Neonatal Outcomes of Children Born from Frozen Embryo: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Giuseppe Gullo.

The growing use of ART (assisted reproductive techniques) has led to a progressive improvement of protocols; embryo freezing is certainly one of the most important innovations. This technique is selectively offered as a tailored approach to reduce the incidence of multiple pregnancies and, most importantly, to lower the risk of developing ovarian hyperstimulation syndrome when used in conjunction with an ovulation-triggering GnRH antagonist. The increase in transfer cycles with frozen embryos made it possible to study the effects of the technique in children thus conceived. Particularly noteworthy is the increase in macrosomal and LGA (large for gestational age) newborns, in addition to a decrease in SGA (small for gestational age) and LBW (low birth weight) newborns.

  • fresh embryo transfer
  • frozen embryo transfer
  • cryopreservation

1. Introduction

Gynecological diseases can lead to severe consequences for the quality of life of those affected [1]. Among these, infertility plays a central role. This is defined as the inability to conceive after at least one year of unprotected intercourse, and it has reached a global prevalence of 15% of couples at reproductive age [2]. The prevalence in the 1990–2017 period grew both for male (by 8.224% from 710.19 per 100,000 to 768.59 per 100,000, i.e., a 0.291% increase on a yearly basis) and female infertility (by 14.962% from 1366.85 per 100, to 1571.35 per 100 in 2017, a 0.370% increase every year) [3]. However, the increase in the prevalence of infertility and subfertility has led to an increasing demand for the use of assisted reproduction techniques. In particular, with the progress of conservation techniques in recent years, frozen embryo transfer has spread rapidly, giving rise to medical as well as ethical debates [4,5,6,7,8][4][5][6][7][8]. This technique, especially freezing by vitrification, lowers the likelihood of multiple pregnancies as well as the risk of incurring ovarian hyperstimulation syndrome. No significant differences have been found compared to transfer from fresh embryo in terms of pregnancy rate per cycle (63.1% vs. 60.9%) and the clinical pregnancy rate per cycle (55.4% vs. 58.7%) [9,10][9][10]. At the same time, as the technique has spread, several authors have investigated the possible issues related to it, such as the greater risk of hypertension syndrome and the increase in macrosomal and Large for Gestational age (LGA) newborns.

2. Differences in Neonatal Outcomes between Freezing Methods

The recent improvements in freezing techniques has led to a gradual abandonment of the slow-freeze technique with cleavage stage embryos in favor of vitrification at the blastocyst stage. Studies comparing the outcomes of the two techniques are still few and with conflicting conclusions. Ginström Ernstad et al. [21][11] conducted a cohort study published in 2019 in which they found comparable neonatal outcomes in children born from the two different techniques. However, Liu et al. [36][12], comparing techniques, found a median birthweight from vitrified embryos (3455.3 g) higher than those from slow freezing (3352.3 g) and fresh (3355.8 g) transfers. The rate of perinatal mortality is instead reported as comparable between the three groups.
Moreover, in a cohort study published in 2014, Li et al. [34][13] suggested that the freezing method can influence neonatal outcome; in particular, they found an higher clinical pregnancy rate in vitrified blastocyst transfer cycles than in slow frozen blastocyst transfer cycles.
In addition, Alviggi et al. [47][14] suggested that the freezing method and the time of transfer may influence pregnancy outcomes in terms of preterm birth, very preterm birth, LGA, SGA, and perinatal mortality.

3. The Role of Confounding Factors

Although most authors agree on the data regarding birth weight, doubts do arise in some studies. According to Ainsworth et al. [19][15], in fact, there is no difference in birth weight when adjusting for gestational age, sex, and maternal factors. However, Vidal et al. [30][16], in a 2017 cohort study, argue that adjusted regression model birthweight is significantly higher in the fresh ET group than the frozen one. In a retrospective cohort study published in 2019, Maris et al. [23][17] also found a higher birthweight after a multivariate analysis adjusted according to confounding factors such as gestational age, maternal age, maternal body mass index (BMI), tobacco exposure, the number of embryos transferred, and birth order. In a 2014 cohort study, Pinborg et al. [33][18] argued that the increased risk of LGA newborns could not be related exclusively to intrinsic maternal factors, but must necessarily be related, at least for the most part, to the freezing procedure. According to Pirtea et al. [14][19], the difference found in neonatal outcomes derives from issues regarding the depth of placentation, possibly being too shallow in the fresh ET group. For Berntsen et al. [26][20], further studies are needed to define what changes, probably epigenetic, may stem from frozen embryo transfers.

4. Congenital Malformations and Long-Term Outcome in Children

In a 1997 study by Wennerholm et al., 255 children from cryopreserved embryos were matched (regard to maternal age, date of delivery, and parity, single or twin pregnancy), with 255 children born after IVF with fresh embryos, and 252 children from spontaneous pregnancies [42][21]. Growth features were similar for both singletons and twins in the three groups. There were six (2.4%) major malformations in the cryopreserved group, nine in standard IVF group (3.5%), and eight (3.2%) in naturally conceived group.
The prevalence of chronic diseases during infancy and early childhood did not differ between the three groups (18.0%, 15.3%, and 16.7% in the cryopreserved group, standard IVF, and spontaneous groups, respectively). In that paper, occurrences of minor behavioral disturbances, learning difficulties, and attention and perception deficits were not reported because of too young an age of the children involved. In the following years, as mentioned above, few studies focused on the long-term health outcomes not exclusively neonatal of children born from frozen embryos. In an RCT published in 2020, Vuong et al. [15][22] performed follow-ups of children in the study group (consisting of 391 pairs) until an age of 37 months. Developmental screening was performed using the well-known ASQ-3 questionnaire that covers 5 domains: communication, gross motor, fine motor, problem solving, and personal social behavior. The study reported relevant findings: problem solving scores were found to be higher in the frozen ET group than in the fresh ET group, but not when singletons and twins were analyzed separately. Other data in favor of the frozen ET group concerned the fine motor skills in the overall analysis (p = 0.056 vs. fresh ET) and twins (p = 0.06 vs. fresh ET) but not in singletons. There were no significant differences in the prevalence of abnormal ASQ-3 scores found among the study groups. This finding is important and indicates that there is no difference in the incidence of neurodevelopmental abnormalities, although for some developmental domains, the scores of children born from frozen embryos are even better. The few data available, however, do not allow for a determination as to whether any difference exists when considering singletons separately from twins.
The same aspect has been evaluated by Djuwantono et al. [18][23] in a 2020 review; in particular, these authors do not report a higher rate of neurodevelopmental abnormalities in children born after frozen embryo transfers. The already-mentioned prospective study by Belva et al. [32][24] collected data from 960 cycles after frozen embryo transfers and 1644 cycles after fresh embryo transfers, performed between 2008 and 2013. Follow-up was performed in the 3 months after birth with a close focus on congenital malformations. Children’s pediatricians were blinded to the transfer method. Data were adjusted for treatment variables and maternal characteristics. The mothers of the children belonging to the frozen ET group tended to be older and more prone to pregnancy-related hypertension, a finding already known in the literature. As for the frequency of major congenital malformations in live births (i.e., malformations that have both a morphological and functional impact), it was found to be comparable between the vitrified group and the fresh group, both among singletons and twins. Even considering major and minor malformations together, the study groups had similar rates. Zhang et al. [28][25], in a 2018 retrospective cohort study, and Maheshwari et al. [25][26] in a 2018 review also reported similar congenital malformation rates between frozen ET groups and fresh ET groups. Ainsworth et al. [22][27] focused on child growth by including 136 women in the study, 87 of whom underwent a fresh embryo transfer and 49 a frozen embryo transfer. Age- and sex-specific weight and body mass index results, considering percentiles, were comparable between the study groups.
Only one retrospective cohort study published in 2019 reported a comparison regarding other health outcomes. Significantly, such a study found that babies born from frozen embryos had greater odds of infectious disease (AOR = 1.46), respiratory conditions (AOR = 1.23), and neurological (AOR = 1.32) conditions. No statistically significant differences were found for birth defects, cardiovascular, hematologic, and gastrointestinal/feeding conditions. [24][28]
In light of the limitations due to the dearth of currently available research data, Table 1 summarizes the long-term follow-up of children born from frozen embryos.
Table 1.
Comparison of long-term health aspects in children between frozen embryo and fresh embryo methods.
Compared Long Term Follow-Up in Children between Freezing Methods
Frozen Embryo > Fresh Embryo Frozen Embryo = Fresh Embryo Frozen Embryo < Fresh Embryo
Problem solving scores Congenital malformations rate  
Fine motricity scores ND prevalence  
  Age- and sex-specific BMI and

weight		  
  Growth and chronic diseases  
BMI: body max index; ND: neurodevelopmental disorders.

References

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