Abstract
Purpose
To study whether placentas of singleton pregnancies conceived after fresh embryo transfer (ET) contain more histopathological lesions compared with placentas of singleton pregnancies conceived after frozen-thawed embryo transfer (FET).
Methods
A prospective cohort study of placental histopathology in 131 women with singleton IVF pregnancies who delivered at a single medical center, between December 2017 and May 2019. The prevalence of different placental histopathology lesions was compared between women who conceived after fresh ET and FET.
Results
Women who conceived after fresh ET (n = 74) did not differ from women who conceived after FET (n = 57) with regard to maternal age, BMI, nulliparity, or infertility diagnosis. Gestational week at delivery was lower in pregnancies conceived after fresh ET (38.5 vs. 39.2 weeks, respectively, p = 0.04), and a trend for a lower birthweight following fresh ET was noted (3040 vs. 3216 g, respectively, p = 0.053). However, placental histopathology analysis from pregnancies conceived after fresh ET was comparable to pregnancies conceived after FET, with regard to the prevalence of maternal vascular malperfusion lesions (45.9% vs. 50.9%, respectively, p = 0.57), fetal vascular malperfusion lesions (17.6% vs. 21.1, p = 0.61), acute inflammatory response lesions (28.4% vs. 28.1%, respectively, p = 0.96), and chronic inflammatory response lesions (13.5% vs. 8.8%, respectively, p = 0.48).
Conclusion
Placental histopathology did not differ between IVF pregnancies conceived after fresh and frozen ET. These results are reassuring for clinicians and patients who wish to pursue with transferring fresh embryos.
Keywords: Placenta, Pathology, Fresh embryo transfer, Frozen embryo transfer, IVF
Introduction
The introduction of vitrification for embryo cryopreservation has dramatically improved the survival of cryopreserved embryos and the results of frozen-thawed embryo transfer (FET) cycles [1]. As a result, the proportion of FET cycles has increased globally [2, 3]. Large studies have consistently demonstrated that singleton pregnancies conceived from FET had a lower risk of preterm deliveries, low birth weight, and small for gestational age (SGA) infants [4–6]. Some have also demonstrated a lower risk of perinatal mortality in FET pregnancies [4], while others have not [5, 6]. On the other hand, singleton FET pregnancies have a higher risk of cesarean deliveries [4, 6], hypertensive disorders [5], and high birthweight [5]. There is no difference in the incidence of congenital anomalies [4, 5, 7].
It has been postulated that the high levels of ovarian steroids in fresh cycles interfere with endometrial receptivity and the placentation process, resulting in preterm deliveries and low birthweight later on [8]. Furthermore, it was postulated that the absence of corpus luteum in programmed (artificial) FET cycles may predispose women to hypertensive disorders of pregnancy [9, 10].
Defective deep placentation has been associated with a spectrum of pregnancy complications, including preeclampsia, fetal growth restriction, preterm labor, and placental abruption. This group of pregnancy complications, also known as “the great obstetrical syndromes,” is the result of impaired placental vascular bed and can be identified on placental biopsy [11, 12]. Specific placental histopathology lesions have been associated with specific pregnancy complications; preterm birth was associated with placental inflammatory lesions on both maternal and fetal sides [13, 14] and with vascular malperfuson lesions, specifically in very early preterm births [15]. Low birthweight and hypertensive disorders were associated with maternal vascular malperfusion lesions [16–18], specifically histological decidual vasculopathy, such as acute atherosis and mural hypertrophy [19].
No differences in morphological or histopathological features of the placenta were observed when comparing term placentas of singleton pregnancies from ART and term placentas of spontaneous pregnancies [20]. However, a recent study has found that pregnancies arising from FET demonstrated more vascular placental pathology than those from fresh transfers [21]. Notably, this study included only FET cycles using artificial preparation of the endometrium.
Based on previous studies, showing that placental histopathology examination may reveal the origin of specific perinatal complications, we assumed that placentas of pregnancies conceived from fresh and frozen ET might also differ in the incidence of pathological lesions. Therefore, our aim was to compare the placental histopathology between placentas of singleton pregnancies conceived after fresh and frozen ET. Comprehensive placental analysis was performed to identify vascular lesions, acute and chronic inflammatory lesions, and pathologies of the umbilical cord.
Materials and methods
We conducted a prospective cohort study of placental histopathology in all women with singleton in vitro fertilization (IVF) pregnancies who delivered at a single medical center (> 22 weeks of gestation), between December 2017 and May 2019. We excluded multifetal pregnancies, women who had pregnancy termination, stillbirth, egg donation cycles, and cases with missing data. The prevalence of different placental histopathology lesions was compared between women who conceived after fresh and frozen-thawed ET. The study was approved by the local ethics committee (Registry No. 0181-17-WOMC). All participants signed an informed consent.
Data collection
Eligible women reported to us whether they had undergone a fresh or a frozen-thawed ET, and how many embryos had been transferred. In cases of FET, women reported to us whether embryos were transferred in natural cycles or programmed (artificial) cycles. The following data were extracted from the medical files: infertility diagnosis, maternal age, gestational age at delivery, birthweight, parity, pre-pregnancy body mass index (BMI, kg/m2), pre-gestational diabetes mellitus, gestational diabetes mellitus, thrombophilia (defined as any thrombophilia, inherited or acquired, which necessitated thromboprophylaxis), gestational hypertension, preeclampsia, smoking, premature rupture of membranes (PROM), induction of labor, type of delivery, intrapartum fever, placental histopathology analysis, and gross placental pathology (defined as any of the following: placenta previa, placenta accrete, manual removal of adherent placenta, and manual revision of uterine cavity due to suspected retained placenta). SGA infant was defined as birthweight < 10th percentile for gestational age. Low birthweight (LBW) was defined as < 2500 g. The primary outcome was the incidence of the different placental pathologies.
Placental histopathology
All placentas were examined by a single pathologist (author L.S) who was blinded to the type of ET and the obstetrical outcome. Placental lesions were classified according to the updated criteria adopted by the Society for Pediatric Pathology [22] and as previously reported by us [17, 23, 24]. Briefly, 24 h after fixation, the placentas were weighted untrimmed. We calculated the ratio between birthweight and placental weight. High neonatal to placental weight ratio may indicate placental insufficiency and was shown to be associated with pathological placental lesions [25]. From each placenta, at least 5 full-thickness samples were taken from the disc, as follows: one at the cord insertion, one from central tissue that appeared abnormal on gross examination, two from central tissue that appeared grossly abnormal, and one at the margin of visibly abnormal tissue. One additional sample was taken from the membrane roll and two from the umbilical cord. Any other abnormal area was sampled as well. The samples were embedded in paraffin blocks and stained for microscopic assessment. Placental lesions were divided into 4 main groups:
Maternal vascular malperfusion (MVM) lesions, including placental hemorrhages (marginal and retro-placental), vascular lesions (acute atherosis, mural hypertrophy, and decidual arteriopathy), and villous changes (increased syncytial knots, villous agglutination, increased intervillous fibrin deposition, distal villous hypoplasia, and villous infarcts).
Fetal vascular malperfusion (FVM) lesions, including vascular lesions (thrombosis of the chorionic plate and stem villous vessels) and villous changes (villi with stromal vascular karyorrhexis and avascular villi).
Acute inflammatory lesions: maternal inflammatory response (MIR) was divided into three stages: stage 1—acute subchorionitis or chorionitis; stage 2—acute chorioamnionitis: polymorphonuclear leukocytes extended; and stage 3—necrotizing chorioamnionitis: karyorrhexis of polymorphonuclear leukocytes, amniocyte necrosis. Fetal inflammatory response (FIR) was also divided into 3 stages: stage 1—umbilical phlebitis; stage 2—involvement of the umbilical vein and one or more umbilical arteritis; and stage 3—necrotizing funisitis.
Chronic inflammatory lesions: villitis of unknown etiology (VUE) or chronic villitis was defined as lymphohistiocytic inflammation localized to the stroma of terminal villi but often extending to the small vessels of upstream villi. Immunohistochemistry studies were performed to identify T cell infiltration by using an antibody against CD3 (rabbit monoclonal SP7, Thermo-Scientific) in all cases suspected of VUE after H&E staining. Chronic deciduitis (CD) was diagnosed by the presence of lymphocytes and plasma cells in the basal plate.
Finally, the following macroscopic pathologies of the umbilical cord were examined: marginal (< 1 cm from the nearest margin) and velamentous insertions, hypercoiling (> 3 coils per 10 cm) and hypocoiling (< 1 coil per 10 cm).
Statistical analysis
Data were analyzed using SPSS software version 25.0 (IBM Inc. Chicago, USA). Continuous variables were compared by Student’s t test, and categorical variables were compared by chi-square test, or Fisher’s exact test, as appropriate. Multivariate logistic regression analyses were performed in order to study the association between fresh ET and placental histopathology lesions after controlling for confounders. First, each individual histopathologic lesion served as the dependent variable (MVM, FVM, MIR, FIR, VUE, and CD). Second, we analyzed combinations of lesions as the dependent variable (any vascular malperfusion lesions, any acute inflammatory response lesion, any chronic inflammatory response lesion). Finally, specific pregnancy outcomes served as the dependent variable (preterm birth, SGA, LBW). Odds ratios were adjusted for maternal age, BMI, and nulliparity, as these variables affect the perinatal outcomes and placental histopathology. p < 0.05 was considered statistically significant.
A previous study has shown that the prevalence of placental vascular malperfusion lesions in pregnancies conceived by IVF is approximately 30% [20]. Based on that, we calculated that a sample size of 42 women in each study group would be sufficient to detect a twofold increase in the prevalence of vascular malperfusion lesions, with power of 80% and alpha of 0.05.
Results
During the study period, 482 women with IVF pregnancies gave birth at our center, of whom 351 were excluded (135 women were not recruited due to the absence of a member of the study team, 128 women had multifetal pregnancies, 86 women received egg donation, and 2 women underwent termination of pregnancy). Overall, 131 women met the inclusion criteria, of whom 74 conceived after fresh ET and 57 conceived after FET. FET was performed based on natural cycle in 40 out of 57 cases (70.1%). Mean age was 33.1 ± 5.4 years, and mean gestational age at delivery was 38.8 ± 1.9 weeks. The most common indication for IVF was male factor infertility (42.7%), followed by unexplained infertility (20.6%). One embryo was transferred in 49.6% of the women, and two embryos were transferred in 40.5% of the women.
Table 1 presents the baseline characteristics of the participants. There were no differences between the study groups with regard to women’s age, BMI, nulliparity rate, infertility diagnosis, chronic hypertension, pregestational diabetes mellitus, or thrombophilia. Table 2 presents the pregnancy outcomes of the study groups. Gestational age at delivery was slightly lower in the fresh ET group compared with the FET group (38.5 vs. 39.2, respectively, p = 0.04), though the rate of preterm birth was comparable. Birthweight was lower in the fresh ET group, though this difference did not reach statistical significance (3040 vs. 3216 g, p = 0.053). There were comparable rates of SGA infants, LBW, cesarean deliveries, gestational diabetes mellitus, and hypertensive disorders (gestational hypertension and preeclampsia). The rate of gross placental pathology was also comparable.
Table 1.
Baseline characteristics of women who conceived by fresh and frozen embryo transfer (ET)
| Fresh ET (n = 74) | Frozen ET (n = 57) | p value | |
|---|---|---|---|
| Age (years) | 33.8 ± 5.5 | 32.2 ± 5.2 | 0.10 |
| BMI (kg/m2) | 25.0 ± 4.4 | 24.7 ± 4.5 | 0.69 |
| Nulliparity | 50 (67.6) | 33 (57.9) | 0.25 |
| Infertility diagnosis | 0.66 | ||
| Male factor | 31 (41.9) | 25 (43.9) | |
| Unexplained | 12 (16.2) | 15 (26.3) | |
| Low ovarian reserve | 10 (13.5) | 5 (8.8) | |
| Tubal factor | 7 (9.5) | 5 (8.8) | |
| Anovulation | 7 (9.5) | 4 (7.0) | |
| Other | 7 (9.5) | 3 (5.3) | |
| Number of embryos transferred | 0.22 | ||
| 1 | 33 (44.6) | 32 (56.1) | |
| 2 | 31 (41.9) | 22 (38.6) | |
| 3 | 6 (8.1) | 3 (5.3) | |
| 4 | 4 (5.4) | 0 | |
| Chronic hypertension | 2 (2.7) | 0 | 0.50 |
| Pregestational diabetes mellitus | 2 (2.7) | 0 | 0.50 |
| Thrombophilia | 1 (1.4) | 1 (1.8) | 1.0 |
| Smoking | 7 (9.5) | 3 (5.3) | 0.51 |
Data are presented as mean ± SD, or n (%)
ET embryo transfer, BMI body mass index
Table 2.
Pregnancy outcomes in women who conceived by fresh and frozen embryo transfer (ET)
| Fresh ET (n = 74) | Frozen ET (n = 57) | p value | |
|---|---|---|---|
| Gestational age at birth (weeks) | 38.5 ± 2.0 | 39.2 ± 1.6 | 0.04 |
| Preterm birth (< 37 weeks) | 9 (12.2) | 3 (5.3) | 0.17 |
| Birthweight (g) | 3040 ± 526 | 3216 ± 484 | 0.053 |
| SGA infants (< 10th percentile) | 5 (6.8) | 3 (5.4) | 1.0 |
| LBW (< 2500 g) | 9 (12.2) | 3 (5.3) | 0.17 |
| Cesarean delivery | 26 (35.1) | 14 (24.6) | 0.19 |
| PROM | 15 (20.3) | 14 (24.6) | 0.55 |
| Gestational diabetes mellitus | 8 (10.8) | 4 (7.0) | 0.45 |
| Gestational hypertension | 1 (1.4) | 1 (1.8) | 1.0 |
| Preeclampsia | 5 (6.8) | 3 (5.3) | 1.0 |
| Induction of labor | 18 (24.3) | 23 (40.4) | 0.050 |
| Intrapartum fever | 4 (5.4) | 4 (7.0) | 0.72 |
| Gross placental pathologya | 7 (9.5) | 6 (10.5) | 0.84 |
Data are presented as mean ± SD, or n (%)
ET embryo transfer, PROM premature rupture of membranes, SGA small for gestational age, LBW low birthweight
aPlacenta previa, placenta accrete, manual removal of adherent placenta, or manual revision of uterine cavity due to suspected retained placenta
Table 3 presents the results of the histopathologic examination of the placenta and the umbilical cord. There were no differences between the study groups regarding placental weight, birthweight to placental weight ratio, umbilical cord anomalies, or the incidence of the different placental histopathology lesions.
Table 3.
Placental histopathology in women who conceived by fresh and frozen embryo transfer (ET)
| Fresh ET (n = 74) | Frozen ET (n = 57) | p value | |
|---|---|---|---|
| Placental weight (g) | 463 ± 105 | 480 ± 102 | 0.35 |
| Birthweight to placental weight ratio | 6.7 ± 1.2 | 6.8 ± 1.1 | 0.59 |
| Umbilical cord anomalies | |||
| Hypercoiling | 51 (68.9) | 41 (71.9) | 0.70 |
| Hypocoiling | 6 (8.1) | 8 (14.0) | 0.27 |
| Abnormal cord insertiona | 20 (27.0) | 19 (33.3) | 0.43 |
| Maternal vascular malperfusion (MVM) lesions | |||
| Placental hemorrhage | 3 (4.1) | 0 | 0.25 |
| Vascular lesions related to MVM | 4 (5.4) | 0 | 0.13 |
| Villous lesions related to MVM | 31 (41.9) | 29 (50.9) | 0.30 |
| Any MVM lesion | 34 (45.9) | 29 (50.9) | 0.57 |
| Fetal vascular malperfusion (FVM) lesions | |||
| Vascular lesions related to FVM | 9 (12.2) | 11 (19.3) | 0.26 |
| Villous lesions related to FVM | 5 (6.8) | 2 (3.5) | 0.69 |
| Any FVM lesion | 13 (17.6) | 12 (21.1) | 0.61 |
| Acute maternal inflammatory response (MIR) lesions | |||
| MIR stage 1 | 16 (21.6) | 11 (19.3) | 0.74 |
| MIR stage 2 | 5 (6.8) | 5 (8.8) | 0.74 |
| MIR stage 3 | 0 | 0 | |
| Any MIR lesion, stages 1–3 | 21 (28.4) | 15 (26.3) | 0.79 |
| Acute fetal inflammatory response (FIR) lesions | |||
| FIR stage 1 | 4 (5.4) | 4 (7.0) | 0.72 |
| FIR stage 2 | 1 (1.4) | 1 (1.8) | 1.0 |
| FIR stage 3 | 0 | 0 | |
| Any FIR lesion, stages 1–3 | 5 (6.8) | 5 (8.8) | 0.74 |
| Chronic inflammatory lesions | |||
| Villitis of unknown etiology (VUE) | 8 (10.8) | 3 (5.3) | 0.34 |
| Chronic deciduitis (CD) | 4 (5.4) | 2 (3.5) | 0.69 |
| Combinations of lesions | |||
| Any vascular malperfusion lesion (MVM and/or FVM) | 41 (55.4) | 33 (57.9) | 0.77 |
| Any acute inflammatory response lesion (MIR and/or FIR) | 21 (28.4) | 16 (28.1) | 0.96 |
| Any chronic inflammatory response lesion (VUE and/or CD) | 10 (13.5) | 5 (8.8) | 0.39 |
Data are presented as mean ± SD, or n (%)
aVelamentous or marginal cord insertion
On multivariate logistic regression analysis, after controlling for maternal age, BMI, and nulliparity, fresh ET was not associated with any histopathologic lesion (MVM, FVM, MIR, FIR, VUE, and CD) or any combination of histopathologic lesions (Table 4). Fresh ET was not associated either with preterm birth, SGA, or LBW.
Table 4.
Multivariate logistic regression analysis—association between fresh embryo transfer and placental/pregnancy outcomes
| Placental and pregnancy outcomes | aOR (95% CI)a |
|---|---|
| Any placental vascular malperfusion lesion | 0.96 (0.47–1.96) |
| Any placental acute inflammatory response lesion (MIR and/or FIR) | 0.97 (0.44–2.15) |
| Any placental chronic inflammatory response lesion (VUE and/or CD) | 1.85 (0.57–6.00) |
| Preterm birth | 2.12 (0.56–8.78) |
| SGA infant | 1.44 (0.26–7.75) |
| Low birthweight | 2.38 (0.58–9.72) |
aOR adjusted odds ratio, CI confidence interval, MIR maternal inflammatory response, FIR fetal inflammatory response, VUE villitis of unknown etiology, CD chronic deciduitis, SGA small for gestational age
aAdjusted for maternal age, BMI, and nulliparity
Subgroup analysis was performed to compare natural (n = 40) and programmed (n = 17) FET cycles. There were no significant differences in perinatal outcomes or placental histopathology. Moreover, on multivariate regression analysis, programmed FET was not associated with poor perinatal outcomes or placental histopathology lesions, after controlling for confounders.
Discussion
The present study demonstrates a significantly lower gestational age at delivery and a non-significantly lower birthweight in singleton pregnancies conceived from fresh ET, compared with frozen ET. Nevertheless, these observations were not associated with differences in the incidence of placental histopathology lesions.
A large body of evidence has accumulated regarding the type of ET and pregnancy outcomes. A recent meta-analysis included 26 retrospective cohort studies comparing obstetric and perinatal outcomes in singleton pregnancies conceived after either fresh or frozen ET. Babies conceived following FET were at a lower relative risk (RR) for preterm birth (RR 0.90, 95% CI 0.84–0.97), low birthweight (RR 0.72, 95% CI 0.67–0.77), and SGA birthweight (RR 0.61, 95% CI 0.56–0.67), but faced an increased risk of hypertensive disorders of pregnancy (RR 1.29, 95% CI 1.07–1.56), large for gestational age birthweight (RR 1.54, 95% CI 1.48–1.61), and high birthweight (RR 1.85, 95% CI 1.46–2.33). The risk of congenital anomalies and the risk of perinatal mortality did not differ between the two groups.
Three multicenter RCTs have compared the reproductive outcome between fresh and elective FET cycles; Chen et al. [26] randomly assigned 1508 infertile women with polycystic ovary syndrome undergoing their first IVF to either fresh ET or embryo cryopreservation followed by FET. Women who underwent FET had a higher birthweight (3511 vs. 3349 g, p = 0.005), but they also had a higher incidence of preeclampsia (OR 3.12, 95% CI 1.26–7.73). Shi et al. [27] randomly assigned 2157 ovulatory women undergoing their first IVF cycle to either fresh ET or FET. Mean birthweight, the rate of preterm birth, and the rate of preeclampsia did not differ between the study groups. In contrast, Wei et al. [16] randomly assigned 1650 ovulatory women to either fresh or frozen single blastocyst transfer and found a higher birthweight in singleton pregnancies from FET (3407 vs. 3293 g, p = 0.001). FET was also associated with a higher risk of preeclampsia (RR 3.13, 95% CI 1.06–9.30). The incidence of preterm birth was comparable.
The association between placental histopathology and pregnancy complications has been studied extensively. It has been demonstrated that placental maternal vascular malperfusion (MVM) lesions, which are thought to be the consequence of abnormal placentation, characterize “placental-related pregnancy complications,” such as fetal growth restriction and preeclampsia [28, 29]. Placental pathology also correlates with the severity of pregnancy complications [30]. Placental inflammatory lesions were associated with preterm birth [13, 14] and might even indicate higher risk for repeat preterm birth in subsequent pregnancy [31].
Only a few studies examined the placental histopathology in pregnancies obtained by assisted reproductive technologies (ART). Daniel et al. [20] could not find any differences in placental morphology and histopathology between pregnancies conceived by IVF/ICSI and matched pregnancies conceived spontaneously. In contrast, another investigator has observed larger placentas and higher ratio between placental weight and birthweight in pregnancies conceived by ART [32].
A recent study compared the placental histopathology between fresh and FET cycles [21]. In this study, Sacha et al. found that pregnancies arising from FET demonstrated more vascular placental pathology than those from fresh transfers. However, this study included only FET cycles using artificial preparation of the endometrium (programmed FET cycles). Several studies have reported a higher risk of preeclampsia in these pregnancies, compared to pregnancies from FET based on natural cycles [9, 33]. It has been postulated that the absence of corpus luteum in artificial cycles is responsible for impaired cardiovascular adaptation, contributing to an increased risk of preeclampsia [34]. In the present study, the incidence of preeclampsia and vascular placental pathology did not differ between the study groups, most probably because natural cycle FET was used in most women. Subgroup analysis did not demonstrate differences in the incidence of pathological lesions in natural and programmed FET cycles. However, the study was not sufficiently powered to detect such differences, as only 17 women underwent programmed FET.
While most studies have observed a higher risk of preterm deliveries and small birthweight in pregnancies conceived by fresh ET, this risk was not supported by placental histopathology examination in our cohort. The similar placental pathology in both groups may imply the presence of other mechanisms responsible for the development of pregnancy complications after fresh ET. These may not be evident by standard histopathology examination. In an attempt to investigate the mechanisms responsible for the adverse pregnancy outcome in fresh ET, Weinerman et al. [35] have developed a novel mouse model, aiming to isolate the independent effects of embryo freezing and the super-ovulated environment. They found that neither superovulation nor embryo vitrification affected trophoblast differentiation and placental architecture (histology) in this mouse model. Yet, they observed changes in umbilical artery resistance and microvascular density in term mice placentas following a fresh transfer in a super-ovulated environment. They suggested that changes in placental vasculogenesis may be responsible for the differences in perinatal outcomes in fresh and frozen ET pregnancies.
Several other reasons may explain the discrepancy between our results and previous findings. First, it should be noted that our small sample size was insufficient to identify small differences in the rate of the different histologic lesions. Second, in previous retrospective studies, women who had surplus embryos for cryopreservation may represent better prognosis patients. Third, the process of freezing and thawing may imply a selection for better embryos. Finally, epigenetic changes and different gene expression in fetal and maternal tissues may affect the obstetric outcome, and not be evident by placental histopathology examination [36, 37].
The strengths of the current study are the inclusion of pregnancies arising from natural cycle FET and the meticulous placental analysis. Importantly, a single pathologist, who was blinded to the type of ET, examined all placentas using the updated “Amsterdam” classification.
Nevertheless, several limitations must be acknowledged. First, the relatively small sample size might not be sufficient to detect small differences in the incidence of placental histopathologic lesions. Moreover, the study was not powered to detect differences between programmed and natural FET cycles. Second, some data regarding the stimulation protocol is lacking. Third, the type of embryo transfer was reported in a questionnaire and therefore was subject to a slight chance of recall bias.
In summary, placental histopathology lesions did not differ between IVF pregnancies resulting from the transfer of fresh or frozen-thawed embryos. These results are reassuring for clinicians and patients who wish to pursue with transferring fresh embryos. Further studies are needed to elucidate the mechanisms responsible for the earlier gestational age at delivery and lower birthweight in fresh ET cycles compared with frozen ET cycles.
Author’s Contribution
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Mizrachi Y., Buchnik Fater G., Torem M., Schreiber L., and Kovo M. The first draft of the manuscript was written by Mizrachi M., Weissman A., and Kovo M., and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Registry No. 0181-17-WOMC) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yossi Mizrachi and Ariel Weissman contributed equally to this work.
References
- 1.Rienzi L, Gracia C, Maggiulli R, LaBarbera AR, Kaser DJ, Ubaldi FM, Vanderpoel S, Racowsky C. Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance. Hum Reprod Update. 2017;23(2):139–155. doi: 10.1093/humupd/dmw038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.De Geyter C, Calhaz-Jorge C, Kupka MS, Wyns C, Mocanu E, Motrenko T, et al. ART in Europe, 2014: results generated from European registries by ESHRE†: the European IVF-monitoring Consortium (EIM)‡ for the European Society of Human Reproduction and Embryology (ESHRE) Hum Reprod. 2018;33(9):1586–1601. doi: 10.1093/humrep/dey242. [DOI] [PubMed] [Google Scholar]
- 3.Kushnir VA, Barad DH, Albertini DF, Darmon SK, Gleicher N. Systematic review of worldwide trends in assisted reproductive technology 2004–2013. Reprod Biol Endocrinol. 2017;15(1):6. doi: 10.1186/s12958-016-0225-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Maheshwari A, Pandey S, Shetty A, Hamilton M, Bhattacharya S. Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of frozen thawed versus fresh embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis. Fertil Steril. 2012;98(2):368–77.e1–9. doi: 10.1016/j.fertnstert.2012.05.019. [DOI] [PubMed] [Google Scholar]
- 5.Maheshwari A, Pandey S, Amalraj Raja E, Shetty A, Hamilton M, Bhattacharya S. Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer? Hum Reprod Update. 2018;24(1):35–58. doi: 10.1093/humupd/dmx031. [DOI] [PubMed] [Google Scholar]
- 6.Zhao J, Xu B, Zhang Q, Li YP. Which one has a better obstetric and perinatal outcome in singleton pregnancy, IVF/ICSI or FET?: a systematic review and meta-analysis. Reprod Biol Endocrinol. 2016;14(1):51. doi: 10.1186/s12958-016-0188-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Beltran Anzola A, Pauly V, Montjean D, Meddeb L, Geoffroy-Siraudin C, Sambuc R, Boyer P, Gervoise-Boyer MJ. No difference in congenital anomalies prevalence irrespective of insemination methods and freezing procedure: cohort study over fourteen years of an ART population in the south of France. J Assist Reprod Genet. 2017;34(7):867–876. doi: 10.1007/s10815-017-0903-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Johnson KM, Hacker MR, Resetkova N, O'Brien B, Modest AM. Risk of ischemic placental disease in fresh and frozen embryo transfer cycles. Fertil Steril. 2019;111(4):714–721. doi: 10.1016/j.fertnstert.2018.11.043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.von Versen-Hoynck F, Schaub AM, Chi YY, Chiu KH, Liu J, Lingis M, et al. Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum. Hypertension. 2019;73(3):640–649. doi: 10.1161/hypertensionaha.118.12043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Conrad KP, Petersen JW, Chi YY, Zhai X, Li M, Chiu KH, Liu J, Lingis MD, Williams RS, Rhoton-Vlasak A, Larocca JJ, Nichols WW, Segal MS. Maternal cardiovascular dysregulation during early pregnancy after in vitro fertilization cycles in the absence of a corpus luteum. Hypertension. 2019;74(3):705–715. doi: 10.1161/hypertensionaha.119.13015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “great obstetrical syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol. 2011;204(3):193–201. doi: 10.1016/j.ajog.2010.08.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Khong Y, Brosens I. Defective deep placentation. Best Pract Res Clin Obstet Gynaecol. 2011;25(3):301–311. doi: 10.1016/j.bpobgyn.2010.10.012. [DOI] [PubMed] [Google Scholar]
- 13.Weiner E, Dekalo A, Feldstein O, Barber E, Schreiber L, Bar J, et al. The placental factor in spontaneous preterm birth in twin vs. singleton pregnancies. European journal of obstetrics, gynecology, and reproductive biology. 2017;214:1–5. 10.1016/j.ejogrb.2017.04.035. [DOI] [PubMed]
- 14.Kovo M, Schreiber L, Ben-Haroush A, Asalee L, Seadia S, Golan A, Bar J. The placental factor in spontaneous preterm labor with and without premature rupture of membranes. J Perinat Med. 2011;39(4):423–429. doi: 10.1515/jpm.2011.038. [DOI] [PubMed] [Google Scholar]
- 15.Catov JM, Scifres CM, Caritis SN, Bertolet M, Larkin J, Parks WT. Neonatal outcomes following preterm birth classified according to placental features. Am J Obstet Gynecol. 2017;216(4):411.e1–411.e14. doi: 10.1016/j.ajog.2016.12.022. [DOI] [PubMed] [Google Scholar]
- 16.Levy M, Kovo M, Schreiber L, Kleiner I, Grinstein E, Koren L, Barda G, Bar J, Weiner E. Pregnancy outcomes in correlation with placental histopathology in subsequent pregnancies complicated by fetal growth restriction. Placenta. 2019;80:36–41. doi: 10.1016/j.placenta.2019.04.001. [DOI] [PubMed] [Google Scholar]
- 17.Weiner E, Mizrachi Y, Grinstein E, Feldstein O, Rymer-Haskel N, Juravel E, Schreiber L, Bar J, Kovo M. The role of placental histopathological lesions in predicting recurrence of preeclampsia. Prenat Diagn. 2016;36(10):953–960. doi: 10.1002/pd.4918. [DOI] [PubMed] [Google Scholar]
- 18.Weiner E, Feldstein O, Tamayev L, Grinstein E, Barber E, Bar J, Schreiber L, Kovo M. Placental histopathological lesions in correlation with neonatal outcome in preeclampsia with and without severe features. Pregnancy Hypertens. 2018;12:6–10. doi: 10.1016/j.preghy.2018.02.001. [DOI] [PubMed] [Google Scholar]
- 19.Stanek J. Histological features of shallow placental implantation unify early-onset and late-onset preeclampsia. Pediatr Dev Pathol. 2019;22(2):112–122. doi: 10.1177/1093526618803759. [DOI] [PubMed] [Google Scholar]
- 20.Daniel Y, Schreiber L, Geva E, Amit A, Pausner D, Kupferminc MJ, et al. Do placentae of term singleton pregnancies obtained by assisted reproductive technologies differ from those of spontaneously conceived pregnancies? Hum Reprod. 1999;14(4):1107–1110. doi: 10.1093/humrep/14.4.1107. [DOI] [PubMed] [Google Scholar]
- 21.Sacha CR, Harris AL, James K, Basnet K, Freret TS, Yeh J, et al. Placental pathology in live births conceived with in vitro fertilization after fresh and frozen embryo transfer. Am J Obstet Gynecol. 2019. 10.1016/j.ajog.2019.09.047. [DOI] [PubMed]
- 22.Khong TY, Mooney EE, Ariel I, Balmus NC, Boyd TK, Brundler MA, Derricott H, Evans MJ, Faye-Petersen OM, Gillan JE, Heazell AE, Heller DS, Jacques SM, Keating S, Kelehan P, Maes A, McKay E, Morgan TK, Nikkels PG, Parks WT, Redline RW, Scheimberg I, Schoots MH, Sebire NJ, Timmer A, Turowski G, van der Voorn J, van Lijnschoten I, Gordijn SJ. Sampling and definitions of placental lesions: Amsterdam placental workshop group consensus statement. Arch Pathol Lab Med. 2016;140(7):698–713. doi: 10.5858/arpa.2015-0225-CC. [DOI] [PubMed] [Google Scholar]
- 23.Levy M, Mizrachi Y, Leytes S, Weiner E, Bar J, Schreiber L, et al. Can placental histopathology lesions predict recurrence of small for gestational age neonates? Reprod Sci. 2018;25:1485. doi: 10.1177/1933719117749757. [DOI] [PubMed] [Google Scholar]
- 24.Weiner E, Barber E, Feldstein O, Schreiber L, Dekalo A, Mizrachi Y, et al. The placental component and neonatal outcome in singleton vs twin pregnancies complicated by gestational diabetes mellitus. Placenta. 2018;63:39–44. doi: 10.1016/j.placenta.2018.01.010. [DOI] [PubMed] [Google Scholar]
- 25.Ganer Herman H, Miremberg H, Schreiber L, Bar J, Kovo M. The association between disproportionate birth weight to placental weight ratio, clinical outcome, and placental histopathological lesions. Fetal Diagn Ther. 2017;41(4):300–306. doi: 10.1159/000448949. [DOI] [PubMed] [Google Scholar]
- 26.Chen ZJ, Shi Y, Sun Y, Zhang B, Liang X, Cao Y, Yang J, Liu J, Wei D, Weng N, Tian L, Hao C, Yang D, Zhou F, Shi J, Xu Y, Li J, Yan J, Qin Y, Zhao H, Zhang H, Legro RS. Fresh versus frozen embryos for infertility in the polycystic ovary syndrome. N Engl J Med. 2016;375(6):523–533. doi: 10.1056/NEJMoa1513873. [DOI] [PubMed] [Google Scholar]
- 27.Shi Y, Sun Y, Hao C, Zhang H, Wei D, Zhang Y, Zhu Y, Deng X, Qi X, Li H, Ma X, Ren H, Wang Y, Zhang D, Wang B, Liu F, Wu Q, Wang Z, Bai H, Li Y, Zhou Y, Sun M, Liu H, Li J, Zhang L, Chen X, Zhang S, Sun X, Legro RS, Chen ZJ. Transfer of fresh versus frozen embryos in ovulatory women. N Engl J Med. 2018;378(2):126–136. doi: 10.1056/NEJMoa1705334. [DOI] [PubMed] [Google Scholar]
- 28.Hendrix MLE, Bons JAP, Alers NO, Severens-Rijvers CAH, Spaanderman MEA, Al-Nasiry S. Maternal vascular malformation in the placenta is an indicator for fetal growth restriction irrespective of neonatal birthweight. Placenta. 2019;87:8–15. doi: 10.1016/j.placenta.2019.09.003. [DOI] [PubMed] [Google Scholar]
- 29.Falco ML, Sivanathan J, Laoreti A, Thilaganathan B, Khalil A. Placental histopathology associated with pre-eclampsia: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2017;50(3):295–301. doi: 10.1002/uog.17494. [DOI] [PubMed] [Google Scholar]
- 30.Kovo M, Schreiber L, Ben-Haroush A, Cohen G, Weiner E, Golan A, Bar J. The placental factor in early- and late-onset normotensive fetal growth restriction. Placenta. 2013;34(4):320–324. doi: 10.1016/j.placenta.2012.11.010. [DOI] [PubMed] [Google Scholar]
- 31.Mizrachi Y, Barber E, Torem M, Tairy D, Weiner E, Bar J, Schreiber L, Kovo M. Is there a role for placental histopathology in predicting the recurrence of preterm birth? Arch Gynecol Obstet. 2019;300(4):917–923. doi: 10.1007/s00404-019-05266-x. [DOI] [PubMed] [Google Scholar]
- 32.Haavaldsen C, Tanbo T, Eskild A. Placental weight in singleton pregnancies with and without assisted reproductive technology: a population study of 536,567 pregnancies. Hum Reprod. 2012;27(2):576–582. doi: 10.1093/humrep/der428. [DOI] [PubMed] [Google Scholar]
- 33.Ginstrom Ernstad E, Wennerholm UB, Khatibi A, Petzold M, Bergh C. Neonatal and maternal outcome after frozen embryo transfer: increased risks in programmed cycles. Am J Obstet Gynecol. 2019. 10.1016/j.ajog.2019.03.010. [DOI] [PubMed]
- 34.von Versen-Hoynck F, Narasimhan P, Selamet Tierney ES, Martinez N, Conrad KP, Baker VL, et al. Absent or excessive corpus luteum number is associated with altered maternal vascular health in early pregnancy. Hypertension. 2019;73(3):680–690. doi: 10.1161/hypertensionaha.118.12046. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Weinerman R, Ord T, Bartolomei MS, Coutifaris C, Mainigi M. The superovulated environment, independent of embryo vitrification, results in low birthweight in a mouse model. Biol Reprod. 2017;97(1):133–142. doi: 10.1093/biolre/iox067. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Hiura H, Hattori H, Kobayashi N, Okae H, Chiba H, Miyauchi N, Kitamura A, Kikuchi H, Yoshida H, Arima T. Genome-wide microRNA expression profiling in placentae from frozen-thawed blastocyst transfer. Clin Epigenetics. 2017;9:79. doi: 10.1186/s13148-017-0379-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Senapati S, Wang F, Ord T, Coutifaris C, Feng R, Mainigi M. Superovulation alters the expression of endometrial genes critical to tissue remodeling and placentation. J Assist Reprod Genet. 2018;35(10):1799–1808. doi: 10.1007/s10815-018-1244-z. [DOI] [PMC free article] [PubMed] [Google Scholar]