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Obstetric and perinatal outcomes of pregnancy in patients with repeated implantation failure
Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 487e491
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Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Original Article
Obstetric and perinatal outcomes of pregnancy in patients with repeated implantation failure Tzu Hsuan Chin, Ya Chiung Hsu, Yung Kuei Soong, Chyi Long Lee, Hsin Shih Wang, Hong Yuan Huang, Hsien Ming Wu, Hsing Tse Yu, Shang Yu Huang, Chia Lin Chang* Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, 5 Fu-Shin Street, Kweishan, Taoyuan, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 15 March 2019
Objective: Despite the great advance of assisted reproductive technology (ART) in recent decades, many IVF patients failed to achieve a pregnancy even after multiple IVF-ET attempts. These patients are considered to have repeated implantation failure (RIF). While exhausting efforts have been devoted to the improvement of pregnancy rate in RIF patients, it is not clear whether RIF patients have aberrant obstetric or perinatal outcomes after they eventually achieved a pregnancy. Materials and methods: Taking advantage of a relatively large database of IVF-ET cycles at the Chang Gung Memorial Hospital, we compared obstetric and perinatal outcomes of RIF patients who have a successful pregnancy after IVF-ET treatment(s) to those of control IVF-ET patients. Results: Because multiple pregnancies are associated with a high risk of obstetric complications, we restricted the analysis to patients who had singleton pregnancies. Analysis of a total of 596 control and 46 RIF cases showed the rates of almost all obstetric and perinatal outcomes investigated are not different between the two groups. However, the rate of placental abruption in the RIF group (4.35%) appeared to be significantly higher than that of controls (0.50%; OR ¼ 8.99). This difference is still statistically significant after adjustment with the age (adjusted OR ¼ 8.2). Conclusion: While the rates of a spectrum of obstetric and perinatal outcomes are normal in RIF patients, these patients could have an enhanced risk of placental abruption. However, investigations with a large sample size are needed to substantiate this inference. © 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: RIF Repeated implantation failure Placental abruption IVF Embryo transfer
Introduction Owing to advances in the last three decades, the pregnancy rate of IVF-ET patients could be up to 60% in young couples [1,2]. Still, many couples failed to achieve a pregnancy after multiple attempts of IVF-ET. These cases were referred to as repeated implantation failure (RIF). Although there is no official definition/criteria for this condition, women who fail to achieve clinical pregnancy after three IVF-ET cycles or receiving at least four high-quality embryo transfers were considered to be RIF [3,4]. While the RIF condition has been associated with high sperm DNA fragmentation [5], cytogenetic abnormalities, uterine etiologies, immunological disturbance [6], hormonal and metabolic disorders [7], and/or inherited
* Corresponding author. Fax: þ886 33288252. E-mail addresses: [email protected] (T.H. (C.L. Chang).
Chin),
[email protected]
thrombophilias [8e10], the exact causes of most RIF cases remain to be vetted. As such, RIF has become one of the most difficult issues facing IVF-ET practitioners. In the last two decades, a number of procedures, including the administration of endometrium scratching before embryo transfer [11], high-dose progesterone support [12], TNF-a antagonist [13], granulocyte colony-stimulating factor (G-CSF) [14], hydroxychloroquine [15], or intravenous immunoglobulin supplement [16,17], have been devised to improve pregnancy rate in RIF patients. While evidences are limited, these interventions have been shown to improve implantation rate in RIF patients, and led to the delivery of live birth in some patients. On the other hand, few studies have investigated obstetric and perinatal outcomes in RIF patients after they achieved a successful pregnancy. Because pregnancies after IVF are associated with a high risk of obstetric and perinatal complications [18e22], we hypothesized that RIF patients could have a high risk of obstetric and perinatal
https://doi.org/10.1016/j.tjog.2019.05.010 1028-4559/© 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
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complications when compared to control IVF-ET patients. Taking advantage of a relatively large database of IVF-ET cycles at the Chang Gung Memorial Hospital, we conducted a retrospective study to compare obstetric and perinatal outcomes between control and RIF patients who achieved a successful pregnancy after IVFET treatment(s). Because multiple births resulting from an IVF-ET are associated with a high risk of obstetric complications [23e25], we limited the analysis to patients with singleton pregnancies. Of importance, we found that the rate of placental abruption in RIF patients could be higher than that of control IVF-ET patients, suggesting obstetricians may need to provide a more individualized antenatal care for RIF patients. Materials and methods Ethics approval The retrospective study was carried out based on the analysis of medical records collected at the Chang Gung Memorial Hospital. It was approved by the Ethics Committee Board of the Chang Gung Medical Foundation per study No. 201701281B0. Data collection Data from a total of 4705 women who received embryo transfer(s), including 3272 fresh and 1433 frozen-thawed cycles, at Chang Gung Memorial Hospital Infertility Center from January 2010 to December 2016 were collected (Fig. 1). A total of 1834 women achieved clinical pregnancies presented with intrauterine gestational sac. Among them, 217 pregnancies ended with blighted ovum; 555 were twin or triplet pregnancies; and 5 lost followups. A total of 1057 singleton pregnancies, which led to 950 successful deliveries after the 20th week of gestation, were eligible for the analysis (Fig. 1). After excluding cases which involved oocyte or sperm recipients (14 cases), pre-implantation genetic diagnosis (i.e., chromosomal or single genetic abnormality, 12 cases), or loss of obstetrical records (282 cases), a total of 642 pregnancy records were included in the analysis of obstetric and perinatal outcomes. Patients' clinical characteristics, including age, BMI, body weight, body height, nulliparity, transfer at the cleavage stage, transfer at the blastocyst stage, fresh cycle transfer, frozen cycle transfer, incidences of diabetes mellitus, hypertension, and thyroid disorder, and the indications for IVF treatment (i.e., male factor, ovulatory factor, diminished ovarian reserve, tubal factor, uterine factor, endometriosis, and unexplained factor) were presented in Table 1. We defined implantation failure as cases who fail to achieve a visible intrauterine gestational sac after embryo transfer regardless whether the transfer used fresh or frozen-thawed embryos. Major obstetric complications included preeclampsia, pregnancy-induced hypertension (PIH), gestational diabetes mellitus (GDM), abnormal placentation (placenta previa and accreta), placental abruption, preterm labor (PTL), preterm premature rupture of the membranes (PPROM), malpresentation, fetal distress, stillbirth, and fetal anomaly. Measurements of perinatal outcomes included incidences of preterm birth (delivered at age <37 weeks), very preterm birth (delivered at age <32 weeks), Cesarean section, and Cesarean section resulted from fetal distress, as well as Apgar scores at 1 and 5 min, fetal body weight, and placental weight. The 642 patients with singleton deliveries were divided into the RIF and the control groups based on the number of prior implantation failures. The RIF group included women who experienced 3 times of prior implantation failure, and the control group patients experienced <3 times of implantation failure. Depending on the
Fig. 1. Flow chart of clinical data collection FHB: Fetal heart beat; IF: Implantation failure.
embryo stage, embryo quality was scored according to the Gardner grading system [26] or the Veeck system [27].
Table 1 Maternal characteristics of patients in the control and repeated implantation failure (RIF) groups.
Age (Mean ± SEM) BMI (Mean ± SEM) Body weight (Mean ± SEM, kg) Body height (Mean ± SEM, cm) Nulliparity Transfer at the cleavage stage Transfer at the blastocyst stage Fresh cycle transfer Frozen cycle transfer Systemic Diseases DMa HTNa Thyroid disorder Indications for IVF treatment Male factor Ovulatory factor Diminished ovarian reserve Tubal factor Uterine factor Endometriosis Unexplained factor a
Control (N ¼ 596)
RIF (N ¼ 46)
P value
34.82 ± 0.15 (22e44) 22.23 ± 0.14 57.05 ± 0.39 160.1 ± 0.21 469 (78.69%) 300 (50.34%) 296 (49.66%) 438 (73.49%) 158 (26.51%)
37.22 ± 0.45 (27e43) 22.2 ± 0.38 56.37 ± 1.07 159.3 ± 0.76 31 (67.39%) 21 (45.65%) 25 (54.35%) 25 (54.35%) 21 (45.65%)
<0.0001 NS NS NS NS NS NS 0.0095 0.0095
6 (1.01%) 5 (0.84%) 17 (2.85%)
0 1 (2.17%) 3 (6.52%)
NS NS NS
208 (34.90%) 315 (52.85%) 10 (1.68%) 144 (24.16%) 68 (11.41%) 18 (3.02%) 51 (8.56%)
14 (30.43%) 30 (65.22%) 2 (4.35%) 11 (23.91%) 6 (13.04%) 3 (6.52%) 2 (4.35%)
NS NS NS NS NS NS NS
DM: diabetes mellitus, HTN: hypertension, NS: not significant.
T.H. Chin et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 487e491
Statistical analysis Fetal body weight and placental weight of newborns as well as maternal characteristics were analyzed by the ManneWhitney U test. Parity number, the embryo stage at transfer, the type of transfer cycle (i.e., fresh or frozen-thawed transfer cycle), and indications for IVF treatment were analyzed by the Fisher's exact test. Obstetric outcome measurements were analyzed by the Fisher's exact test, two-sided, and adjusted with binary logistic regression test. GraphPad PRISM 7.0d and SPSS Statistics version 25.0 were used to determine statistical significance, which was defined as a p value <0.05. Results Maternal characteristics and obstetric complications Data from a total of 642 singleton pregnancies delivered after the 20th weeks of gestation were recorded (Fig. 1). Among them, 46 cases belong to the RIF group, and the rest (i.e., 596 cases) are control cases. Among controls, 183 cases experienced 1 implantation failure, and 413 cases had successful implantation after the first IVF-ET. The average age of control and RIF patients was 34.82 ± 0.15 (22e44) and 37.22 ± 0.45 (27e43) years old, respectively. For the control and RIF groups, 73.49% and 54.35% of successful cycles had fresh-embryo transfers, respectively. There were no significant differences in BMI, body weight, body height, the number of parity, the embryo stage at transfer, and the indications for IVF treatment between the two groups (Table 1). Recorded obstetric complications included preeclampsia (N ¼ 22, 3.43% of the overall population), pregnancy-induced hypertension (PIH, N ¼ 23, 3.58%), gestational diabetes (GDM, N ¼ 30, 4.67%), abnormal placentation (N ¼ 39, 6.07%), placental abruption (N ¼ 5, 0.78%), preterm labor (PTL, N ¼ 60, 9.35%), PPROM (N ¼ 39, 6.07%), malpresentation (N ¼ 67, 10.44%), fetal distress (N ¼ 44, 6.85%), stillbirth (N ¼ 6, 0.93%), and congenital anomalies (N ¼ 17, 2.65%) (Table 2). Among the 17 births with congenital anomalies, 12 cases ended with termination (Supplemental Table 1). Rates of obstetric complications, including preeclampsia, PIH, GDM, abnormal placentation, PTL, PPROM, malpresentation, fetal distress and stillbirth, were not statistically different between the two groups (Table 2). On the other hand, 4.35% of RIF patients had placental abruption (2 out of 46), which was significantly higher than that of the control group (0.50%, 3 out of 596). The odds ratio was 8.99 (95% CI ¼ 1.55e44.59, p <0.05). Because there was a significant difference in the age of control and RIF populations, we calculated the odds ratio with adjustment of the age. The adjusted odds ration remained statistically significant (adjusted odds ratio ¼ 8.2, 95% CI ¼ 1.21e55.43, p < 0.05). The five placental
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abruption cases resulted in two stillbirths; one was at 21 weeks of gestation in the control group, and the other was at 36 weeks of gestation in the RIF group. Perinatal outcomes To compare the perinatal outcomes, we excluded cases with early terminations (i.e., pregnancies terminated at 24 weeks of gestations due to poor perinatal prognosis such as the occurrence of congenital lethal fetal anomaly or PPROM). Analysis of data from a total of 574 newborns of control patients and 46 newborns of RIF patients showed that there is no difference in the rates of preterm birth (delivered at <37 weeks), very preterm birth (delivered at <32 weeks), Cesarean section, and the Apgar score at birth between the RIF and control groups (Table 3). Likewise, the average fetal body weight of newborns (3145 ± 18 g [control] versus 3182 ± 65 g [RIF], p ¼ 0.468) and the average placental weight (696 ± 6 g [control] versus 731 ± 24 g [RIF], p ¼ 0.158) were similar in the two groups (Table 3). Discussion Analysis of a cohort of IVF-ET patients who achieved singleton pregnancies showed that, except for the rate of placental abruption, other obstetric and perinatal outcomes in RIF patients are similar to those of control IVF-ET patients, suggesting that RIF patients do not suffer obvious adverse outcomes when compared to controls. Still, the analysis raises the possibility that RIF patients could have an enhanced risk of placental abruption. Because RIF could comprise a spectrum of heterogeneous etiologies and because the sample size in the present study is relatively small, future studies with a large cohort of RIF patients are needed to affirm this observation. It is well recognized that the implantation rate in RIF patients is twenty-fold lower than that of non-RIF patients [28]. In the last two decades, surgical and pharmacological methods, including transcutaneous electrical acupoint stimulation (TEAS) [29], hysteroscopic injury [30], short-term copper intrauterine device placement [31], use of immunomodulatory drugs (e.g., IVIG and glucocorticoids) [16,17,32], intrauterine instillation of G-CSF [33], and administration of autologous peripheral blood mononuclear cells [34] or platelet-rich plasma [35,36], as well as the use of endometrial receptivity array for predicting the optimal implantation window [37], have been developed to improve pregnancy outcomes in RIF patients. In addition, a study based on eight RIF cases reported in 2015 that obstetric complications of RIF patients are similar to those of non-RIF patients [38]. Except for the observation of an enhanced risk of placental abruption in RIF patients, our results are consistent with that of the prior report.
Table 2 Rates of obstetric complications in control and repeated implantation failure (RIF) patients. Complications
Total (N ¼ 642)
Control (N ¼ 596)
RIF (N ¼ 46)
Odds ratio (95% CI)
Adjusted odds ratio (95% CI)
Preeclampsia PIHa GDMa Abnormal placentation Placental abruption PTLa PPROMa Malpresentation Fetal distress Stillbirth Anomaly
22 (3.43%) 23 (3.58%) 30 (4.67%) 39 (6.07%) 5 (0.78%) 60 (9.35%) 39 (6.07%) 67 (10.44%) 44 (6.85%) 6 (0.93%) 17 (2.65%)
21 (3.52%) 23 (3.86%) 28 (4.70%) 36 (6.04%) 3 (0.50%) 56 (9.40%) 36 (6.04%) 61 (10.23%) 42 (7.05%) 5 (0.84%) 17 (2.85%)
1 0 2 3 2 4 3 6 2 1 0
0.61 e 0.92 1.09 8.99 0.92 1.09 1.32 0.60 2.63 e
0.53 e 1.27 0.99 8.20 0.29 1.11 1.36 0.61 1.81 e
(2.17%) (4.35%) (6.52%) (4.35%) (8.7%) (6.52%) (13.04%) (4.35%) (2.17%)
(0.06e3.51) (0.21e3.52) (0.34e3.44) (1.55e44.59)* (0.34e2.56) (0.34e3.44) (0.57e3.21) (0.14e2.18) (0.22e19.78)
*P value < 0.05. a PIH: pregnancy induced hypertension, GDM: gestational diabetes, PTL: preterm labor, PPROM: preterm premature rupture of membranes.
(0.07e4.13) (0.36e4.44) (0.29e3.41) (1.21e55.43)* (0.28e2.43) (0.32e3.83) (0.55e3.40) (0.14e2.64) (0.20e16.67)
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Table 3 Perinatal outcomes of the control and repeated implantation failure (RIF) groups. Outcomes
Total (N ¼ 620)
Control (N ¼ 574)
RIF (N ¼ 46)
Odds ratio (95% CI)
Adjusted odds ratio (95% CI)
Term Delivery at <37 weeks Delivery at <32 weeks C/Sa rate C/Sa due to fetal distress Apgar score &7 at 1 min at term Apgar score &7 at 5 min at term FBWa at term (Mean ± SEM) Placental weight at term (Mean ± SEM)
523/620 (84.35%) 97/620 (15.65%) 8/620 (1.29%) 310/620 (50%) 41/620 (6.61%) 16/523 (3.06%)
486/574 (84.67%) 88/574 (15.33%) 8/574 (1.39%) 289/574 (50.35%) 40/574 (6.97%) 15/486 (3.09%)
37/46 (80.43%) 9/46 (19.57%) 0 21/46 (45.65%) 1/46 (2.17%) 1/37 (2.7%)
e 1.34 e 0.83 0.30 0.87
e 1.07 e 0.72 0.32 0.85
3/523 (0.57%)
3/486 (0.62%)
0
e
3147 ± 17 698 ± 6
3145 ± 18 696 ± 6
3182 ± 65 731 ± 24
P ¼ 0.468 P ¼ 0.158
a
(0.62e2.88) (0.46e1.54) (0.03e1.77) (0.08e5.55)
(0.50e2.31) (0.39e1.34) (0.04e2.43) (0.25e2.86)
e
C/S: Cesarean section, FBW: fetal body weight.
Even though conflicting results have been reported, assisted reproductive technology (ART) pregnancies are generally associated with an enhanced risk of adverse obstetric outcomes, including hypertensive disorders, GDM, placenta previa, preterm rupture of membranes, preterm delivery, small for gestational age, antepartum hemorrhage, and placental abruption [18,20,21,39e41]. In addition, IVF-ET in aged women had an increased risk of placenta previa [42] and a decreased live-birth rate as the number of prior failed IVF treatment cycle increased [43]. Accordingly, we hypothesized that RIF could negatively impact obstetric and perinatal outcomes. Because multiple births resulting from IVF-ET are associated with a high risk of obstetric complications, including perinatal mortality [23], preterm delivery [24], first-trimester bleeding, and GDM [25], and because the maternal age is a risk factor for small for gestational age, placenta previa, placental abruption, a high Cesarean section rate, and preterm birth [42,44,45], we restricted the analysis to those with singleton pregnancy, and adjusted the odds ratio analysis with the age. The results showed the rate of placental abruption in the overall population (0.78%; 5 out of 642 cases) is similar to reported rates in the general population after ART treatment (i.e., 0.9%) [46,47]; however, RIF patients could have an enhanced risk of placental abruption. Nonetheless, the conclusion needs to be taken with caution because only two cases of RIF patients had placental abruption. Earlier studies have suggested that some RIF cases could be associated with (1) sperm DNA fragmentation, (2) unsynchronized endometrium receptivity, and (3) thrombophilic factors such as mutations in prothrombin, factor V Leiden, or methylene tetrahydrofolate reductase (MTHFR), and/or deficiency of protein C, protein S and antithrombin III [48]. In addition, because placental abruption and RIF share multiple risk factors such as antiphospholipid syndrome (APS), factor V Leiden mutation, hyperhomocysteinemia, and prothrombin mutation [49e53], the enhanced risk of placental abruption in RIF patients may be associated with some of these shared risk factors. Because placental abruption could lead to serious obstetric morbidity and perinatal death (up to 12.9%) [54], early detection of placental abruption may improve pregnancy outcomes. Accordingly, measurement of maternal serum alpha-fetoprotein in the second-trimester [55,56], and mean platelet volume and platelet distribution width [57] as well as Doppler study at the 20th weeks of gestation [58], have been developed for early detection of placental abruption. As such, these methods may also be useful for the prediction of placental abruption during antenatal care of RIF patients. Funding/Support statement Not applicable.
Conflict of interests The authors declare that they have no conflict of interest. Acknowledgements We thank Mei Li Wang, Chieh Yu Lin, Chia Jung Li, and Chiung Hui Hou (Chang Gung Memorial Hospital) for technical assistance. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tjog.2019.05.010. References [1] Margalioth EJ, Ben-Chetrit A, Gal M, Eldar-Geva T. Investigation and treatment of repeated implantation failure following IVF-ET. Hum Reprod 2006;21(12): 3036e43. [2] Rinehart J. Recurrent implantation failure: definition. J Assist Reprod Genet 2007;24(7):284e7. [3] Coughlan C, Ledger W, Wang Q, Liu F, Demirol A, Gurgan T, et al. Recurrent implantation failure: definition and management. Reprod Biomed Online 2014;28(1):14e38. [4] Tan BK, Vandekerckhove P, Kennedy R, Keay SD. Investigation and current management of recurrent IVF treatment failure in the UK. BJOG 2005;112(6): 773e80. [5] Collins JA, Barnhart KT, Schlegel PN. Do sperm DNA integrity tests predict pregnancy with in vitro fertilization? Fertil Steril 2008;89(4):823e31. [6] Liang PY, Diao LH, Huang CY, Lian RC, Chen X, Li GG, et al. The pro-inflammatory and anti-inflammatory cytokine profile in peripheral blood of women with recurrent implantation failure. Reprod Biomed Online 2015;31(6): 823e6. [7] RoyChoudhury S, Singh A, Gupta NJ, Srivastava S, Joshi MV, Chakravarty B, et al. Repeated implantation failure versus repeated implantation success: discrimination at a metabolomic level. Hum Reprod 2016;31(6):1265e74. [8] Bellver J, Soares SR, Alvarez C, Munoz E, Ramirez A, Rubio C, et al. The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion. Hum Reprod 2008;23(2): 278e84. [9] Martinez-Zamora MA, Creus M, Tassies D, Reverter JC, Civico S, Carmona F, et al. Reduced plasma fibrinolytic potential in patients with recurrent implantation failure after IVF and embryo transfer. Hum Reprod 2011;26(3): 510e6. [10] Khosravi F, Zarei S, Ahmadvand N, Akbarzadeh-Pasha Z, Savadi E, Zarnani AH, et al. Association between plasminogen activator inhibitor 1 gene mutation and different subgroups of recurrent miscarriage and implantation failure. J Assist Reprod Genet 2014;31(1):121e4. [11] Potdar N, Gelbaya T, Nardo LG. Endometrial injury to overcome recurrent embryo implantation failure: a systematic review and meta-analysis. Reprod Biomed Online 2012;25(6):561e71. [12] Nardo LG, Sallam HN. Progesterone supplementation to prevent recurrent miscarriage and to reduce implantation failure in assisted reproduction cycles. Reprod Biomed Online 2006;13(1):47e57. [13] Winger EE, Reed JL, Ashoush S, El-Toukhy T, Taranissi M. Die-off ratio correlates with increased TNF-alpha: IL-10 ratio and decreased IVF success rates correctable with humira. Am J Reprod Immunol 2012;68(5):428e37. [14] Santjohanser C, Knieper C, Franz C, Hirv K, Meri O, Schleyer M, et al. Granulocyte-colony stimulating factor as treatment option in patients with recurrent miscarriage. Arch Immunol Ther Exp (Warsz) 2013;61(2):159e64.
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Original Article
Obstetric and perinatal outcomes of pregnancy in patients with repeated implantation failure Tzu Hsuan Chin, Ya Chiung Hsu, Yung Kuei Soong, Chyi Long Lee, Hsin Shih Wang, Hong Yuan Huang, Hsien Ming Wu, Hsing Tse Yu, Shang Yu Huang, Chia Lin Chang* Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, 5 Fu-Shin Street, Kweishan, Taoyuan, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 15 March 2019
Objective: Despite the great advance of assisted reproductive technology (ART) in recent decades, many IVF patients failed to achieve a pregnancy even after multiple IVF-ET attempts. These patients are considered to have repeated implantation failure (RIF). While exhausting efforts have been devoted to the improvement of pregnancy rate in RIF patients, it is not clear whether RIF patients have aberrant obstetric or perinatal outcomes after they eventually achieved a pregnancy. Materials and methods: Taking advantage of a relatively large database of IVF-ET cycles at the Chang Gung Memorial Hospital, we compared obstetric and perinatal outcomes of RIF patients who have a successful pregnancy after IVF-ET treatment(s) to those of control IVF-ET patients. Results: Because multiple pregnancies are associated with a high risk of obstetric complications, we restricted the analysis to patients who had singleton pregnancies. Analysis of a total of 596 control and 46 RIF cases showed the rates of almost all obstetric and perinatal outcomes investigated are not different between the two groups. However, the rate of placental abruption in the RIF group (4.35%) appeared to be significantly higher than that of controls (0.50%; OR ¼ 8.99). This difference is still statistically significant after adjustment with the age (adjusted OR ¼ 8.2). Conclusion: While the rates of a spectrum of obstetric and perinatal outcomes are normal in RIF patients, these patients could have an enhanced risk of placental abruption. However, investigations with a large sample size are needed to substantiate this inference. © 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: RIF Repeated implantation failure Placental abruption IVF Embryo transfer
Introduction Owing to advances in the last three decades, the pregnancy rate of IVF-ET patients could be up to 60% in young couples [1,2]. Still, many couples failed to achieve a pregnancy after multiple attempts of IVF-ET. These cases were referred to as repeated implantation failure (RIF). Although there is no official definition/criteria for this condition, women who fail to achieve clinical pregnancy after three IVF-ET cycles or receiving at least four high-quality embryo transfers were considered to be RIF [3,4]. While the RIF condition has been associated with high sperm DNA fragmentation [5], cytogenetic abnormalities, uterine etiologies, immunological disturbance [6], hormonal and metabolic disorders [7], and/or inherited
* Corresponding author. Fax: þ886 33288252. E-mail addresses: [email protected] (T.H. (C.L. Chang).
Chin),
[email protected]
thrombophilias [8e10], the exact causes of most RIF cases remain to be vetted. As such, RIF has become one of the most difficult issues facing IVF-ET practitioners. In the last two decades, a number of procedures, including the administration of endometrium scratching before embryo transfer [11], high-dose progesterone support [12], TNF-a antagonist [13], granulocyte colony-stimulating factor (G-CSF) [14], hydroxychloroquine [15], or intravenous immunoglobulin supplement [16,17], have been devised to improve pregnancy rate in RIF patients. While evidences are limited, these interventions have been shown to improve implantation rate in RIF patients, and led to the delivery of live birth in some patients. On the other hand, few studies have investigated obstetric and perinatal outcomes in RIF patients after they achieved a successful pregnancy. Because pregnancies after IVF are associated with a high risk of obstetric and perinatal complications [18e22], we hypothesized that RIF patients could have a high risk of obstetric and perinatal
https://doi.org/10.1016/j.tjog.2019.05.010 1028-4559/© 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
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complications when compared to control IVF-ET patients. Taking advantage of a relatively large database of IVF-ET cycles at the Chang Gung Memorial Hospital, we conducted a retrospective study to compare obstetric and perinatal outcomes between control and RIF patients who achieved a successful pregnancy after IVFET treatment(s). Because multiple births resulting from an IVF-ET are associated with a high risk of obstetric complications [23e25], we limited the analysis to patients with singleton pregnancies. Of importance, we found that the rate of placental abruption in RIF patients could be higher than that of control IVF-ET patients, suggesting obstetricians may need to provide a more individualized antenatal care for RIF patients. Materials and methods Ethics approval The retrospective study was carried out based on the analysis of medical records collected at the Chang Gung Memorial Hospital. It was approved by the Ethics Committee Board of the Chang Gung Medical Foundation per study No. 201701281B0. Data collection Data from a total of 4705 women who received embryo transfer(s), including 3272 fresh and 1433 frozen-thawed cycles, at Chang Gung Memorial Hospital Infertility Center from January 2010 to December 2016 were collected (Fig. 1). A total of 1834 women achieved clinical pregnancies presented with intrauterine gestational sac. Among them, 217 pregnancies ended with blighted ovum; 555 were twin or triplet pregnancies; and 5 lost followups. A total of 1057 singleton pregnancies, which led to 950 successful deliveries after the 20th week of gestation, were eligible for the analysis (Fig. 1). After excluding cases which involved oocyte or sperm recipients (14 cases), pre-implantation genetic diagnosis (i.e., chromosomal or single genetic abnormality, 12 cases), or loss of obstetrical records (282 cases), a total of 642 pregnancy records were included in the analysis of obstetric and perinatal outcomes. Patients' clinical characteristics, including age, BMI, body weight, body height, nulliparity, transfer at the cleavage stage, transfer at the blastocyst stage, fresh cycle transfer, frozen cycle transfer, incidences of diabetes mellitus, hypertension, and thyroid disorder, and the indications for IVF treatment (i.e., male factor, ovulatory factor, diminished ovarian reserve, tubal factor, uterine factor, endometriosis, and unexplained factor) were presented in Table 1. We defined implantation failure as cases who fail to achieve a visible intrauterine gestational sac after embryo transfer regardless whether the transfer used fresh or frozen-thawed embryos. Major obstetric complications included preeclampsia, pregnancy-induced hypertension (PIH), gestational diabetes mellitus (GDM), abnormal placentation (placenta previa and accreta), placental abruption, preterm labor (PTL), preterm premature rupture of the membranes (PPROM), malpresentation, fetal distress, stillbirth, and fetal anomaly. Measurements of perinatal outcomes included incidences of preterm birth (delivered at age <37 weeks), very preterm birth (delivered at age <32 weeks), Cesarean section, and Cesarean section resulted from fetal distress, as well as Apgar scores at 1 and 5 min, fetal body weight, and placental weight. The 642 patients with singleton deliveries were divided into the RIF and the control groups based on the number of prior implantation failures. The RIF group included women who experienced 3 times of prior implantation failure, and the control group patients experienced <3 times of implantation failure. Depending on the
Fig. 1. Flow chart of clinical data collection FHB: Fetal heart beat; IF: Implantation failure.
embryo stage, embryo quality was scored according to the Gardner grading system [26] or the Veeck system [27].
Table 1 Maternal characteristics of patients in the control and repeated implantation failure (RIF) groups.
Age (Mean ± SEM) BMI (Mean ± SEM) Body weight (Mean ± SEM, kg) Body height (Mean ± SEM, cm) Nulliparity Transfer at the cleavage stage Transfer at the blastocyst stage Fresh cycle transfer Frozen cycle transfer Systemic Diseases DMa HTNa Thyroid disorder Indications for IVF treatment Male factor Ovulatory factor Diminished ovarian reserve Tubal factor Uterine factor Endometriosis Unexplained factor a
Control (N ¼ 596)
RIF (N ¼ 46)
P value
34.82 ± 0.15 (22e44) 22.23 ± 0.14 57.05 ± 0.39 160.1 ± 0.21 469 (78.69%) 300 (50.34%) 296 (49.66%) 438 (73.49%) 158 (26.51%)
37.22 ± 0.45 (27e43) 22.2 ± 0.38 56.37 ± 1.07 159.3 ± 0.76 31 (67.39%) 21 (45.65%) 25 (54.35%) 25 (54.35%) 21 (45.65%)
<0.0001 NS NS NS NS NS NS 0.0095 0.0095
6 (1.01%) 5 (0.84%) 17 (2.85%)
0 1 (2.17%) 3 (6.52%)
NS NS NS
208 (34.90%) 315 (52.85%) 10 (1.68%) 144 (24.16%) 68 (11.41%) 18 (3.02%) 51 (8.56%)
14 (30.43%) 30 (65.22%) 2 (4.35%) 11 (23.91%) 6 (13.04%) 3 (6.52%) 2 (4.35%)
NS NS NS NS NS NS NS
DM: diabetes mellitus, HTN: hypertension, NS: not significant.
T.H. Chin et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 487e491
Statistical analysis Fetal body weight and placental weight of newborns as well as maternal characteristics were analyzed by the ManneWhitney U test. Parity number, the embryo stage at transfer, the type of transfer cycle (i.e., fresh or frozen-thawed transfer cycle), and indications for IVF treatment were analyzed by the Fisher's exact test. Obstetric outcome measurements were analyzed by the Fisher's exact test, two-sided, and adjusted with binary logistic regression test. GraphPad PRISM 7.0d and SPSS Statistics version 25.0 were used to determine statistical significance, which was defined as a p value <0.05. Results Maternal characteristics and obstetric complications Data from a total of 642 singleton pregnancies delivered after the 20th weeks of gestation were recorded (Fig. 1). Among them, 46 cases belong to the RIF group, and the rest (i.e., 596 cases) are control cases. Among controls, 183 cases experienced 1 implantation failure, and 413 cases had successful implantation after the first IVF-ET. The average age of control and RIF patients was 34.82 ± 0.15 (22e44) and 37.22 ± 0.45 (27e43) years old, respectively. For the control and RIF groups, 73.49% and 54.35% of successful cycles had fresh-embryo transfers, respectively. There were no significant differences in BMI, body weight, body height, the number of parity, the embryo stage at transfer, and the indications for IVF treatment between the two groups (Table 1). Recorded obstetric complications included preeclampsia (N ¼ 22, 3.43% of the overall population), pregnancy-induced hypertension (PIH, N ¼ 23, 3.58%), gestational diabetes (GDM, N ¼ 30, 4.67%), abnormal placentation (N ¼ 39, 6.07%), placental abruption (N ¼ 5, 0.78%), preterm labor (PTL, N ¼ 60, 9.35%), PPROM (N ¼ 39, 6.07%), malpresentation (N ¼ 67, 10.44%), fetal distress (N ¼ 44, 6.85%), stillbirth (N ¼ 6, 0.93%), and congenital anomalies (N ¼ 17, 2.65%) (Table 2). Among the 17 births with congenital anomalies, 12 cases ended with termination (Supplemental Table 1). Rates of obstetric complications, including preeclampsia, PIH, GDM, abnormal placentation, PTL, PPROM, malpresentation, fetal distress and stillbirth, were not statistically different between the two groups (Table 2). On the other hand, 4.35% of RIF patients had placental abruption (2 out of 46), which was significantly higher than that of the control group (0.50%, 3 out of 596). The odds ratio was 8.99 (95% CI ¼ 1.55e44.59, p <0.05). Because there was a significant difference in the age of control and RIF populations, we calculated the odds ratio with adjustment of the age. The adjusted odds ration remained statistically significant (adjusted odds ratio ¼ 8.2, 95% CI ¼ 1.21e55.43, p < 0.05). The five placental
489
abruption cases resulted in two stillbirths; one was at 21 weeks of gestation in the control group, and the other was at 36 weeks of gestation in the RIF group. Perinatal outcomes To compare the perinatal outcomes, we excluded cases with early terminations (i.e., pregnancies terminated at 24 weeks of gestations due to poor perinatal prognosis such as the occurrence of congenital lethal fetal anomaly or PPROM). Analysis of data from a total of 574 newborns of control patients and 46 newborns of RIF patients showed that there is no difference in the rates of preterm birth (delivered at <37 weeks), very preterm birth (delivered at <32 weeks), Cesarean section, and the Apgar score at birth between the RIF and control groups (Table 3). Likewise, the average fetal body weight of newborns (3145 ± 18 g [control] versus 3182 ± 65 g [RIF], p ¼ 0.468) and the average placental weight (696 ± 6 g [control] versus 731 ± 24 g [RIF], p ¼ 0.158) were similar in the two groups (Table 3). Discussion Analysis of a cohort of IVF-ET patients who achieved singleton pregnancies showed that, except for the rate of placental abruption, other obstetric and perinatal outcomes in RIF patients are similar to those of control IVF-ET patients, suggesting that RIF patients do not suffer obvious adverse outcomes when compared to controls. Still, the analysis raises the possibility that RIF patients could have an enhanced risk of placental abruption. Because RIF could comprise a spectrum of heterogeneous etiologies and because the sample size in the present study is relatively small, future studies with a large cohort of RIF patients are needed to affirm this observation. It is well recognized that the implantation rate in RIF patients is twenty-fold lower than that of non-RIF patients [28]. In the last two decades, surgical and pharmacological methods, including transcutaneous electrical acupoint stimulation (TEAS) [29], hysteroscopic injury [30], short-term copper intrauterine device placement [31], use of immunomodulatory drugs (e.g., IVIG and glucocorticoids) [16,17,32], intrauterine instillation of G-CSF [33], and administration of autologous peripheral blood mononuclear cells [34] or platelet-rich plasma [35,36], as well as the use of endometrial receptivity array for predicting the optimal implantation window [37], have been developed to improve pregnancy outcomes in RIF patients. In addition, a study based on eight RIF cases reported in 2015 that obstetric complications of RIF patients are similar to those of non-RIF patients [38]. Except for the observation of an enhanced risk of placental abruption in RIF patients, our results are consistent with that of the prior report.
Table 2 Rates of obstetric complications in control and repeated implantation failure (RIF) patients. Complications
Total (N ¼ 642)
Control (N ¼ 596)
RIF (N ¼ 46)
Odds ratio (95% CI)
Adjusted odds ratio (95% CI)
Preeclampsia PIHa GDMa Abnormal placentation Placental abruption PTLa PPROMa Malpresentation Fetal distress Stillbirth Anomaly
22 (3.43%) 23 (3.58%) 30 (4.67%) 39 (6.07%) 5 (0.78%) 60 (9.35%) 39 (6.07%) 67 (10.44%) 44 (6.85%) 6 (0.93%) 17 (2.65%)
21 (3.52%) 23 (3.86%) 28 (4.70%) 36 (6.04%) 3 (0.50%) 56 (9.40%) 36 (6.04%) 61 (10.23%) 42 (7.05%) 5 (0.84%) 17 (2.85%)
1 0 2 3 2 4 3 6 2 1 0
0.61 e 0.92 1.09 8.99 0.92 1.09 1.32 0.60 2.63 e
0.53 e 1.27 0.99 8.20 0.29 1.11 1.36 0.61 1.81 e
(2.17%) (4.35%) (6.52%) (4.35%) (8.7%) (6.52%) (13.04%) (4.35%) (2.17%)
(0.06e3.51) (0.21e3.52) (0.34e3.44) (1.55e44.59)* (0.34e2.56) (0.34e3.44) (0.57e3.21) (0.14e2.18) (0.22e19.78)
*P value < 0.05. a PIH: pregnancy induced hypertension, GDM: gestational diabetes, PTL: preterm labor, PPROM: preterm premature rupture of membranes.
(0.07e4.13) (0.36e4.44) (0.29e3.41) (1.21e55.43)* (0.28e2.43) (0.32e3.83) (0.55e3.40) (0.14e2.64) (0.20e16.67)
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Table 3 Perinatal outcomes of the control and repeated implantation failure (RIF) groups. Outcomes
Total (N ¼ 620)
Control (N ¼ 574)
RIF (N ¼ 46)
Odds ratio (95% CI)
Adjusted odds ratio (95% CI)
Term Delivery at <37 weeks Delivery at <32 weeks C/Sa rate C/Sa due to fetal distress Apgar score &7 at 1 min at term Apgar score &7 at 5 min at term FBWa at term (Mean ± SEM) Placental weight at term (Mean ± SEM)
523/620 (84.35%) 97/620 (15.65%) 8/620 (1.29%) 310/620 (50%) 41/620 (6.61%) 16/523 (3.06%)
486/574 (84.67%) 88/574 (15.33%) 8/574 (1.39%) 289/574 (50.35%) 40/574 (6.97%) 15/486 (3.09%)
37/46 (80.43%) 9/46 (19.57%) 0 21/46 (45.65%) 1/46 (2.17%) 1/37 (2.7%)
e 1.34 e 0.83 0.30 0.87
e 1.07 e 0.72 0.32 0.85
3/523 (0.57%)
3/486 (0.62%)
0
e
3147 ± 17 698 ± 6
3145 ± 18 696 ± 6
3182 ± 65 731 ± 24
P ¼ 0.468 P ¼ 0.158
a
(0.62e2.88) (0.46e1.54) (0.03e1.77) (0.08e5.55)
(0.50e2.31) (0.39e1.34) (0.04e2.43) (0.25e2.86)
e
C/S: Cesarean section, FBW: fetal body weight.
Even though conflicting results have been reported, assisted reproductive technology (ART) pregnancies are generally associated with an enhanced risk of adverse obstetric outcomes, including hypertensive disorders, GDM, placenta previa, preterm rupture of membranes, preterm delivery, small for gestational age, antepartum hemorrhage, and placental abruption [18,20,21,39e41]. In addition, IVF-ET in aged women had an increased risk of placenta previa [42] and a decreased live-birth rate as the number of prior failed IVF treatment cycle increased [43]. Accordingly, we hypothesized that RIF could negatively impact obstetric and perinatal outcomes. Because multiple births resulting from IVF-ET are associated with a high risk of obstetric complications, including perinatal mortality [23], preterm delivery [24], first-trimester bleeding, and GDM [25], and because the maternal age is a risk factor for small for gestational age, placenta previa, placental abruption, a high Cesarean section rate, and preterm birth [42,44,45], we restricted the analysis to those with singleton pregnancy, and adjusted the odds ratio analysis with the age. The results showed the rate of placental abruption in the overall population (0.78%; 5 out of 642 cases) is similar to reported rates in the general population after ART treatment (i.e., 0.9%) [46,47]; however, RIF patients could have an enhanced risk of placental abruption. Nonetheless, the conclusion needs to be taken with caution because only two cases of RIF patients had placental abruption. Earlier studies have suggested that some RIF cases could be associated with (1) sperm DNA fragmentation, (2) unsynchronized endometrium receptivity, and (3) thrombophilic factors such as mutations in prothrombin, factor V Leiden, or methylene tetrahydrofolate reductase (MTHFR), and/or deficiency of protein C, protein S and antithrombin III [48]. In addition, because placental abruption and RIF share multiple risk factors such as antiphospholipid syndrome (APS), factor V Leiden mutation, hyperhomocysteinemia, and prothrombin mutation [49e53], the enhanced risk of placental abruption in RIF patients may be associated with some of these shared risk factors. Because placental abruption could lead to serious obstetric morbidity and perinatal death (up to 12.9%) [54], early detection of placental abruption may improve pregnancy outcomes. Accordingly, measurement of maternal serum alpha-fetoprotein in the second-trimester [55,56], and mean platelet volume and platelet distribution width [57] as well as Doppler study at the 20th weeks of gestation [58], have been developed for early detection of placental abruption. As such, these methods may also be useful for the prediction of placental abruption during antenatal care of RIF patients. Funding/Support statement Not applicable.
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