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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 177-183

Comparative neonatal outcomes of vitrified versus fresh embryo transfers: A systematic review and meta-analysis


Center for Reproductive Medicine, Assisted Reproductive Technology Laboratory, Shenyang Jinghua Hospital, Shenyang 110005, China

Date of Submission03-Jan-2020
Date of Decision03-Feb-2020
Date of Acceptance21-Apr-2020
Date of Web Publication03-Jul-2020

Correspondence Address:
Peng Xu
Assisted Reproductive Technology Laboratory, Shenyang Jinghua Hospital, No. 156 Nanjing South Street, Heping District, Shenyang 110005
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.288961

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  Abstract 


Objective: Vitrification prevents ice formation within the high concentration of cryoprotectant agents and allows the cells and extracellular milieu to solidify into a glass-like state. This study aimed to provide objective information on the available data regarding singleton births comparing embryo vitrification with fresh embryo transfers.
Methods: PubMed and Cochrane databases were searched for studies conducted up to 2017. Low birth weight (LBW), very low birth weight (VLBW), preterm birth (PTB), very PTB, small for gestational age (SGA), large for gestational age, perinatal mortality, cesarean section, and preeclampsia were measured.
Results: The search returned 220 articles, and 13 of these met the inclusion criteria. A significantly lower risk of SGA birth was observed in the vitrified embryo transfer group than in the fresh transfer group. Conversely, a higher risk of very PTB, VLBW, large size for gestational age, and perinatal mortality was observed more frequently in the vitrified embryo transfer group.
Conclusions: Vitrified embryo transfer was associated with the improved outcome of neonates regarding the SGA rate compared with fresh embryo transfer, but included a higher risk of very PTB, VLBW, large size for gestational age, and perinatal mortality. Caution should be exercised in interpreting these findings given the low level of evidence of the studies.

Keywords: Birth; Embryo Transfer; Neonate; Vitrification


How to cite this article:
Li CH, Cheng DK, Yu HJ, Li CY, Ren HQ, Weng N, Li BS, Yang N, Xu P. Comparative neonatal outcomes of vitrified versus fresh embryo transfers: A systematic review and meta-analysis. Reprod Dev Med 2020;4:177-83

How to cite this URL:
Li CH, Cheng DK, Yu HJ, Li CY, Ren HQ, Weng N, Li BS, Yang N, Xu P. Comparative neonatal outcomes of vitrified versus fresh embryo transfers: A systematic review and meta-analysis. Reprod Dev Med [serial online] 2020 [cited 2020 Oct 28];4:177-83. Available from: https://www.repdevmed.org/text.asp?2020/4/3/177/288961




  Introduction Top


With the development of assisted reproductive technology (ART), a large number of embryos are being frozen, and embryo cryopreservation is becoming an increasingly important part of successful ART treatment. The slow freezing of embryos has been used for over 30 years, and data concerning infant outcome seem reassuring given that the process results in singletons with higher birth weights and lower rates of preterm birth (PTB) and low birth weights (LBWs) compared with singletons born as a result of freshin vitro fertilization (IVF)/intracytoplasmic sperm injection.[1] Vitrification of embryos wasfirst clinically introduced in Australia in 2006,[2],[3] and limited data have been reported on obstetric and neonatal outcomes compared with fresh embryos. Compared with the traditional slow-freezing method, vitrification is relatively simple, inexpensive, and potentially faster as the ultra-rapid cooling technique requires no expensive programmable freezing instrument. Moreover, it could prevent ice formation, which is thought to damage cell structures.[4],[5],[6] Data from systematic reviews comparing the slow-freezing and vitrification methods suggest that vitrification is better than slow freezing for the cryopreservation of all developmental stages, from mature oocytes to embryos at the blastocyst stage.[7] In their meta-analysis, AbdelHafez et al. find that embryo vitrification is superior to slow freezing in terms of survival rate, clinical pregnancy rate, and implantation rate,[8] although they do not report the perinatal outcomes. Due to the potential cytotoxicity related to high concentrations of cryoprotectants in vitrification and the potential liquid nitrogen contamination associated with vitrification, there are still concerns regarding the safety of the procedure.[9]

Several systematic reviews and cohort studies indicate similar or even better neonatal outcomes for singletons born as a result of cryopreservation compared with those born as a result of fresh embryo transfer regardless of the freezing method.[10],[11],[12],[13] However, a higher rate of large-for-gestational-age (LGA) births was observed in singletons born as a result of cryotransfer compared with those born as a result of fresh embryo transfer.[14] There is no systematic review that compares the perinatal and neonatal outcomes of vitrified embryo transfer with those of fresh embryo transfer. To date, there have been a limited number of single-center studies that investigate the perinatal outcomes of births following the vitrification of embryos compared with those following fresh transfer controls.[15]

Because it is difficult to perform a large-scale prospective study in a single institution to compare the outcomes of vitrified versus fresh embryo transfer due to ART,[16],[17] a meta-analysis seems to be the best option. However, the major limitation of meta-analysis is heterogeneity of studies included.

One limitation of previous meta-analyses regarding this topic is that the researchers merged data from fresh and frozen embryo transfers (FETs) and did not consider the effect of the freezing method on the results. The aim of this systematic review and meta-analysis is to compare the perinatal outcomes of singleton pregnancies resulting from vitrified embryo transfer with those resulting from fresh embryo transfer and to assess whether vitrification is superior to fresh cycles.


  Methods Top


Selection of studies and data search

A systematic review was conducted to identify all studies that compared perinatal outcomes of vitrified embryo transfer to those of fresh embryo transfer. Our inclusion criteria comprised both observational and prospective study designs. The studies were independently reviewed for possible inclusion by two authors (L.C.H. and C.D.K.) using Medline, EMBASE, Cochrane Central Register of Controlled Trials, DARE, and CINAHL. After the titles and abstracts retrieved by the search were initially screened, the full texts of all potentially eligible studies were obtained.

A systematic search was conducted using the following keywords: "fresh AND (vitrified OR vitrification OR freezing) AND (perinatal OR neonatal OR birth) AND embryo" to identify all the potentially relevant studies published in the English language up to December 2017.

Data extraction

Data were extracted from eligible studies, and predesigned forms were independently completed by two authors L.C.H and C.D.K. Any discrepancy was resolved by consulting with a third author Y.H.J. For the selected studies, quality assessments were performed using the Newcastle–Ottawa Quality Assessment Scale (NOS) for selection, comparability at baseline, exposure, or outcome measure and were reported on a scale of zero to nine stars.

Description of studies

Our electronic search retrieved 220 articles. After we screened titles and abstracts, we determined that 198 of these articles did not include the objectives of our meta-analysis; thus, we obtained the full texts of 22 articles, and we further identified five articles through a manual search based on the studies' reference lists. Of these 27 articles, 14 were excluded for the following reasons: the articles did not contain relevant comparisons or outcome measures (n = 8), the articles did not mention the cryopreservation method (n = 3), and the articles were reviews (n = 3). Thirteen retrospective/cohort studies were included in the completed review [Figure 1]. All studies scored ≥6 on the NOS checklists, and the data were pooled from the previously mentioned databases.
Figure 1: Selection of studies included in the article.

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Characteristics of included studies

Thirteen eligible studies with a total of 53,619 participants who reported obstetric and perinatal outcomes of vitrified and fresh embryo transfer cycles were included in the present study. The study characteristics are provided in [Supplementary Table 1]. Of these studies, seven included blastocysts,[17],[18],[19],[20],[21],[22],[23] two included cleavage-stage embryos,[24],[25] two included both blastocysts and cleavage-stage embryos,[26],[27] one included 2PN embryos,[15] and one did not mention the embryo freezing stage.[28]



Outcomes

The outcomes were LBW, very LBW, PTB, very PTB, small for gestational age (SGA), LGA, perinatal mortality, cesarean section, and preeclampsia.

LBW and very LBW were defined as a birth weight <2,500 and 1,500 g, respectively. PTB was defined as live birth before 37 weeks' gestation, while very PTB was defined as live birth before 32–34 weeks' gestation. SGA was defined as a birth weight below the 10th percentile, whereas LGA was defined as a birth weight above the 90th percentile.

Statistical analysis and assessment for heterogeneity

Statistical analysis was carried out using RevMan 5.3 (The Cochrane Collaboration, Oxford, UK). For dichotomous outcome data, the Mantel–Hazel method was used. We considered whether the clinical and methodological characteristics of the included studies were sufficiently similar to one another for meta-analysis to provide a clinically meaningful summary was considered. Forest plots were used to graphically evaluate the heterogeneity of the exposure effects, and I2 was applied to assess the heterogeneity between studies. I2 represented the percentage of total variation in the estimated effect across studies, with I2 > 50% indicating substantial heterogeneity. A sensitivity analysis was performed by altering the fixed-to-random effect analysis in the event of moderate heterogeneity (I2 > 50%). P < 0.05 was considered statistically significant.


  Results Top


Outcome of measures

Preterm birth (<37 weeks)

PTBs were assessed in 10 studies (vitrified [n = 17,262] vs. fresh [n = 21,240]). The rate of PTB in singletons born after vitrified embryo transfer was similar to that of those born after fresh embryo transfer (relative risk [RR] = 1.04, 95% confidence interval [CI] = 0.83–1.31, P = 0.75, I2 = 64%) [Figure 2].
Figure 2: Forest plot showing the results of meta-analysis of studies comparing preterm birth after frozen blood transfusion versus fresh blood transfusion.

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Very preterm birth (preterm birth < 32 weeks/< 34 weeks)

Cases of very PTB were analyzed in nine studies (vitrified [n = 17,036] vs. fresh (n = 20,733)). The overall effect size revealed a significant difference between vitrified and fresh embryo transfer (RR = 1.61, 95% CI = 1.22–2.13, P = 0.0008, I2 = 0%). A subgroup analysis of singletons born after < 32 weeks' gestation revealed a higher risk of very PTB in cases of vitrified embryo transfer compared with fresh embryo transfer (RR = 1.75, 95% CI = 1.29–2.37, P = 0.0003, I2 = 0%). A subgroup analysis of singletons born after < 34 weeks' gestation did not reveal any significant differences between cases of vitrified and fresh embryo transfer (RR = 1.06, 95% CI = 0.53–2.14, P = 0.86, I2 = 0%) [Figure 3].
Figure 3: Forest plot showing the results of meta-analysis of studies comparing very preterm birth after frozen blood transfusion versus fresh blood transfusion.

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Small for gestational age

SGA was addressed in six studies (vitrified (n = 17,930) vs. fresh [n = 30,237]). The pooled estimate showed a significantly lower risk of SGA births in cases of vitrified embryo transfer compared with cases of fresh embryo transfer (RR = 0.82, 95% CI = 0.72–0.93, P = 0.002, I2 = 0%) [Figure 4].
Figure 4: Forest plot showing the results of meta-analysis of studies comparing small for gestational age after frozen blood transfusion versus fresh blood transfusion.

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Large for gestational age

LGA was investigated in four studies (vitrified (n = 14,908) vs. fresh (n = 16,538)), and a significantly higher risk of LGA in singletons born as a result of vitrified embryo transfer compared with those born as a result of fresh embryo transfer was revealed (RR = 1.86, 95% CI = 1.29–2.66, P = 0.0008, I2 = 63%) [Figure 5].
Figure 5: Forest plot showing the results of meta-analysis of studies comparing large for gestational age after frozen blood transfusion versus fresh blood transfusion.

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Low birth weight (< 2,500 g)

LBW (< 2,500 g) was evaluated in 11 studies (vitrified [n = 17,448] vs. fresh [n = 21,511]). There was no significant difference in the rate of LBW between vitrified and fresh embryo transfer (RR = 1.10, 95% CI = 0.98–1.24, P = 0.11, I2 = 17%) [Supplementary Figure 1].



Very low birth weight (< 1,500 g)

Very LBW (< 1,500 g) was assessed in eight studies (vitrified [n = 15,965) vs. fresh [n = 19,296]). The results showed a significantly higher risk of very LBW in the vitrified embryo transfer group compared with the fresh embryo transfer group (RR = 1.47, 95% CI = 1.03–2.11; P = 0.04, I2 = 0%) [Supplementary Figure 2].



Perinatal mortality

The incidence of perinatal mortality was addressed in three studies (vitrified [n = 15,104] vs. fresh (n = 17,601)), revealing a significantly higher risk of perinatal mortality in singletons born as a result of vitrified embryo transfer compared with those born as a result of fresh embryo transfer (RR = 2.04, 95% CI = 1.11–3.73, P = 0.02, I2 = 0%) [Supplementary Figure 3].



Cesarean section

The proportion of cesarean sections was investigated in four studies (vitrified [n = 725] vs. fresh [n = 1,418]), and no significant difference was found between vitrified and fresh embryo transfer (RR = 1.02, 95% CI = 0.98–1.07, P = 0.29, I2 = 16%) [Supplementary Figure 4].



Preeclampsia

The risk of preeclampsia was analyzed in three studies (vitrified [n = 461] vs. fresh [n = 1,525]). The incidence of the vitrified embryo transfer group was slightly higher compared with the fresh embryo transfer group, but there was no statistical significance between the two groups (RR = 1.73, 95% CI = 0.76–3.93, P = 0.19, I2 = 72%) [Supplementary Figure 5].




  Discussion Top


Previous systematic reviews comparing perinatal and neonatal outcomes of singleton pregnancies between frozen and fresh embryo transfer have not considered the effect of the freezing method.[29] This systematic review compared the perinatal and neonatal outcomes of vitrification with those of fresh embryo transfer for thefirst time.

Some evidence indicates that obstetrics outcomes, such as PTB, SGA, and LBW, might be improved after FET.[30],[31],[32] One meta-analysis comparing perinatal outcomes of frozen versus fresh embryo transfer indicated that PTB, very PTB, SGA, LBW, and perinatal mortality were significantly lower in women who received a FET compared with those who received a fresh embryo transfer. The FET was associated with an increased risk of cesarean section compared with the fresh embryo transfer. There was no significant difference in very LBW between the frozen and fresh groups.[33] Some of our outcomes are inconsistent with those results comparing frozen and fresh embryo transfer.[11],[33],[34],[35]

Unlike previous studies that compared frozen with fresh embryo transfer, our results indicate that the vitrified cycles are associated with a higher risk of very PTB (RR = 1.61, 95% CI = 1.22–2.13) and very LBW (RR = 1.47, 95% CI = 1.03–2.11) compared with fresh cycles. There are several possible explanations for this. First, previous meta-analyses included both slow freezing and vitrification,[34] while our research included only vitrification methods using high-concentration cryoprotectant. Further evidence is needed to determine whether vitrification induces changes in the developmental processes in the early embryo stages and hence changes the intrauterine growth potential. Second, most reports investigating neonatal outcomes after the transfer of vitrified embryos have used blastocyst-stage embryos.[17] No report separately compared oocytes, cleavage-stage embryos, and blastocysts of vitrified and fresh cycles. Our comparison included both cleavage-stage embryos and blastocysts and thus might yield different results from the previous studies. Third, the proportion of two embryos transfer is high in conventional fresh cycle.[36],[37] The article with the largest sample size, both fresh and frozen groups, is single-embryo transfer. Therefore, the conclusions may be different from other articles. More well-designed randomized trials are needed before a definitive conclusion can be drawn regarding this issue. One study concerning prematurity and LBW suggested that these perinatal outcomes are associated with future health implications, such as adult-onset cardiovascular diseases.[38] Further investigation and validation of these findings are needed.

Furthermore, this article indicated that the vitrified embryo transfer group had a higher incidence of LGA than the fresh embryo transfer group. One possible reason for this might be undergoing controlled ovarian stimulation, and the expression of E2 andPreceptors is altered in stimulated cycles, indicating an advance in the endometrium maturation compared with natural cycles, which may alter the subsequent trajectory of fetal growth and development.[39] One study comparing LGA and appropriate-gestational-age (AGA) infants reported that although LGA singletons were larger and had greater adiposity at birth, the rate of growth in length and weight decreases in LGA infants in early infancy, leading to a similar anthropometry in AGA infants by 6 months of age, and the differences observed in the early lives of LGA and AGA infants were not associated with epigenetic changes.[40]

In our study, the incidence of preeclampsia in the vitrified group was slightly higher than in the fresh group, but there was no statistical significance between the two groups. Embryo vitrification was found to cause aberrant methylation to H19-imprinted control regions, and this abnormal epigenetic modification was related to preeclampsia.[41],[42] However, in this review, only three studies involving a total of 1,986 singletons (vitrified [n = 461] vs. fresh [n = 1,525]) reported data regarding preeclampsia. Further studies with large sample sizes are needed to confirm whether vitrification is related to preeclampsia.

Limitations

As there are little well-designed randomized controlled trials reporting perinatal outcomes in singleton pregnancies that compare vitrified with fresh embryo transfers,[43] this article is limited to data from observational studies. Hence, the evidence was considered low-grade despite 53,619 participants included in this study. There were heterogeneity for the studies not only in design but also in population and ascertainment of outcomes. We were also unable to adjust for confounders such as age, duration of infertility, and preexisting medical illness. Furthermore, four of the outcomes (LGA, perinatal mortality, cesarean section, and preeclampsia) have been reported by very few studies. Although the vitrification of embryos is now a well-established procedure, long-term follow-up studies of children born as a result of embryo vitrification are still scarce. In addition, more research is required to determine whether vitrification affects other factors in IVF.

In conclusion, this meta-analysis of the neonatal outcomes of pregnancy after vitrified embryo transfer compared with those after fresh embryo transfer showed that compared with fresh transfers, vitrified embryo transfer is associated with improved outcomes of neonates regarding the rates of SGA, but is associated with a higher risk of very PTB, very LBW, LGA, and perinatal mortality. Therefore, more data are needed to determine the potential cytotoxic effects of the cryoprotectant and whether embryos are ready for long-term storage. With more vitrification applications, more problems will arise, including its unsolved inherent medical risks and emerging social risks concerning the health and outcomes of children born as a result of vitrification. Long-term follow-up studies are still needed to evaluate the health of children born as a result of vitrified embryo transfer.

Acknowledgments

We acknowledge the professional language editing services of ELSEVIER Author Services.

Supplementary information is linked to the online version of the paper on the Reproductive and Developmental Medicine website.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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