Development of assisted reproductive technology and its contribution to reproductive health
On November 10, 1977, laparoscopic egg retrieval, in vitro fertilization (IVF), and embryo growth in the culture medium were achieved for the first time, followed by the first successful transfer of an 8-cell embryo into the uterus. Eight months later, on July 25, 1978, the first IVF baby was safely delivered by cesarean section with a healthy female baby weighing 2700 g[1]. Thereafter, assisted reproductive technology (ART) constituted an alternative tool for human reproduction and entered a phase of rapid development. The first successful pregnancy following frozen embryo transfer was reported in 1983[2], and the first successful delivery via gestational surrogacy was reported in 1985[3]. In 1988, the first child was born after oocyte donation[4]. In 1990, preimplantation genetic testing (PGT) was first used for the genetic analysis of the X chromosome in human embryos to avoid X chromosome aberrations[5]. In 1992, intracytoplasmic sperm injection (ICSI) was successfully performed in humans[6]. In 1999, cryopreservation of all embryos generated in a stimulated IVF cycle for subsequent transfer in a non-stimulated cycle was proposed as a new approach to reduce the risk of ovarian hyperstimulation syndrome[7]. Subsequently, the feasibility of elective single-embryo transfer (eSET) was first proposed in 2001[8]. As of 2018, more than 8 million IVF babies have been born worldwide, with more than 2.5 million ART cycles performed and over 500,000 deliveries achieved each year[9]. Today, with the age of marriage and conception rising and fertility rates decreasing, ART offers more comprehensive coverage and hope for patients with infertility.
The impact of ART on pregnancy outcomes and offspring health
Although its prospects are promising, ART is accompanied by many challenges. A 2017 study published by Luke et al. on women with low fertility, revealed a significantly increased risk of uterine bleeding, placental complications, antepartum hospitalization, initial cesarean delivery (CS), low and very low birth weights (LBWs), and preterm and very preterm births (PTBs) in women receiving IVF treatment[10]. Several studies have also explored the correlation between individuals treated with ART or with low fertility and adverse perinatal outcomes, such as prenatal hemorrhage, birth defects, hypertensive disorders of pregnancy, premature rupture of membranes, CS, and LBW, and have attempted to explore the mechanisms of the development of these outcomes in order to provide strategies and preventive options for future treatment[11]. Moreover, researchers have prioritized perinatal and postnatal safety in more recent iterations of ART development[12–15].
Multiple births have become more common since the early years of ART development. Several studies have reported increased rates of multiple births in infertile individuals undergoing ART. For example, in the Netherlands, the state of Victoria, Britain, and Denmark, a 28% increase in twin births and a 58% increase in triplet births were observed from 1979 to 1994[16–19].
Another cohort study also suggested that the causes of neonatal morbidity often involved LBW, PTB, and multiple births, and observed, for example, that the incidence of cerebral palsy was 1.6/1000 in singleton pregnancies, 13/1000 in twin pregnancies, and 28/1000 in triplet pregnancies[20]. Several studies from 2006 to 2010 reported a significant increase in the incidence of adverse perinatal outcomes such as reduced birth weight, PTB, LBW, and fetal growth restriction due to twin or multiple embryo transfers[21–23]. With the development of in vitro culture techniques and cryopreservation, eSETs have gradually begun to replace multiple embryo transfers. Since 2002, the Reproductive Technology Accreditation Committee in Australia and New Zealand has advocated for reducing adverse perinatal outcomes by reducing the number of multiple births[24]. In 2007, the Human Fertilization and Embryo Authority (HFEA) in the United Kingdom launched the collaborative “One at a Time” campaign to reduce high multiple births from IVF, and the multiple birth rate decreased most among patients aged under 35 years (from 27% in 2007 to 6% in 2019) and over 44 years (from 31% in 2007 to 5% in 2019) until 2019[25].
Large birth cohort studies have also explored the effects of ART on various organ systems of offspring[26,27], and although the conclusions vary widely, research continues. Epigenetic research has demonstrated that normal development depends on more than a healthy genome alone. Important epigenetic reprogramming occurs during gametogenesis and embryonic preimplantation, especially in imprinted genes of parental origin. This period includes a window of sensitivity to environmental changes that can alter the reprogramming process, thus affecting the survival and development of embryos. Some of the known mechanisms include cytosine adenine methylation, histone modifications, and control of gene expression by different microRNAs. Traditional knowledge refers to the “all or none” effects of physicochemical factors on the embryo two weeks after fertilization; “all” means leading to a definite abortion, while “none” means that the embryo continues to develop without abnormalities. Combined with epigenetic theory, the embryo continues to develop without any abnormalities that can be clearly observed for the time being, although the long-term effects are unknown. Embryo formation is a natural selection process. Therefore, one area of discussion is whether embryos that survive in harsh environments are better adapted for survival. Replicating the conditions of a realistic female reproductive system environment to reduce the unnatural effects of ART on the perinatal and postnatal development of offspring has become a common goal. In this study, we discuss the possible effects of each type of ART based on its characteristics.
Ovarian stimulation
Animal experiments have demonstrated that superovulation reduces the number of sperm in the oviduct, uterus, and anterior segment of the cervix of ewes and increases the proportion of quiescent, dead, or broken cell membranes[28]. Subsequent studies have found that supraphysiological levels of estrogen affect the endometrium, oocytes, embryo quality, and level of gene transcription in the endometrium in animal models such as rats[29], mice[30], and cattle[31]. Another human study demonstrated that ovarian stimulation decreased endometrial natural killer cell levels and the vascularization index, while increasing vascular endothelial growth factor levels[32]. Several long-term studies in both animals and humans have demonstrated that changes in hormone levels after superovulation affect the endometrium, oocytes, fallopian tube function, uterine environment, and maternal immune function before and after embryo implantation.
An observational study published in 2015 investigated all IVF cycles performed in the United Kingdom over a 17-year period starting in 1991. This study included 402,185 IVF cycles and 65,868 singleton live births. Women who underwent IVF and embryo transfer (IVF-ET) in a fresh cycle with a very high oocyte yield (>20) had an increased risk of PTB and LBW[33]. A retrospective cohort study estimated different perinatal outcomes with estradiol (E2) levels above or below the 95% cutoff value (3069.2 pg/mL) on the human chorionic gonadotropin trigger day and found an increased incidence of LBW in women who underwent fresh IVF-ET cycles with peak E2 > 3069.2 pg/mL[34]. In contrast, another retrospective study from 2018 indicated no association between poor neonatal outcomes and the number of oocytes harvested[35]. However, this study included only singleton live births (n = 27,359) after fresh IVF cycles in Sweden from 2002 to 2015.
Most studies, including both animal and human studies, have arrived at a similar conclusion that superovulation has a clear effect on the environment of the female reproductive system, oocytes, and embryo quality. However, the embryos that survive and develop after harsh environmental screening appear to be of higher quality. They may naturally adapt to harsh environments by epigenetic methods of self-modification and alteration during later development.
In vitro culture
In vitro culture of embryos involves constant exposure to microenvironments that differ from the natural environment of conception. This may include differences in oxygen concentration, pH, and temperature, all of which can become stressors and affect the growth and development of the embryo. The in vitro culture environment should be optimized to reduce its impact on embryos, through approaches that consider different perspectives.
Culture media
Early in the development of in vitro embryo culture, laboratories prepared their own culture medium. This has evolved into different commercial media manufacturers, providing their own distinct culture media. Although the techniques involved in in vitro embryo culture development are well established, the quality of culture media remains inconsistent, and detailed information regarding the culture medium composition used in ART is rarely available. Thus, there is a lack of research on this issue.
One study published in 2010 compared the pregnancy rates and perinatal outcomes from singleton pregnancies in 826 individuals who underwent first-time IVF cycles. Oocytes and embryos were randomly assigned to one of two commercially available culture systems, and the type of medium was found to be significantly associated with birth weight (P = 0.01), conclusively demonstrating that the in vitro culture of human embryos can affect the birthweight of live birth singletons[36]. Another study found significant differences in perinatal outcomes between groups of offspring from embryos developed in different media following singleton pregnancy, twin pregnancy, and frozen embryo transfer, thus clarifying that the in vitro culture process is an important factor that affects perinatal outcomes[37].
A study in 2014 included 1432 individuals who underwent fresh embryo transfer from July 2003 to December 2006, all of whom were randomly assigned to Vitrolite (n = 715) or Cook (n = 717) culture media. The growth and development of the offspring were followed for two years after birth. A significant difference in the weight at birth was observed between the two groups of offspring, and this difference persisted for the following 2 years. However, longitudinal observation of the growth rates of the offspring revealed no significant differences[38]. Another 2018 study on 9-year-old singleton IVF offspring found that the choice of in vitro culture medium was associated with differences in offspring body weight, body mass index (BMI), trunk obesity, waist circumference, and waist-to-hip ratio at 9 years of age, whereas no significant differences were observed in cardiovascular development[39]. A study by Kleijkers et al. epigenetically confirmed that gene expression in embryos was altered by the media used during IVF and provided insight into the biological pathways affected; however, it remains unclear whether these changes in gene expression have any long-term effects on children born after IVF[40].
The above research indicates that different media have clear effects on ART offspring, which may persist long after birth. However, there were no significant differences in the rate of growth and development between groups when offspring were observed longitudinally. Therefore, future studies should focus on the effects of culture media on embryo development. Moreover, work must be done to maintain the artificial culture environment in a manner as close as possible to that of natural embryonic development.
Duration of culture
A 2002 randomized controlled trial (RCT) that included 162 IVF patients randomized to day 3 embryo transfer (n = 82) and blastocyst transfer (n = 80) groups found that significantly fewer embryos were required for transfer at the blastocyst stage than at the day 3 stage, and that the rate of multiple pregnancies was significantly lower for blastocyst transfer. This suggests that fewer embryos are needed for transfer at the blastocyst stage than at the day 3 stage without reducing the overall pregnancy rate[41]. In contrast, in another RCT published in the same year, in which 90 couples were randomly assigned to day 3 (n = 44) or day 5 (n = 46) blastocyst-stage embryo transfers, individuals in the day 3 transfer group had more embryos suitable for transfer or cryopreservation (63.0%) than those in the day 5 transfer group (34.2%). The implantation rates were 38.7% in the day 3 transfer group and 20.2% in the day 5 transfer group. Thus, prolonging culture time may significantly reduce the success rate. This demonstrates that day 3 embryo transfer may be more beneficial than blastocyst transfer, and that the extended culture may negatively affect in vitro embryo development and implantation at the beginning of blastocyst transfer[42]. However, blastocyst transfer has become increasingly popular with the development of embryo culture technology. A single-center, randomized, open-label, active-controlled, non-inferiority study including 600 women between October 2015 and April 2017 found that the ongoing pregnancy rates from day 3 cleavage-stage SET using hierarchical classification time-lapse selection were significantly lower than those from day 5 blastocyst SET using conventional morphology[43].
A 2016 review that included 27 RCTs (4031 couples or women) found that live birth rates (OR 1.48, 95% CI: 1.20–1.82) and clinical pregnancy rates were higher in those in the blastocyst transfer group (OR 1.30, 95% CI: 1.14–1.47), embryo freezing rates were lower in those in the blastocyst group (OR 0.48, 95% CI: 0.40–0.57), and the rate of failure to transfer any embryos was higher in those in the blastocyst group (OR 2.50, 95% CI: 1.76–3.55)[44]. Three systematic reviews of studies from 2016 to 2018 summarized the literature related to the timing of in vitro culture, concluding that embryos transferred at the blastocyst stage were at a higher risk of extremely PTB and delivery[45–47].
A 2019 study included 3650 children born after vitrified blastocyst transfer, 8123 children born after slow freezing cleavage-stage embryo transfer, and 4469 children born after fresh blastocyst transfer from 2002 to 2015; the perinatal and gestational outcomes of the singleton babies born after vitrified blastocyst transfer, slow-frozen cleavage-stage transfer, and fresh blastocyst transfer were compared. The risk of PTB was higher in the vitrification blastocyst group than in the slow-frozen cleavage-stage group. No significant differences in the incidence of LBW, SGA, and LGA, or the risk of hypertensive disorders of pregnancy, placenta previa, placental abruption, and postpartum hemorrhage were observed between the vitrification blastocyst and slow-frozen cleavage-stage groups[48]. However, animal experiments have shown that the longer the in vitro culture and the embryo are exposed to an environment different from that of the human body, the more likely they are to be exposed to different stressors that can affect growth and development[49].
In conclusion, cleavage-stage embryo transfer was a standard practice in the early history of IVF. With the continued development of freezing technologies, blastocyst transfer has several benefits. First, the primary advantage of blastocyst transfer is facilitating eSET and reducing multiple pregnancies. Second, exposure of early embryos to superovulation and high estrogen levels may be detrimental to embryonic development[50]. Third, blastocysts have a greater implantation potential than cleavage-stage embryos. Advocates of blastocyst culture believe that only the most viable embryos will survive after extended culture (ie, up to day 5–6); the microenvironment is highly influential and less controllable. Therefore, there is still an urgent need for future RCTs to clarify the later-stage mechanisms of the effects of embryo transfer in different states at different time periods.
Research into various aspects of in vitro culture highlights the need to first establish an open and transparent community, define a specification for in vitro culture, determine optimal culture media and timing, and create a culture environment highly similar to that of humans to minimize its deleterious effects on epigenetic reprogramming and development. Second, we must determine the methods with which we can detect significant changes in the epigenetic characteristics of zygotes when using in vitro culture. The ability to characterize significant alterations in epigenetic characteristics will allow the development of suitable guidelines and preventive measures for the future health of ART offspring.
Intracytoplasmic sperm injection
Since the birth of the first child conceived by ICSI in 1992[6], ICSI has been the subject of controversy and interest. A wide range of patients with varying degrees of male factor infertility have been the largest beneficiaries of this technique.
In a prospective follow-up study published in 1998, a 2-year follow-up observation and clinical examination of 1987 ICSI-conceived children born between April 1991 and August 1997 showed no significant differences in intelligence quotient development between offspring conceived from ICSI and from natural pregnancy[51]. However, an Australian study published in 2005 showed that conception via ICSI or IVF conferred twice as high a risk of major birth defects as natural conception[52]. Another study in 2008 came to a similar conclusion: a higher-than-normal incidence of de novo chromosomal abnormalities in ICSI-conceived offspring was reported[53]; however, neither study could identify the outcomes of perinatal birth defects caused by ICSI and IVF or the low-fertility population itself. A retrospective cohort study of placental pathology included 464 live births conceived from autologous fresh IVF cycles at an academic fertility center from 2004 to 2017. The placental pathology was compared between live births arising from patients with male factor infertility alone and those arising from patients with another infertility diagnosis. Male factor infertility was not significantly associated with different placental pathologies[54]. This study clarified that there were no significant differences in short-term placental development, from which it could be inferred that the differences in ART-conceived offspring due to male factor infertility were more likely to originate from infertility itself.
Large-scale RCTs in animal experiments are particularly important ethical constraints that prevent the realization of large-scale RCTs in normal populations. In 2010, to clarify whether ICSI affects the transcriptome of mouse blastomeres, Giritharan et al. experimentally compared the gene expression and development of mouse blastocysts, produced by ICSI and cultured in either Whitten’s medium or KSOM medium containing amino acids, with control blastocysts flushed out of the uterus on post-coital day 3.5 (in vivo). Blastocysts from ICSI fertilization display reduced numbers of trophoblastic and inner cell mass cells compared to embryos generated in vivo. Approximately 1000 genes were differentially expressed between ICSI blastocysts and in vivo blastocysts. Therefore, it can be concluded that fertilization by ICSI may play a more important role in shaping the transcriptome of the developing mouse embryo than the culture media used[55]. Pre- and postnatal effects of ICSI were assessed under strict conditions using comprehensive transcriptome and phenotypic analyses in mice. In contrast to IVF, ICSI induces distinct, long-lasting transcriptome changes that persist at the neonatal stage. Importantly, no remarkable differences in gene expression or phenotypic profiles were observed in adults who underwent ICSI, and there was no indication of transmission to the next generation[56].
Clarification needs to be sought as to whether the risk comes from the ICSI itself or from the population. Therefore, more long-term large-scale studies are required. This demonstrates that prenatal diagnostic techniques can be used as screening technologies to provide more efficacious options for disease detection and prevention.
PGT for aneuploidy (PGT-A) or for genetic disorders
PGT was first proposed by Edwards et al., and animal testing began in 1968[57]. After further research, the first procedure was performed in 1989 by Handyside in a group of couples at risk of transmitting sex-linked diseases to their children[5]. Thus, PGT has been used in humans for over 30 years. By 2003, more than 50,000 cycles of PGT had been performed worldwide, resulting in the delivery of more than 10,000 babies[58].
A 2009 study conducted in mouse models found that mice born after blastomere biopsy (the 4-cell embryo) showed weight gain and memory loss, and a proteomic approach revealed a significantly different expression of 36 proteins associated with neurological development, leading to the development of neurodegenerative diseases in offspring[59]. In 2014, one study found that blastomere biopsy (the 8-cell embryo) had long-term effects on body weight and behavior in male mice[60], while another study found that mice with a single blastomere removal from four-cell stage embryos had severely affected placental function that could lead to premature rupture of membranes, preterm delivery, and intrauterine growth restriction (IUGR)[61].
In contrast, the results of population studies have reached differing conclusions. A cohort study published in 2016 compared deliveries following preimplantation genetic diagnosis (PGD) for single-gene and sex-linked disorders or structural chromosomal aberrations, IVF/ICSI treatment, and spontaneous conception. Adverse outcomes were only observed in offspring receiving PGT, and the incidence was comparable to adverse outcomes in offspring not receiving PGT who were conceived, due to parental monogenic disorders but displayed a higher risk of placenta previa. Therefore, the risk of adverse obstetric and neonatal outcomes is primarily related to the underlying parental condition and not necessarily due to the technique of PGT[62]. A British study published in 2017, which included data from 1996 to 2011 involving 88,010 singleton live births (87,571 after IVF ± ICSI and 439 after PGD cycles), compared perinatal outcomes of preterm and LBW in singleton live births and reported no increased risk of poor perinatal outcomes after PGD compared with the risk after autologous IVF[63]. A retrospective cohort study published in 2019 explored whether women subjected to and children conceived after PGD resulted in greater risk of adverse pregnancy and birth outcomes than when children were conceived spontaneously or after IVF with or without ICSI. This study found that blastocyst biopsy may not increase the risk of poor neonatal prognoses[64].
A systematic review and meta-analysis published in 2021 that analyzed studies up to December 2020 and included 785,445 participants showed that PGT did not increase the risk of adverse obstetric outcomes. However, the association between PGT and risk of IUGR requires further study[65]. A 2019 study that included live births resulting from IVF with PGT (n = 177) and IVF without PGT (n = 180), arrived at a different conclusion. The authors performed a comparative analysis of outcomes such as preeclampsia, placenta previa, birth weight, and birth defects and found a statistically significant 3-fold increase in the incidence of preeclampsia associated with trophoblastic ectodermal biopsy. Further investigative studies are warranted owing to the increased use of PGT[66].
Most population-based observational studies have concluded that PGT does not increase the risk of adverse perinatal outcomes; however, some studies suggest that the incidence of preeclampsia and IUGR is slightly altered after PGT. This form of testing has only been performed in humans for just over 30 years, and more long-term population studies are urgently needed to investigate the long-term health outcomes of offspring and propose corresponding preventive strategies.
Fresh and frozen embryo transfer
The first successful pregnancy from frozen embryo transfer in humans was reported in 1983[2]; since then, cryopreservation of embryos has become crucial in the use of ART. With the continuous development of freezing techniques, pregnancy rates have increased correspondingly[67]. Successful cryopreservation of oocytes and embryos not only maximizes the safety and efficacy of ovarian stimulation cycles but also is essential for maintaining fertility. There are two common cryopreservation methods, slow freezing and vitrification. Slow freezing allows freezing to occur at a slow rate to minimize intracellular icing in the presence of adequate cell dehydration. Vitrification allows intracellular and extracellular environments to solidify into a glassy state without the formation of ice. Numerous studies of different freezing techniques have found that vitrification leads to better pregnancy and perinatal outcomes[68–71].
Several studies have consistently concluded that frozen embryo transfer is superior to fresh transfer in terms of perinatal outcomes such as birth weight and PTB[72,73]. A systematic evaluation in 2016 found otherwise. The authors compared frozen and fresh embryo transfer techniques and found no significant differences in birth weight, size at gestational age, PTB rate, and perinatal mortality[74]. Other studies have concluded that the risk of complications such as gestational hypertension, preeclampsia, and macrosomia is significantly increased following frozen embryo transfer[75]. Some researchers believe that embryo freezing may act as a selection process in which high-quality embryos that survive the freezing and thawing process have a growth advantage. Another possible explanation is that the cryopreservation technique may cause epigenetic modifications (eg, DNA methylation) in early-stage embryos, thus affecting the growth potential of the fetus. Some believe that because the frozen embryo transfer cycle does not include an ovarian stimulation protocol, the uterine environment is closer to the natural state, resulting in a growth advantage.
Most studies on pregnancy and live birth rates following frozen and fresh embryo transfer found no significant differences between the two techniques. The main factor affecting outcomes was ovarian hyperstimulation. Two high-quality studies published in 2018 confirmed that the rate of sustained pregnancy or live birth with frozen embryo transfer in infertile women was consistent with that of women carrying fresh embryos; however, frozen embryo transfer reduced the risk of ovarian hyperstimulation[76,77]. An RCT conducted in China showed that frozen embryo transfer reduced the risk of ovarian hyperstimulation in infertile women with polycystic ovarian syndrome, resulting in increased pregnancy and live birth rates[75]. A 2021 study also concluded that embryo freezing reduced the risk of ovarian hyperstimulation but found no significant differences between the two techniques in terms of live birth and pregnancy rates[78].
Vitrification of frozen embryos is currently recommended and widely used; however, long-term follow-up studies of these techniques are lacking. Further studies should be conducted to clarify the mechanism of complications, such as hypertension, preeclampsia, and macrosomia, caused by vitrification. There is an urgent need to develop an appropriate freezing strategy to maximize benefits and minimize complications.
Oocyte donation and surrogacy
Donation of oocytes
In recent years, there has been an increase in the number of donor oocyte cycles due to female age-related fertility decline.
Since the birth of the first child following oocyte donation was reported in 1988[4], the frequency of oocyte donation has increased. According to the 2016 Assisted Reproductive Technology National Summary Report, 65% of patients over the age of 44 years who received ART in the United States received donor eggs[79]. A retrospective study published in 2010 followed 20 egg donor and 33 non-donor IVF pregnancies of >24 weeks of gestation and examined perinatal complications (gestational hypertension, abruption, preterm delivery, and cesarean section), microscopic features indicating immune response and trophoblast damage, and characterization of inflammatory cells using immunohistochemistry. The authors found an increase in gestational hypertension and preterm delivery in egg-donor pregnancies. Examination of egg donor placentas revealed the presence of dense fibrinoid deposition in the basal plate with severe chronic deciduitis, containing significantly increased numbers of T helper cells and natural killer cells. Trophoblast damage also increased in preterm egg-donor pregnancies[80].
A 2013 review of more than 70 studies from 1995 to 2010, found an increased risk of PTB, LBW, and preeclampsia in offspring conceived following oocyte donation[81]. In a 2016 systematic evaluation, which included 19 studies with a total of 86,515 pregnant individuals, also showed a significantly increased risk of preeclampsia and gestational hypertension in donor egg pregnancies compared to that in other ARTs[82]. A retrospective cohort study published in 2016, which analyzed the effects of ART on a Swedish population sample between 2003 and 2012, found a higher risk of preeclampsia, postpartum hemorrhage, preterm delivery, and LBW in individuals receiving oocyte donation than in those receiving other ARTs[83]. A 2017 study analyzed oocyte donation treatment cycles from 1982 to 2016 in Europe and the United States, and arrived at similar conclusions[84]. A 2007 study that assessed the rates of obstetric outcomes in oocyte donation recipients aged <35 and ≥40 years found that the incidence of hyperemesis was the highest in young oocyte donation recipients[85].
Several high-quality studies have come to the same conclusion; the underlying reasons for pregnancy complications may be that (1) oocyte donation recipients are often at an advanced age and at high risk of infertility, which may lead to an increase in various adverse perinatal complications; (2) allogeneic oocytes mediate the immune response, and this effect is more concentrated in placenta-mediated diseases; and (3) poor or loss of ovarian function may affect other physical functions, thus leading to complications. In conclusion, more animal and population studies are needed to clarify the mechanisms of complications resulting from oocyte donation, and to inform the development of preventive strategies and treatment options.
Surrogacy
Surrogacy is a highly controversial procedure in women with infertility caused by uterine factors. However, it is also becoming more accepted as fertility declines owing to increased childbearing age. In China, surrogacy of any form is prohibited. However, in the international ART community, surrogacy exists as a special technique, and researchers should have an objective understanding of this technology.
A study in 1999 evaluated the perinatal outcomes of pregnancies (single and multiple) after IVF surrogacy and compared them with those of standard IVF. The occurrence of pregnancy-induced hypertension and bleeding in the third trimester was four to five times lower in IVF-surrogacy pregnancies, independent of whether they were carrying multiple embryos. The incidence of cesarean section was 21.3% for singleton gestations, whereas it was two times higher in IVF-surrogacy multiple pregnancies[86]. A systematic analysis published in 2016 included 55 relatively high-quality studies comparing post-surrogate pregnancies and fresh IVF pregnancies and found no significant differences in the occurrence of PTB, LBW, birth defect rates, or perinatal mortality. At the age of 10 years, there were no major psychological differences between children born from surrogacy and those born from other types of ART or natural conception[87]. A 2017 study analyzed 103,160 single live births obtained from HFEA, including 244 after gestational surrogacy, 87,571 after autologous fresh IVF and ICSI, and 15,345 after autologous frozen embryo transfer. There was no increased risk of PTB, LBW, or birth defects after surrogacy compared to those after autologous IVF[88]. A study published in 2021 retrospectively analyzed all surrogate pregnancies from one of the largest surrogacy facilities in California between 2008 and 2018, including a total of 836 surrogate pregnancies. This study also collected available demographic information and the obstetric history of each surrogate, including history of previous CS and PTB; both primary CS and PTB rates in singleton gestational carrier (GC) pregnancies were higher than the national averages. The CS rates were independent of age, BMI, and interpregnancy interval. In GCs with a history of CS, the rates of vaginal birth after cesarean section exceeded the national average and were higher in younger GCs with lower BMIs. PTB rates were primarily affected by obstetric history of GCs. In GCs without a history of PTB, PTB rates were low, even in those with multifetal gestation[89].
This leads to the conclusion that perinatal outcomes appear to be better in IVF surrogates than in standard IVF surrogates, supporting the idea that most variation in perinatal outcomes and offspring in the ART population may be due to the population itself, and that the poor perinatal outcomes observed in the surrogate population may be more related to status and obstetric history. These findings also emphasize the importance of a healthy intrauterine environment during pregnancy.
A 2017 study utilized an innovative research model to compare perinatal outcomes between singleton live births achieved using commissioned vs spontaneously conceived embryos carried by the same gestational surrogate. The study included 124 surrogates, with a total of 494 pregnancies. The results showed that neonates born from gestational surrogates carrying commissioned embryos had an increased incidence of adverse perinatal outcomes, demonstrating that, even in a healthy uterine environment, ART procedures may potentially affect embryonic quality[90].
In conclusion, perinatal outcomes and health risks of offspring in the surrogate population appear to be much better than those of other standard ARTs. However, ARTs still have the potential to affect the entire course of pregnancy. Therefore, it is crucial to maintain the current rates of research in order to better identify risks and develop preventive measures.
Conclusion
ART has been in use in humans for more than 40 years. In recent years, numerous researchers and physicians have continued to work on the development and safety of these technologies. Each stage of embryo formation and development is a finely regulated process, in which researchers have continued to improve the in vitro environment to replicate the conditions of the human intrauterine environment. However, the objective challenges remain. The health of ART offspring populations is predicted to be a long-term and significant scientific challenge that needs to be addressed. Therefore, it is crucial to urgently establish long-term follow-up, multicenter trials with large sample sizes to conduct correlative studies on different ARTs and characterize the health problems of offspring. This should be done in combination with large-sample RCT animal experiments to elucidate the mechanisms related to the development of systemic disease, develop scientific planning principles and preventive strategies for ART perinatal and offspring health, and provide new hope and guidance for future innovations in ART.
Acknowledgments
We sincerely thank Dr. Sesh K. Sunkara of King’s College London for her constructive guidance and for improving this manuscript.
Author contributions
Y.J.S. and Y.M.S. designed the review. H.J. collected literature and wrote the manuscript. Y.J.S. and Y.M.S. revised the manuscript. All authors approved the final manuscript.
Funding(s)
None.
Conflicts of interest
All authors declare no conflict of interest.
References
[1]. Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet. 1978;2(8085):366. doi:10.1016/s0140-6736(78)92957-4.
[2]. Trounson A, Mohr L. Human pregnancy following cryopreservation, thawing and transfer of an eight-cell embryo. Nature. 1983;305(5936):707–709. doi:10.1038/305707a0.
[3]. Utian WH, Sheean L, Goldfarb JM, et al. Successful pregnancy after in vitro fertilization and embryo transfer from an infertile woman to a surrogate. N Engl J Med. 1985;313(21):1351–1352. doi:10.1056/nejm198511213132112.
[4]. Devroey P, Wisanto A, Camus M, et al. Oocyte donation in patients without ovarian function. Hum Reprod. 1988;3(6):699–704. doi:10.1093/oxfordjournals.humrep.a136769.
[5]. Handyside AH, Kontogianni EH, Hardy K, et al. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature. 1990;344(6268):768–770. doi:10.1038/344768a0.
[6]. Palermo G, Joris H, Devroey P, et al. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet. 1992;340(8810):17–18. doi:10.1016/0140-6736(92)92425-f.
[7]. Ferraretti AP, Gianaroli L, Magli C, et al. Elective cryopreservation of all pronucleate embryos in women at risk of ovarian hyperstimulation syndrome: efficiency and safety. Hum Reprod. 1999;14(6):1457–1460. doi:10.1093/humrep/14.6.1457.
[8]. Tiitinen A, Halttunen M, Härkki P, et al. Elective single embryo transfer: the value of cryopreservation. Hum Reprod. 2001;16(6):1140–1144. doi:10.1093/humrep/16.6.1140.
[9]. Fauser BC. Towards the global coverage of a unified registry of IVF outcomes. Reprod Biomed Online. 2019;38(2):133–137. doi:10.1016/j.rbmo.2018.12.001.
[10]. Luke B, Gopal D, Cabral H, et al. Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology. Am J Obstet Gynecol. 2017;217(3):327.e1–327.e14. doi:10.1016/j.ajog.2017.04.006.
[11]. Pandey S, Shetty A, Hamilton M, et al. Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update. 2012;18(5):485–503. doi:10.1093/humupd/dms018.
[12]. Weng SS, Huang YT, Huang YT, et al. Assisted reproductive technology and risk of childhood cancers. JAMA Netw Open. 2022;5(8):e2230157. doi:10.1001/jamanetworkopen.2022.30157.
[13]. Wennerholm UB, Henningsen AKA, Romundstad LB, et al. Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group. Hum Reprod. 2013;28(9):2545–2553. doi:10.1093/humrep/det272.
[14]. Maheshwari A, Raja EA, Bhattacharya S. Obstetric and perinatal outcomes after either fresh or thawed frozen embryo transfer: an analysis of 112,432 singleton pregnancies recorded in the Human Fertilisation and Embryology Authority anonymized dataset. Fertil Steril. 2016;106(7):1703–1708. doi:10.1016/j.fertnstert.2016.08.047.
[15]. Kamath MS, Antonisamy B, Mascarenhas M, et al. High-risk of preterm birth and low birth weight after oocyte donation IVF: analysis of 133,785 live births. Reprod Biomed Online. 2017;35(3):318–324. doi:10.1016/j.rbmo.2017.06.013.
[16]. van Duivenboden YA, Merkus JM, Verloove-Vanhorick SP. Infertility treatment: implications for perinatology. Eur J Obstet Gynecol Reprod Biol. 1991;42(3):201–204. doi:10.1016/0028-2243(91)90220-f.
[17]. Jonas HA, Lumley J. Triplets and quadruplets born in Victoria between 1982 and 1990. The impact of IVF and GIFT on rising birthrates. Med J Aust. 1993;158(10):659–663. doi:10.5694/j.1326-5377.1993.tb121910.x.
[18]. Levene MI, Wild J, Steer P. Higher multiple births and the modern management of infertility in Britain. The British Association of Perinatal Medicine. Br J Obstet Gynaecol. 1992;99(7):607–613. doi:10.1111/j.1471-0528.1992.tb13831.x.
[19]. Westergaard T, Wohlfahrt J, Aaby P, et al. Population based study of rates of multiple pregnancies in Denmark, 1980-94. BMJ. 1997;314(7083):775–779. doi:10.1136/bmj.314.7083.775.
[20]. Addor V, Santos-Eggimann B, Fawer CL, et al. Impact of infertility treatments on the health of newborns. Fertil Steril. 1998;69(2):210–215. doi:10.1016/s0015-0282(97)00468-8.
[21]. De Sutter P, Delbaere I, Gerris J, et al. Birthweight of singletons after assisted reproduction is higher after single- than after double-embryo transfer. Hum Reprod. 2006;21(10):2633–2637. doi:10.1093/humrep/del247.
[22]. Wang YA, Sullivan EA, Healy DL, et al. Perinatal outcomes after assisted reproductive technology treatment in Australia and New Zealand: single versus double embryo transfer. Med J Aust. 2009;190(5):234–237. doi:10.5694/j.1326-5377.2009.tb02381.x.
[23]. Luke B, Brown MB, Stern JE, et al. Effect of embryo transfer number on singleton and twin implantation pregnancy outcomes after assisted reproductive technology. J Reprod Med. 2010;55(9-10):387–394.
[24]. McBain J. Impact of improvement in implantation rates and reduction in the frequency of double embryo transfer in fresh and frozen cycles at Melbourne IVF between 2000 and 2005. Aust N Z J Obstet Gynaecol. 2006;46(s1):S19–S19. doi:10.1111/j.1479-828x.2006.00613_3.x.
[25]. The Human Fertilisation and Embryology Authority. Multiple births in fertility treatment 2019. Available from:
https://www.hfea.gov.uk/about-us/publications/research-and-data/multiple-births-in-fertility-treatment-2019/.
[26]. Valenzuela-Alcaraz B, Cruz-Lemini M, Rodríguez-López M, et al. Fetal cardiac remodeling in twin pregnancy conceived by assisted reproductive technology. Ultrasound Obstet Gynecol. 2018;51(1):94–100. doi:10.1002/uog.17527.
[27]. Norrman E, Petzold M, Clausen TD, et al. Type 1 diabetes in children born after assisted reproductive technology: a register-based national cohort study. Hum Reprod. 2020;35(1):221–231. doi:10.1093/humrep/dez227.
[28]. Hawk HW, Cooper BS, Conley HH. Inhibition of sperm transport and fertilization in superovulating ewes. Theriogenology. 1987;28(2):139–153. doi:10.1016/0093-691x(87)90262-7.
[29]. Kramer B, Stein BA, Van der Walt LA. Exogenous gonadotropins--serum oestrogen and progesterone and the effect on endometrial morphology in the rat. J Anat. 1990;173:177–186.
[30]. Gidley-Baird AA, O’Neill C, Sinosich MJ, et al. Failure of implantation in human in vitro fertilization and embryo transfer patients: the effects of altered progesterone/estrogen ratios in humans and mice. Fertil Steril. 1986;45(1):69–74. doi:10.1016/s0015-0282(16)49099-0.
[31]. Forde N, Carter F, di Francesco S, et al. Endometrial response of beef heifers on day 7 following insemination to supraphysiological concentrations of progesterone associated with superovulation. Physiol Genomics. 2012;44(22):1107–1115. doi:10.1152/physiolgenomics.00092.2012.
[32]. Junovich G, Mayer Y, Azpiroz A, et al. Ovarian stimulation affects the levels of regulatory endometrial NK cells and angiogenic cytokine VEGF. Am J Reprod Immunol. 2011;65(2):146–153. doi:10.1111/j.1600-0897.2010.00892.x.
[33]. Sunkara SK, La Marca A, Seed PT, et al. Increased risk of preterm birth and low birthweight with very high number of oocytes following IVF: an analysis of 65 868 singleton live birth outcomes. Hum Reprod. 2015;30(6):1473–1480. doi:10.1093/humrep/dev076.
[34]. Pereira N, Reichman DE, Goldschlag DE, et al. Impact of elevated peak serum estradiol levels during controlled ovarian hyperstimulation on the birth weight of term singletons from fresh IVF-ET cycles. J Assist Reprod Genet. 2015;32(4):527–532. doi:10.1007/s10815-015-0434-1.
[35]. Magnusson A, Wennerholm UB, Källén K, et al. The association between the number of oocytes retrieved for IVF, perinatal outcome and obstetric complications. Hum Reprod. 2018;33(10):1939–1947. doi:10.1093/humrep/dey266.
[36]. Dumoulin JC, Land JA, Van Montfoort AP, et al. Effect of in vitro culture of human embryos on birthweight of newborns. Hum Reprod. 2010;25(3):605–612. doi:10.1093/humrep/dep456.
[37]. Nelissen EC, Van Montfoort AP, Coonen E, et al. Further evidence that culture media affect perinatal outcome: findings after transfer of fresh and cryopreserved embryos. Hum Reprod. 2012;27(7):1966–1976. doi:10.1093/humrep/des145.
[38]. Kleijkers SHM, van Montfoort APA, Smits LJM, et al. IVF culture medium affects post-natal weight in humans during the first 2 years of life. Hum Reprod. 2014;29(4):661–669. doi:10.1093/humrep/deu025.
[39]. Zandstra H, Brentjens LBPM, Spauwen B, et al. Association of culture medium with growth, weight and cardiovascular development of IVF children at the age of 9 years. Hum Reprod. 2018;33(9):1645–1656. doi:10.1093/humrep/dey246.
[40]. Kleijkers SH, Eijssen LM, Coonen E, et al. Differences in gene expression profiles between human preimplantation embryos cultured in two different IVF culture media. Hum Reprod. 2015;30(10):2303–2311. doi:10.1093/humrep/dev179.
[41]. Karaki RZ, Samarraie SS, Younis NA, et al. Blastocyst culture and transfer: a step toward improved in vitro fertilization outcome. Fertil Steril. 2002;77(1):114–118. doi:10.1016/s0015-0282(01)02939-9.
[42]. Levron J, Shulman A, Bider D, et al. A prospective randomized study comparing day 3 with blastocyst-stage embryo transfer. Fertil Steril. 2002;77(6):1300–1301. doi:10.1016/s0015-0282(02)03090-x.
[43]. Yang L, Cai S, Zhang S, et al. Single embryo transfer by Day 3 time-lapse selection versus Day 5 conventional morphological selection: a randomized, open-label, non-inferiority trial. Hum Reprod. 2018;33(5):869–876. doi:10.1093/humrep/dey047.
[44]. Glujovsky D, Quinteiro Retamar AM, Alvarez Sedo CR, et al. Cleavage-stage versus blastocyst-stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev. 2022;5(5):CD002118. doi:10.1002/14651858.CD002118.pub6.
[45]. Martins WP, Nastri CO, Rienzi L, et al. Obstetrical and perinatal outcomes following blastocyst transfer compared to cleavage transfer: a systematic review and meta-analysis. Hum Reprod. 2016;31(11):2561–2569. doi:10.1093/humrep/dew244.
[46]. Wang X, Du M, Guan Y, et al. Comparative neonatal outcomes in singleton births from blastocyst transfers or cleavage-stage embryo transfers: a systematic review and meta-analysis. Reprod Biol Endocrinol. 2017;15(1):36. doi:10.1186/s12958-017-0255-4.
[47]. Alviggi C, Conforti A, Carbone IF, et al. Influence of cryopreservation on perinatal outcome after blastocyst- vs cleavage-stage embryo transfer: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2018;51(1):54–63. doi:10.1002/uog.18942.
[48]. Ginström Ernstad E, Spangmose AL, Opdahl S, et al. Perinatal and maternal outcome after vitrification of blastocysts: a Nordic study in singletons from the CoNARTaS group. Hum Reprod. 2019;34(11):2282–2289. doi:10.1093/humrep/dez212.
[49]. Sunde A, Brison D, Dumoulin J, et al. Time to take human embryo culture seriously. Hum Reprod. 2016;31(10):2174–2182. doi:10.1093/humrep/dew157.
[50]. Valbuena D, Martin J, de Pablo JL, et al. Increasing levels of estradiol are deleterious to embryonic implantation because they directly affect the embryo. Fertil Steril. 2001;76(5):962–968. doi:10.1016/s0015-0282(01)02018-0.
[51]. Bonduelle M, Joris H, Hofmans K, et al. Mental development of 201 ICSI children at 2 years of age. Lancet. 1998;351(9115):1553. doi:10.1016/S0140-6736(98)24021-9.
[52]. Hansen M, Kurinczuk JJ, Bower C, et al. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med. 2002;346(10):725–730. doi:10.1056/NEJMoa010035.
[53]. Palermo GD, Neri QV, Takeuchi T, et al. Genetic and epigenetic characteristics of ICSI children. Reprod Biomed Online. 2008;17(6):820–833. doi:10.1016/s1472-6483(10)60411-7.
[54]. Mortimer R, James K, Bormann CL, et al. Male factor infertility and placental pathology in singleton live births conceived with in vitro fertilization. J Assist Reprod Genet. 2021;38(12):3223–3232. doi:10.1007/s10815-021-02344-5.
[55]. Giritharan G, Li MW, Di Sebastiano F, et al. Effect of ICSI on gene expression and development of mouse preimplantation embryos. Hum Reprod. 2010;25(12):3012–3024. doi:10.1093/humrep/deq266.
[56]. Kohda T, Ogonuki N, Inoue K, et al. Intracytoplasmic sperm injection induces transcriptome perturbation without any transgenerational effect. Biochem Biophys Res Commun. 2011;410(2):282–288. doi:10.1016/j.bbrc.2011.05.133.
[57]. Gardner RL, Edwards RG. Control of the sex ratio at full term in the rabbit by transferring sexed blastocysts. Nature. 1968;218(5139):346–349. doi:10.1038/218346a0.
[58]. Harper JC, Boelaert K, Geraedts J, et al. ESHRE PGD Consortium data collection V: cycles from January to December 2002 with pregnancy follow-up to October 2003. Hum Reprod. 2006;21(1):3–21. doi:10.1093/humrep/dei292.
[59]. Yu Y, Wu J, Fan Y, et al. Evaluation of blastomere biopsy using a mouse model indicates the potential high risk of neurodegenerative disorders in the offspring. Mol Cell Proteomics. 2009;8(7):1490–1500. doi:10.1074/mcp.M800273-MCP200.
[60]. Sampino S, Zacchini F, Swiergiel AH, et al. Effects of blastomere biopsy on post-natal growth and behavior in mice. Hum Reprod. 2014;29(9):1875–1883. doi:10.1093/humrep/deu145.
[61]. Sato BLM, Sugawara A, Ward MA, et al. Single blastomere removal from murine embryos is associated with activation of matrix metalloproteinases and Janus kinase/signal transducers and activators of transcription pathways of placental inflammation. Mol Hum Reprod. 2014;20(12):1247–1257. doi:10.1093/molehr/gau072.
[62]. Bay B, Ingerslev HJ, Lemmen JG, et al. Preimplantation genetic diagnosis: a national multicenter obstetric and neonatal follow-up study. Fertil Steril. 2016;106(6):1363–1369.e1. doi:10.1016/j.fertnstert.2016.07.1092.
[63]. Sunkara SK, Antonisamy B, Selliah HY, et al. Pre-term birth and low birth weight following preimplantation genetic diagnosis: analysis of 88 010 singleton live births following PGD and IVF cycles. Hum Reprod. 2017;32(2):432–438. doi:10.1093/humrep/dew317.
[64]. He H, Jing S, Lu CF, et al. Neonatal outcomes of live births after blastocyst biopsy in preimplantation genetic testing cycles: a follow-up of 1,721 children. Fertil Steril. 2019;112(1):82–88. doi:10.1016/j.fertnstert.2019.03.006.
[65]. Hou W, Shi G, Ma Y, et al. Impact of preimplantation genetic testing on obstetric and neonatal outcomes: a systematic review and meta-analysis. Fertil Steril. 2021;116(4):990–1000. doi:10.1016/j.fertnstert.2021.06.040.
[66]. Zhang WY, von Versen-Höynck F, Kapphahn KI, et al. Maternal and neonatal outcomes associated with trophectoderm biopsy. Fertil Steril. 2019;112(2):283–290.e2. doi:10.1016/j.fertnstert.2019.03.033.
[67]. Calhaz-Jorge C, De Geyter C, Kupka MS, et al.; European IVF-monitoring Consortium (EIM)European IVF-monitoring Consortium (EIM). Assisted reproductive technology in Europe, 2013: results generated from European registers by ESHRE. Hum Reprod. 2017;32(10):1957–1973. doi:10.1093/humrep/dex264.
[68]. Rienzi L, Gracia C, Maggiulli R, et al. 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.
[69]. AbdelHafez FF, Desai N, Abou-Setta AM, et al. Slow freezing, vitrification and ultra-rapid freezing of human embryos: a systematic review and meta-analysis. Reprod Biomed Online. 2010;20(2):209–222. doi:10.1016/j.rbmo.2009.11.013.
[70]. Liu SY, Teng B, Fu J, et al. Obstetric and neonatal outcomes after transfer of vitrified early cleavage embryos. Hum Reprod. 2013;28(8):2093–2100. doi:10.1093/humrep/det104.
[71]. Li Z, Wang YA, Ledger W, et al. Clinical outcomes following cryopreservation of blastocysts by vitrification or slow freezing: a population-based cohort study. Hum Reprod. 2014;29(12):2794–2801. doi:10.1093/humrep/deu246.
[72]. Wennerholm UB, Söderström-Anttila V, Bergh C, et al. Children born after cryopreservation of embryos or oocytes: a systematic review of outcome data. Hum Reprod. 2009;24(9):2158–2172. doi:10.1093/humrep/dep125.
[73]. Maheshwari A, Pandey S, Amalraj Raja E, et al. 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.
[74]. Belva F, Bonduelle M, Roelants M, et al. Neonatal health including congenital malformation risk of 1072 children born after vitrified embryo transfer. Hum Reprod. 2016;31(7):1610–1620. doi:10.1093/humrep/dew103.
[75]. Chen ZJ, Shi Y, Sun Y, et al. Fresh versus Frozen Embryos for Infertility in the Polycystic Ovary Syndrome. N Engl J Med. 2016;375(6):523–533. doi:10.1056/NEJMoa1513873.
[76]. Vuong LN, Dang VQ, Ho TM, et al. IVF Transfer of Fresh or Frozen Embryos in Women without Polycystic Ovaries. N Engl J Med. 2018;378(2):137–147. doi:10.1056/NEJMoa1703768.
[77]. Shi Y, Sun Y, Hao C, et al. Transfer of Fresh versus Frozen Embryos in Ovulatory Women. N Engl J Med. 2018;378(2):126–136. doi:10.1056/NEJMoa1705334.
[78]. Zaat T, Zagers M, Mol F, et al. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database Syst Rev. 2021;2:CD011184. doi:10.1002/14651858.CD011184.pub3.
[79]. Assisted Reproductive Technology National Summary Report. (cdc.gov). Page 55.
[80]. Gundogan F, Bianchi DW, Scherjon SA, et al. Placental pathology in egg donor pregnancies. Fertil Steril. 2010;93(2):397–404. doi:10.1016/j.fertnstert.2008.12.144.
[81]. Malchau SS, Loft A, Larsen EC, et al. Perinatal outcomes in 375 children born after oocyte donation: a Danish national cohort study. Fertil Steril. 2013;99(6):1637–1643. doi:10.1016/j.fertnstert.2013.01.128.
[82]. Masoudian P, Nasr A, de Nanassy J, et al. Oocyte donation pregnancies and the risk of preeclampsia or gestational hypertension: a systematic review and metaanalysis. Am J Obstet Gynecol. 2016;214(3):328–339. doi:10.1016/j.ajog.2015.11.020.
[83]. Nejdet S, Bergh C, Källén K, et al. High risks of maternal and perinatal complications in singletons born after oocyte donation. Acta Obstet Gynecol Scand. 2016;95(8):879–886. doi:10.1111/aogs.12904.
[84]. Storgaard M, Loft A, Bergh C, et al. Obstetric and neonatal complications in pregnancies conceived after oocyte donation: a systematic review and meta-analysis. BJOG. 2017;124(4):561–572. doi:10.1111/1471-0528.14257.
[85]. Keegan DA, Krey LC, Chang HC, et al. Increased risk of pregnancy-induced hypertension in young recipients of donated oocytes. Fertil Steril. 2007;87(4):776–781. doi:10.1016/j.fertnstert.2006.08.105.
[86]. Parkinson J, Tran C, Tan T, et al. Perinatal outcome after in-vitro fertilization-surrogacy. Hum Reprod. 1999;14(3):671–676. doi:10.1093/humrep/14.3.671.
[87]. Söderström-Anttila V, Wennerholm UB, Loft A, et al. Surrogacy: outcomes for surrogate mothers, children and the resulting families-a systematic review. Hum Reprod Update. 2016;22(2):260–276. doi:10.1093/humupd/dmv046.
[88]. Sunkara SK, Antonisamy B, Selliah HY, et al. Perinatal outcomes after gestational surrogacy versus autologous IVF: analysis of national data. Reprod Biomed Online. 2017;35(6):708–714. doi:10.1016/j.rbmo.2017.08.024.
[89]. Smith MB, Mandelbaum RS, McGinnis LK, et al. Examining pre-term birth and cesarean section rates in gestational carrier pregnancies. J Assist Reprod Genet. 2021;38(10):2707–2712. doi:10.1007/s10815-021-02296-w.
[90]. Woo I, Hindoyan R, Landay M, et al. Perinatal outcomes after natural conception versus in vitro fertilization (IVF) in gestational surrogates: a model to evaluate IVF treatment versus maternal effects. Fertil Steril. 2017;108(6):993–998. doi:10.1016/j.fertnstert.2017.09.014.
