PRECIS: The early miscarriage rate in fresh embryo transfer was higher, but other complications were not different between the two groups.

Introduction

Infertility is defined as failure to achieve pregnancy after a year of unprotected sexual intercourse without the use of contraceptive methods. Infertility affects an average of 10% of couples of the reproductive age. Risk factors for infertility include old reproductive age, genetic disorders, infections, and environmental pollutants^(1,2,3).

There are few methods of assisted reproductive technology, such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and intrauterine insemination. In IVF, eggs extracted from the ovary are fertilized with sperm in the laboratory. If infertility is also caused by a male factor, ICSI is also performed with IVF^(1,2,3).

In IVF, there are two methods of embryo transfer: Frozen and fresh. In fresh embryo transfer, the embryos are transferred to the uterus in the same hormonal stimulation cycle. However, in frozen embryo transfer, the embryos are frozen and later taken to the uterus in a normal cycle or a cycle in which the endometrium has been prepared with hormone therapy. Factors affecting the selection of frozen or fresh embryos can depend on the progesterone level of the mother, endometrial thickness, polycystic ovary syndrome, and maternal age^(1,2,3).

Many studies have compared fresh and frozen embryo transfer in terms of pregnancy outcomes and complications. However, their results vary and do not provide a firm conclusion on the matter. The goal of this study was to compare maternal complications in two methods of IVF pregnancies, frozen and fresh embryo transfer, during pregnancy.

Materials and Methods

This is a retrospective cohort study and was approved by the Ethics Committee of Tehran University of Medical Sciences (approval number: IR.TUMS.MEDICINE.REC.1400.061, date: 17.04.2021). All data were gathered through patient files in the hospital and phone calls. Patient information was kept private, and each patient was given a specific code to keep the information private. All stages of this study complied with the Declaration of Helsinki.

Study samples were infertile women treated with IVF/ICSI who were referred to Shariati Hospital Infertility Center from 2018 to 2021 and became pregnant. The exclusion criteria were unable to make phone calls, lack of data files, if embryo or egg was donated, and if pregnancy was surrogacy.

Three hundred ninety-six infertile women received IVF/ICSI treatment. Three hundred two of them (76%) received frozen embryo transfer and 94 of them (24%) received fresh embryo transfer. Patients in both groups were similar in terms of age (shown in Figure 1) and number of transferred embryos (p>0.05). Endometrial preparation for the frozen embryo transfer group was performed artificially using hormones. Data concerning maternal complications were gathered, and the two groups of fresh and frozen embryo transfer were compared in terms of threatened miscarriage, early miscarriage, placenta previa occurrence, gestational hypertension, gestational diabetes, preterm birth, and pre-eclampsia.

The two groups were not similar in size due to the lack of fresh embryo transfer patients who were referred to the hospital for treatment. Frozen embryo transfer was much more popular; therefore, embryo transfers are mostly frozen. This matter should not significantly affect the statistical outcomes of this study because of the high patient count in both groups compared to past studies⁽⁴⁾.

Statistical Analysis

Data regarding infertility duration, number of oocytes retrieved, total gonadotrophin dose used, and number of blastocysts did not exist in the hospital files or were not gathered; therefore, they are not mentioned in this study. In addition, the pre-implantation genetic testing for aneuploidy) test was not performed for any patient.

Comparison of the groups was performed using Fisher’s exact test, independent sample t-test, and chi-square test. Data analysis was performed using IBM SPSS 26 and significance level was less than 0.05.

Results

The patient characteristics in both groups are shown in Table 1. Patient’s age was 31.4 vs. 31.6 years and was similar in both groups (p=0.722). The number of transferred embryos was 2.7 vs. 2.5 and was similar between groups (p=0.081).

Maternal complications are listed in Table 2. Early miscarriage in the frozen vs. fresh group was 16.2% vs. 34%, and the fresh embryo transfer group was significantly higher than the frozen embryo transfer group (p<0.001). Threatened miscarriage was 9.9% vs. 7.4% and was not different between the two groups (p=0.469). Placenta previa occurrence was 4.3% vs. 4.8% and was not different between the two groups (p=0.743). Preterm birth was 26.8% vs. 24.5% and was not different between the two groups (p=0.651). Gestational diabetes was 16.9% vs. 15.3% and was not different between the two groups (p=0.098). Gestational hypertension was 8.2% vs. 6.7% and was not different between the two groups (p=1). Pre-eclampsia was 5.3% vs. 3.3% and was not different between the two groups (p=0.744).

It is worth mentioning that other maternal complications such as premature rupture of the membrane did not occur in any patient.

Discussion

Early Miscarriage

In past studies, the early pregnancy loss rate in frozen vs. fresh embryo transfer was not significantly different^(4,5,6,7) and is as follows: 7.8% vs. 6.8%⁽⁴⁾, 13.3% vs. 19.4%⁽⁵⁾, 9.6% vs. 13.1%⁽⁶⁾ and 21.5% vs. 25.3%⁽⁷⁾. Zargar et al.⁽⁸⁾ found that first trimester loss was much higher in the fresh embryo transfer group (17.69% vs. 23.01%). Our results (16.2% vs. 34%) show that the chance of early miscarriage in the fresh embryo transfer group is 2.66 times higher than that in the frozen embryo transfer group. Higher early miscarriage rate in fresh embryo transfer may be due to the effect of hormones on the endometrium. Because in fresh embryo transfer, the embryos are taken to the uterus in the same ovarian stimulation cycle, the endometrium is under the influence of high levels of progesterone and estrogen. Theories have proposed that estrogen interferes with the angiogenesis of the endometrium and therefore has a negative effect on the continuation of pregnancy. In addition, ovulation stimulation by hormone therapy causes incoordination between the endometrium and embryo and thus has a negative effect on the implantation of the embryo in the uterus^(5,9,10).

Threatened Miscarriage

Korosec et al.⁽¹¹⁾ found that first trimester bleeding occurrence was not different between the frozen and fresh groups (6.6% vs. 8.1%). Our results show no difference between groups and are similar to those of a previous study (9.9% vs. 7.4%).

Placenta Previa

Wikland et al.⁽¹²⁾  concluded that placenta previa occurrence is not different between frozen and fresh embryo transfer (1% vs. 2.5%). However, according to Korosec et al.⁽¹¹⁾, Sazonova et al.⁽¹³⁾ and Sha et al.⁽¹⁴⁾, placenta previa occurrence was much higher in fresh embryo transfer [adjusted odds ratio (AOR) 0.32 [5% confidence interval (CI) 0.19-0.55)⁽¹¹⁾ and 0% vs. 3.5%⁽¹³⁾]. Ishihara et al.⁽¹⁵⁾ found that placenta previa occurrence was much higher in frozen embryo transfer (AOR 3.16, 95% CI 1.71-6.23). Also, Rombauts et al.⁽¹⁶⁾ concluded that increased risk of placenta previa is not related to the type of embryo transfer (fresh and frozen), but is related to the type of endometrial preparation. Our results showed no difference between frozen and fresh embryo transfer (4.3% vs. 4.8%).

Preterm Birth

Preterm birth rate was not different in frozen vs. fresh embryo transfer according to past studies^{(6,11,17,18,19)} (18.7% vs. 15.9%⁽⁶⁾, 9% vs. 12.1%⁽¹¹⁾, 21.2% vs. 18.8%⁽¹⁷⁾, 4.9% vs. 5.8%⁽¹⁸⁾, and 7.2% vs. 7.5%⁽¹⁹⁾). However, some studies found that the preterm birth rate was higher in fresh embryo transfer^(7,8,15) [0% vs. 11.1%⁽⁷⁾, 3.93% vs. 8.3%⁽⁸⁾ and AOR 0.90 (95% CI 0.82-0.98)⁽¹⁵⁾]. Our results showed no difference between frozen and fresh embryo transfer (26.8% vs. 24.5%).

Gestational Diabetes

Past studies have shown that gestational diabetes is not different between frozen and fresh embryo transfer^{(4,7,8,12,13,14,18,19)} (3.1% vs. 3.9%⁽⁴⁾, 1.8% vs. 0%⁽⁷⁾, 23.66% vs. 24.64%⁽⁸⁾, 2.9% vs. 2%⁽¹²⁾, 0.9% vs. 1.5%⁽¹³⁾, 1.3% vs. 1.8%⁽¹⁸⁾ and 7.2% vs. 8%⁽¹⁹⁾). Our results show no difference between groups and are similar to those of past studies (16.9% vs. 15.3%).

Gestational Hypertension

Many studies have found that gestational hypertension is not different between frozen and fresh embryo transfer^{(4,6,7,12,18)} (0.9% vs. 1.1%⁽⁴⁾, 2.3% vs. 1.2%⁽⁶⁾, 3.5% vs. 3.6%⁽⁷⁾, 1.9% vs. 1%⁽¹²⁾ and 0.8% vs. 1.3%⁽¹⁸⁾). However, another study by Ishihara et al.⁽¹⁵⁾ found that gestational hypertension was higher in frozen embryo transfer [AOR 1.58 (95% CI 1.35-1.86]). Our study showed no difference between the frozen and fresh groups (8.2% vs. 6.7%).

Pre-eclampsia

Some studies have shown that pre-eclampsia is not different between frozen and fresh embryo transfer^{(4,7,8,12,18,19)} (4.4% vs. 3.3%⁽⁴⁾, 7.0% vs. 7.3%⁽⁷⁾, 7.3% vs. 7.66%⁽⁸⁾, 2.9% vs. 3%⁽¹²⁾, 0.5% vs. 0.3%⁽¹⁸⁾ and 2% vs. 1.4%⁽¹⁹⁾). However, other studies found a higher pre-eclampsia rate in frozen embryo transfer^(6,13,20) [4.4% vs. 1.4%⁽⁶⁾, AOR 1.32 (95% CI 1.07-1.63)⁽¹³⁾ and 3.1% vs. 1%⁽²⁰⁾]. Our study found no difference between the frozen and fresh groups (5.3% vs. 3.3%).

In fresh embryo transfer, the time to get pregnant is shorter compared with frozen embryo transfer. However, frozen embryo transfer has some advantages, such as reducing the risk of contracting OHSS, the ability to characterize embryo quality through genetics before implantation, and adjusting the natural physiological environment for better implantation.

In general, the early miscarriage rate, gestational hypertension rate, pre-eclampsia rate, and placenta previa rate for fresh and frozen embryo transfer differ in past studies. However, all studies concluded that the gestational diabetes rate and threatened miscarriage rate are similar in fresh and frozen embryo transfer.

Study Limitations

The retrospective nature of this study was a limitation. Prospective cohort studies and accurate long-term follow-up of patients can lead to a better understanding of the complications of embryo transfer methods. For future studies, it is suggested to evaluate the cost-effectiveness of these methods.

Conclusion

Fresh embryo transfer can increase the early miscarriage rate in IVF patients, and frozen embryo transfer is safer.

Ethics

Ethics Committee Approval: This is a retrospective cohort study and was approved by the Ethics Committee of Tehran University of Medical Sciences (approval number: IR.TUMS.MEDICINE.REC.1400.061, date: 17.04.2021).

Informed Consent: Informed consent was obtained from all participants.

Peer-review: Internally peer-reviewed.

Authorship Contributionsx

Surgical and Medical Practices: S.H., Concept: S.H., M.Z., S.M.G., Design: S.H., M.Z., H.Z., Data Collection or Processing: S.H., M.Z., S.M.G., Analysis or Interpretation: S.H., H.Z., Literature Search: M.Z., S.M.G., Writing: S.H., M.Z., S.M.G.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.