinical scenario for patients with a multiple pregnancy. The number of fetal hearts at discharge by maximal gestational sacs is shown in Table 1.

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TABLE 1 Spontaneous embryo reduction rate by number of maximal gestational sacs per patient (n total ⴝ 3,467 patients). Number of fetal hearts at discharge

1 GS (%) 2 GS (%) 3 GS (%) 4 GS (%) 5 GS (%) Total (%)

0

1

2

3

4

5

Total

490 (23.73) 49 (4.21) 5 (2.44) 0 0 544 (15.69)

1,575 (76.27) 108 (9.27) 5 (2.44) 0 0 1,688 (48.69)

0 1,008 (86.52) 23 (1.22) 1 (3.33) 0 1,032 (29.77)

0 0 172 (83.90) 4 (13.33) 0 176 (5.08)

0 0 0 25 (83.33) 1 (50.00) 26 (0.75)

0 0 0 0 1 (50.00) 1 (0.03)

2,065 (100.00) 1,165 (100.00) 205 (100.00) 30 (100.00) 2 (100.00) 3,467 (100.00)

Note: GS ⫽ maximal gestational sacs. Glujovsky. Synergism may reduce pregnancy loss. Fertil Steril 2007.

When analyzing clinical features, the numbers of maximal gestational sacs, age, BMI, number and stage of transferred embryos, and availability of embryos for freezing were statistically significantly associated with spontaneous embryo reduction. However, when adjusting for all analyzed parameters, a statistically significant association with embryonic loss was found only for maximal gestational sacs, age, and BMI (Table 2). The following variables were not associated with spontaneous embryo reduction: the presence of a low basal antral follicle count (fewer than 10); the number of oocytes retrieved, mature and fertilized; semen parameters; endometrial thickness; polycystic ovarian syndrome; ICSI; the percentage of high-quality embryos available on day 3; and rates of miscarriage or uterine anomaly.

Twins had a lower chance of spontaneous embryo reduction than singletons (odds ratio [OR] 0.6, 95% confidence interval [CI] 0.48 – 0.75). When only a single gestational sac reduction was evaluated, women with two (OR 0.41, 95% CI 0.32– 0.53) or three (OR 0.49, 95% CI 0.30 – 0.80) gestational sacs were less prone to have a spontaneous single embryo reduction than women with one gestational sac (Table 3). Younger women had a lower incidence of a one-sac loss. The receiver-operating characteristic (ROC) curve of the model has an area under the curve of 0.65 (Fig. 1). The goodness-of-fit test (Hosmer-Lemeshow test, P⫽.12), confirms good calibration performance by showing that no statistically significant difference was found between predicted and observed probabilities in the model.

TABLE 2 Multivariate regression model: variables associated with spontaneous embryo reduction.

Maximal gestational sacs 1 2 3 4 Age ⬍35 y 35–37 y 38–40 y 41–42 y ⬎42 y Body mass index ⱖ28 ⬍28

Odds ratio

95% confidence interval

P

1.0 0.60 0.68 0.43

— 0.48–0.75 0.44–1.06 0.10–1.94

⬍.001 NS NS

1.0 1.60 2.58 3.48 4.47

— 1.25–2.04 1.92–3.48 1.87–6.49 1.79–11.15

⬍.001 ⬍.001 ⬍.001 ⬍.001

1.0 0.79

— 0.63–0.99

.04

Note: This model included all the variables assessed in the univariate analysis. This table shows only those that were independently associated with spontaneous embryo reduction (n ⫽ 2,852). NS ⫽ not significant. Glujovsky. Synergism may reduce pregnancy loss. Fertil Steril 2007.

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TABLE 3 Multivariate regression model: variables associated with a one-sac spontaneous embryo reduction.

Maximal gestational sacs 1 2 3 4 Age ⬍35 y 35–37 y 38–40 y 41–42 y ⬎42 y

Odds ratio

95% confidence interval

P

1.0 0.41 0.49 0.44

— 0.32–0.53 0.30–0.80 0.10–1.94

⬍.001 .005 NS

1.0 1.60 2.41 3.77 4.60

— 1.24–2.06 1.77–3.28 1.95–7.29 1.79–11.85

⬍.001 ⬍.001 ⬍.001 .002

Note: This table shows only those that were independently associated with spontaneous embryo reduction (n ⫽ 2,803). NS ⫽ not significant. Glujovsky. Synergism may reduce pregnancy loss. Fertil Steril 2007.

DISCUSSION Early pregnancy loss is very common in both natural and iatrogenic pregnancies and is of multiple etiologies. In performing a univariate analysis on several clinical variables, a number of parameters were significantly associated with the rate of spontaneous reduction. When adjusting for all analyzed parameters, only age, BMI, and maximum number of gestational sacs were found to be statistically significantly associated with spontaneous embryonic loss. This study showed a significant correlation between increasing maternal age and increased rate of spontaneous

FIGURE 1 Receiver-operating curve of the multivariate logistic regression model for the prediction of spontaneous embryo reduction.

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embryo reduction. It is generally well accepted that age has a substantial influence on rates of pregnancy and pregnancy loss (1, 4, 13–16) Not unexpectedly, an analysis of our study population data showed age as a predictor of spontaneous embryo reduction. Tummers et al. (4) and Dickey et al. (13) reported similar results regarding age and spontaneous loss in multiple pregnancy. La Sala et al. (6) found age to be a significant factor only in IVF pregnancies resulting from conventional fertilization but not in those after ICSI. Interestingly, Ulug et al. (5) failed to show any significant effect of age on loss with multiple pregnancies. Ulug et al. (5) performed a retrospective analysis of 1,448 multiple pregnancies after IVF with ICSI and did not find a significant association between age and loss rate for multiple pregnancies. However, they showed a significantly higher chance of spontaneous reduction to a twin or singleton pregnancy for a triplet pregnancy (11.7%) compared with a quadruplet pregnancy (3.5%). Our analysis shows a direct relationship between increasing BMI and spontaneous embryo reduction. Maternal obesity has a significant effect on the entire cycle of reproduction, from altered oocyte development (17–19) to adverse maternal and fetal outcomes at delivery (20). Research examining the effect of BMI on early pregnancy loss has been inconsistent. Increasing BMI has been associated with miscarriage in natural conception (21) as well as in pregnancies resulting from IVF and ICSI cycles (22–25). Not all studies have shown a link between BMI and pregnancy loss (26, 27). The mechanism by which obesity may affect implantation and miscarriage may be related to altered oocyte/embryo quality, altered endometrial receptivity, or both. A few recent studies have examined the effect of BMI on pregnancy rate and spontaneous embryo reduction rate by studying the oocyte donation model (28 –31). All but

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one of those studies showed no association between BMI of the embryo recipients, pregnancy, and spontaneous embryo reduction rates, suggesting that BMI does not affect endometrial receptivity, but rather BMI affects oocyte quality secondary to an altered hormonal milieu in the obese patient (28). This study presents a comprehensive analysis showing the influence of several clinical variables on spontaneous embryo reduction. Others have also shown that there is reduced chance of embryo loss with a multiple pregnancy but have limited their analysis to the number of initial sacs, maternal age, and method of fertilization. An analysis of 1,597 clinical pregnancies from IVF and ICSI found a significantly higher risk of abortion per gestational sac for singleton pregnancies when compared with twins (4). In this study, the only additional parameter analyzed was maternal age. Although we found a higher loss rate with increased age, when controlling for maternal age, an increased spontaneous embryo reduction rate between twins and singletons persisted. The investigators point out that with IVF, the higher-than-expected rate of multiple pregnancies indicates that the probability of implantation is not independent. They suggest that the unexpected higher implantation rate and lower loss rate of multiple pregnancies may be caused by differences in the quality of the original embryo cohort. The data did not show a difference in spontaneous embryo reduction between ICSI and conventional IVF cycles. A retrospective analysis of 1,076 clinical pregnancies from ART cycles with and without ICSI was reported by La Sala et al. (6). The investigators found that the rate of spontaneous embryo reduction was unrelated to mode of conception; i.e., conventional IVF vs. ICSI; however, there was an agerelated increased risk of loss only in the former group. Their data describing an increased risk for loss in a singleton vs. twin pregnancy corroborated the report from Tummers et al. (4), and also extended this finding to triplet and quadruplet pregnancies. The investigators speculate that these results may be caused by an improved capacity of the uterus during multiple pregnancy to support pregnancy and/or better embryo quality; however, factors were not specifically analyzed. Our data indicate that twin pregnancies have a lower chance of spontaneous embryo reduction than singletons. This difference is not explained by age, uterine disease, recurrent loss, PCOS, male factor, embryologic parameters, embryo stage at transfer, or embryo quality and quantity. This was also true for both twins and triplets in comparison with singleton pregnancies when analyzing the outcome of spontaneous single embryo reduction. These data provide evidence that the implantation of more than one sac may enhance the chance of sustained pregnancy, namely embryo synergism. Two recent studies have addressed the concept of embryonic synergism by creating mathematical models that predict implantation potential and comparing predicted with actual Fertility and Sterility姞

outcomes (9, 10). These mathematical models assume that the implantation rate per embryo is an independent event, and hence that each embryo does not affect the other. However, both studies found higher actual percentages of twins and triplets, greater than predicted by their mathematical models. The investigators’ reasoning for these discrepancies was that embryonic synergism likely plays a role in implantation, and therefore implantation may occur independently from embryo to embryo. Matorras et al. (10) estimated that the implantation probability is increased by 22% for each embryo additionally implanted. The concept of embryonic synergism may also account for the lower risk of spontaneous loss seen for multiples in our study. Embryonic synergism may not only improve the local environment for implantation, but may also promote a more favorable environment for embryonic maintenance and growth. Certainly, embryos with higher implantation potential can inherently have a lower risk for miscarriage simply because of being embryos of better quality. Therefore, if all variables were equal, a patient who conceives with at least a twin gestation more likely has embryos with a greater implantation potential and a lower likelihood of loss. This hypothesis may at least partially account for the differences in spontaneous embryo reduction found in this study. Univariate analysis supports this hypothesis by showing a decreased spontaneous embryo reduction rate with blastocyst transfer and availability of embryos for cryopreservation, but does not account for confounding variables. When using multivariate analysis, there were no differences noted between groups with regard to predictors of implantation, including number of high-quality embryos on day 3 as well as blastocyst transfer and cryopreservation potential. Therefore, if higher implantation potential rather than embryo synergism were to account for the differences in spontaneous embryo reduction, current methods of embryonic assessment are unable to detect these potential predictors of implantation. Furthermore, this study cannot account for subtle physical or biochemical endometrial factors that may account for differences in implantation, although endometrial thickness or character did not differ among groups. Our study shows a significantly reduced likelihood of fetal loss when patients conceived with multiple gestations rather than a singleton and suggests the action of embryonic synergism as a plausible explanation for this discrepancy. Embryonic synergism may further complicate our patient counseling and decisions on how many embryos to replace at the time of embryo transfer. Thurin et al. (7, 8) have shown that single embryo transfer of quality embryos in patients with a good prognosis can produce acceptable cumulative pregnancy rates with a negligible number of multiples. However, these studies did not address embryonic loss in this setting. As previous studies and our data suggest, the intrauterine environment resulting from a single embryo transfer may change when multiple embryos implant. Thus, as we continue to strive to reduce multiple pregnancies, the expectation for sustained pregnancy with single embryo 513

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