Review
HJOG 2022, 21 (2), 85-91 | doi: 10.33574/hjog.0503
Konstantina Papadatou, Eleftherios Zachariou, Vasilios Pergialiotis, George Daskalakis
1st Department of Obstetrics and Gynecology, Alexandra Hospital, National and Kapodistrian University of Athens, Greece
Correspondence: Konstantina Papadatou MD, MSc, 80, Vasilissis Sofias Ave., Athens 11528, Greece, e-mail: konstantina.papadatou@gmail.com
Abstract
Nowadays, infertility affects approximately 8-12% of the population. Μultiple causative factors are leading to the failure of subfertile couples to achieve a normal pregnancy, as well as various types of assisted reproductive techniques that have developed globally in order to confront infertility. Over the past few years, especially after the birth of the world’s first baby to be conceived by In Vitro Fertilization (IVF) in 1978, numerous studies have been conducted concerning the risk of obstetric and perinatal complications. In this review, we aimed to detail the perinatal outcomes in relation to the ART procedures routinely applied. Consequently, the above-mentioned procedures have been associated with the presentation of hypertensive disorders and gestational diabetes mellitus in women, multiple pregnancy, preterm birth and low birth weight. Furthermore, studies indicate that infants born from assisted reproductive technologies appear to suffer much more frequently not only by congenital or epigenetic abnormalities, but also by neurodevelopmental disorders and specific types of cancer. Indisputably, artificial fertilization methods still continue growing worldwide with new medical technologies’ evolvement. It becomes, therefore, evident that the possible long-term, adverse neonatal outcomes have not been completely clarified yet. Taking into consideration that the number of the couples that undergo fertility treatments is constantly rising, more research is of vital importance so that their potential impact of such exposure on maternal and neonatal health can be understood.
Keywords: Infertility, in vitro fertilization, complications, morbidity, autism, cancer
Introduction
It is widely believed that the pioneers of IVF tried to introduce their innovative ideas in a still unprepared world, where social, political and scientific institutions were not able to embrace the development of assisted reproduction technologies. Until 1978, the process of reproduction was considered the work of nature and God, not of researchers. It is therefore easy to understand the harsh criticism that the latter faced until, over the years, the presence of assisted reproductive technologies became established as a modern and desirable, constantly evolving reality.
Undeniably, infertility has been recognized as a major public health issue. The reality is that, while the provision of treatment options to address infertility has increased at an impressive rate over the last two decades, its incidence rates have remained the same over the last century (10-13%). Overall estimates suggest that, globally, more than eighty million couples experience fertility problems, particularly in developing countries.1
Numerous factors can affect the complex process of normal conception, not only endogenous but also exogenous.2 Among them, we could distinguish the age of the woman3,4, the presence of disturbed anatomy in the female reproductive system, and the presence of endocrine disorders, while the male factor of infertility also plays a role.
Therefore, it was expected that the use of assisted reproductive technology (ART) would become widespread. Perinatal outcomes and long-term safety for the women and children are paramount. More specifically, while there seems to be a higher risk of adverse perinatal outcomes with some of the ART procedures, the absolute risk increase is generally low.
Material and Method
The objective of our study was to provide a systematic review of perinatal outcomes among infants conceived with the use of assisted reproductive technology.
A search was performed through the database of PubMed and Scopus, including articles from 2012 to March 2020, with emphasis on the literature over the course of the last 5 years.
Review of the literature and Discussion
Οbstetric risks
1.1. Gestational hypertension
Hypertensive disorders of pregnancy include gestational hypertension, pre-eclampsia, and eclampsia.5 A meta-analysis6 and a subsequent retrospective cohort study7 showed a significantly increased likelihood of gestational hypertension in singleton pregnancies after using in vitro fertilization (IVF) and intra-cytoplasmic sperm injection (ICSI), compared with singleton pregnancies from natural conception. The risk of pre-eclampsia was also higher, but the difference did not reach the limits of statistical significance.8 Similarly, no statistically significant difference was found in the incidence of hypertensive disorders of pregnancy between twin pregnancies by ART and by natural conception.7
1.2. Gestational diabetes mellitus
Studies have shown an increased incidence of gestational diabetes in pregnancies resulting from assisted reproductive technology compared to natural pregnancies.7,9 Moreover, research suggests that the risk is likely due to the older age of women who tend to undergo infertility treatments.10
1.3. Premature birth
Αccording to studies, pregnancies resulting from ΑRT have an increased risk of preterm delivery.6,10,11 However, this risk has been described to be lower when the technique used is IVF involving the transfer of cryopreserved rather than fresh embryos.12
2. Morbidity and outcome of newborns by assisted reproductive technology (ART)
2.1. Low birth weight (<2500g)
According to the MOSART study12, a longitudinal cohort study, singleton pregnancies from IVF have a higher risk of low birth weight (LBW) newborns, compared to infants born of infertile and fertile couples, while this difference does not seem to be evident in the case of multiple pregnancy.
According to further studies, a lower incidence of low birth weight newborns is noticeable in the case of IVF using the transfer of cryopreserved embryos.13-16
2.2. Neonatal prematurity
Preterm birth is a significant factor related to perinatal morbidity and mortality. According to the literature, premature birth is more frequently associated with singleton pregnancies resulting from IVF techniques.17 There seems to be no distinction depending on the method chosen in each case.18 No statistically significant difference has been found in terms of prematurity in multiple pregnancy, probably because it consist already an independent risk factor for preterm birth.
Studies also show an increased risk of preterm delivery in pregnancies carried out by assisted reproductive technology with reported use of fertility drugs, for example ovarian stimulation treatments.19,20
2.3. Multiple pregnancy
With the increasing use of assisted reproduction methods, twin pregnancies are now estimated to represent 20% of all twin pregnancies in Europe, while the percentage for multiple pregnancy is around 3%.21 Multiple pregnancies are known to be associated with several obstetric complications (gestational hypertension, pre-eclampsia, gestational diabetes mellitus, prematurity). In other words, infants born from such pregnancies have increased morbidity and mortality.
2.4. Congenital abnormalities
An increased incidence of cardiovascular, musculoskeletal, and genitourinary disorders has been reported in neonates after the application of both classical IVF (8.6%) and ICSI (9%).22 In particular, congenital heart disease, congenital hip dislocation, congenital talipes equinovarus, spina bifida, and esophageal atresia have been reported.23 Similarly, increased numbers of congenital anomalies are described in infants born through the transfer of cryopreserved embryos.24
2.5. Imprinting disorders
Studies conclude that there is a correlation between assisted reproductive techniques and imprinting disorders.25,26 Τhese disorders include syndromes such as Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Russell-Silver syndrome (SRS). However, due to the rarity of the aforementioned syndromes, the knowledge of the scientific community regarding the impact of assisted reproductive techniques on the occurrence of imprinting disorders is incomplete, thus further research is needed.
2.6. Chromosomal abnormalities
It has been described that the rate of spontaneous abortions in the first trimester of pregnancies achieved using assisted reproduction methods reaches 22-63%, with the main cause being chromosomal abnormalities.27 The risk of aneuploidy increases in women over 35 years of age who have achieved pregnancy using these methods.28 It is also believed that the type of technique used in each case may determine the risk of chromosomal abnormalities in the fetus. In particular, in a study of a large series of embryos, chromosomal abnormalities occurred in 3% of those resulting from ICSI, a number significantly higher than the percentage in the general population (1%).28
The incidence of sex chromosome anomalies is , also, found to be increased 3-4-fold in ART pregnancies, with Klinefelter’s syndrome being the most common.
2.7. Neurodevelopmental disorders
In ART-conceived neonates, both their short-term and long-term neurodevelopmental development may be affected with greater frequency.5 A population-based retrospective cohort study demonstrated an increased risk of cerebral palsy in children from IVF.29,30 The forms of cerebral palsy included spastic diplegia, spastic hemiplegia, and spastic quadriplegia. Data, however, remain inadequate due to the lack of long-term studies focusing on the neurological effects of ART methods.
2.8. Autism
Τhe available data are conflicting regarding the impact of ART methods on the development of autism.18 A Swedish study did not show an increased risk of autism in singleton pregnancies from IVF. However, an increased risk was found when ICSI was the method used.
2.9. Endocrine disorders
Thyroid gland function in children with ART is still a relatively unexplored field. Elevated serum TSH hormone levels in IVF children have been described, without this being due to the presence of antithyroid antibodies;31,32 while other studies link ART methods to early insulin resistance.
2.10. Cardiovascular and metabolic profile
Assisted reproductive methods have been shown to carry a risk of cardiometabolic disorders, arterial hypertension, and high body fat in children.33
2.11. Body mass index and body fat
Children conceived by IVF appear to show an increased rate of weight gain in early childhood. This rapid weight regain, also known as “catch-up” growth, is associated with higher rates of central obesity.34 In vitro fertilization, furthermore, has been documented to be responsible for increased rates of peripheral fat deposition, as well as significantly lower rates of lean mass.
2.12. Blood pressure in children conceived by ART
According to the dutch OMEGA cohort study,33 children resulting from IVF pregnancies have twice the risk of developing high systolic or diastolic blood pressure, even after the elimination of confounding factors. indeed, higher arterial pressure has been recorded in prepubertal offspring of pregnancies resulting from ovarian stimulation followed by IVF or a combination of IVF and ICSI.
2.13. Serum lipids in children conceived by ART
There are reports of increased levels of total cholesterol and low-density cholesterol (LDL) and low levels of high-density cholesterol (HDL) in children from IVF pregnancies compared to children conceived naturally.5 There is conflicting data regarding triglycerides in childhood. Several studies have shown their levels to be elevated in IVF conceived children. However, different studies have not found statistically significant differences in triglyceride levels between these two groups of children.
2.14. Serum glucose in children conceived by ART
Similarly, available data on fasting blood sugar and insulin levels in children from pregnancies achieved through ART remain limited and contradictory. Τhus, some studies show these levels to be elevated in children from IVF, while others do not conclude a substantial difference between these children and those conceived naturally.5
2.15. Puberty in children conceived by ART
A cohort study comparing adolescents conceived through IVF and ICSI techniques and adolescents from natural conception showed delayed breast development, advanced bone age, and increased DHEAS and LH levels in females of the former category. Similarly, reduced testosterone was found in male offspring from ART methods.18
2.16. Cancer in children conceived by ART
A large number of studies have shown an increased risk of malignancy in children from ART. These appear to involve hematological malignancies, with leukemia and Hodgkin’s lymphoma occurring with high frequency. Furthermore, same studies indicate high percentage of retinoblastoma, hepatoblastoma, as well as rhabdomyosarcoma.35-38
2.17. Psychoemotional and social behavior of children conceived by ART
According to five-year research conducted in two countries, females conceived through ART were more prone to depression and anxiety, while males were more prone to aggressive behavior. Ultimately, however, no difference was found in terms of mental health and social development of these children.39
Conclusion
The modern era is characterized by a plethora of scientific advances aimed at improving the quality of human life. Medically assisted reproduction is part of this. Its role in society today is of crucial importance.
In general, the assisted reproductive methods that have been developed are considered safe, and the offspring of these methods are healthy. However, studies have shown an increased incidence of perinatal events. These include congenital and chromosomal abnormalities, epigenetic changes as well as neurodevelopmental disorders in children resulting from one of the ART techniques.
Of course, there are still many unanswered questions regarding the safety of ART techniques and the morbidity of newborns resulting from them. Thus, a greater number of well-designed studies are needed, with long-term follow-up, to draw sound conclusions.
Disclosure
The authors report no conflict of interest.
Funding
None to disclose for all authors.
References
1. Zegers-Hochschild, F., Adamson, G. D., Mouzon, J., Ishihara, O., Mansour, R., Nygren, K., Sullivan, E., Vanderpoel, S. (2009). International Committee for Monitoring Assisted Reproductive Technology; World Health Organization. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009. Fertil Steril, Nov;92(5):1520-4.
2. Borght, M. V., & Wyns, C. (2018). Fertility and infertility: Definition and epidemiology. Clin Biochem, Dec;62:2-10.
3. Eijkemans, M. J. C., van Poppel, F., Habbema, D. F., Smith, K. R., Leridon, H., & te Velde, E. R. (2014). Too old to have children? Lessons from natural fertility populations. Hum Reprod, Jun;29(6):1304-12.
4. Sabarre, K. A., Khan, Z., Whitten, A. N., Remes, O., & Phillips, K..P. (2013). A qualitative study of Ottawa university students’ awareness, knowledge and perceptions of infertility, infertility risk factors and assisted reproductive technologies (ART). Reprod Health, Aug 20;10:41.
5. Sullivan-Pyke, C. S., Senapati, S., Mainigi, M. A., & Barnhart, K. T. (2017). In Vitro fertilization and adverse obstetric and perinatal outcomes. Semin Perinatol, Oct;41(6):345-353.
6. Pandey, S., Shetty, A., Hamilton, M., Bhattacharya, S., & Maheshwari, A. (2012). Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update, Sep-Oct;18(5):485-503.
7. Zhu, L., Zhang, Y., Liu, Y., Zhang, R., Wu, Y., Huang, Y., Liu, F., Li, M., Sun, S., Xing, L., Zhu, Y., Chen, Y., Xu, L., Zhou, L., Huang, H., & Zhang, D. (2016). Maternal and Live-birth Outcomes of Pregnancies following Assisted Reproductive Technology: A Retrospective Cohort Study. Sci Rep, Oct 20;6:35141.
8. Schieve, L.A., Ferre, C., Peterson, H. B., Macaluso, M., Reynolds, M. A., & Wright, V. C. (2004). Perinatal outcome among singleton infants conceived through assisted reproductive technology in the United States. Obstet Gynecol, Jun;103(6):1144-53.
9. Ashrafi, M., Gosili, R., Hosseini, R., Arabipoor, A., Ahmadi, J., & Chehrazi, M. (2014). Risk of gestational diabetes mellitus in patients undergoing assisted reproductive techniques. Eur J Obstet Gynecol Reprod Biol, May;176:149-52.
10. Qin, J., Sheng, X., Wu, D., Gao, S., You, Y., Yang, T., & Wang, H. (2017). Adverse Obstetric Outcomes Associated With In Vitro Fertilization in Singleton Pregnancies. Reprod Sci, Apr;24(4):595-608.
11. Cavoretto, P. I., Giorgione, V., Sotiriadis, A., Viganò, P., Papaleo, E., Galdini, A., Gaeta, G., & Candiani, M. (2020). IVF/ICSI treatment and the risk of iatrogenic preterm birth in singleton pregnancies: systematic review and meta- analysis of cohort studies. J Matern Fetal Neonatal Med, Jun 4;1-10.
12. Marino, J. L., Moore, V. M., Willson, K. J., Rumbold, A., Whitrow, M. J., Giles, L. C., & Davies, M. J. (2014). Perinatal Outcomes by Mode of Assisted Conception and Sub-Fertility in an Australian Data Linkage Cohort. PLoS One, Jan 8;9(1): e80398.
13. Wennerholm, U., Henningsen, A. A., Romundstad, L. B., Bergh, C., Pinborg, A., Skjaerven, R., Forman, J., Gissler, M., Nygren, K. G., & Tiitinen, A. (2013). Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group. Hum Reprod, Sep;28(9):2545-53.
14. Vidal, M., Vellvé, K., González-Comadran, M., Robles, A., Prat, M., Torné, M., Carreras, R., & Checa, M. A. (2017). Perinatal outcomes in children born after fresh or frozen embryo transfer: a Catalan cohort study based on 14,262 newborns. Fertil Steril, Apr;107(4):940-947.
15. Kalra, S. K., Ratcliffe, S. J., Coutifaris, C., Molinaro, T., & Barnhart, K. T. (2011). Ovarian stimulation and low birth weight in newborns conceived through in vitro fertilization. Obstet Gynecol, Oct;118(4):863-71.
16. Maheshwari, A., Raja, E. A., & Bhattacharya, S. (2016). 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, Dec;106(7):1703-1708.
17. Declercq, E., Luke, B., Belanoff, C., Cabral, H., Diop, H., Gopal, D., Hoang, L., Kotelchuck, M., Stern, J. E., & Hornstein, M. D. (2015). Perinatal outcomes associated with assisted reproductive technology: the Massachusetts Outcomes Study of Assisted Reproductive Technologies (MOSART). Fertil Steril, Apr;103(4):888-95.
18. Zore, T., & Wang, E. T. (2017). Perinatal and Childhood Outcomes Associated with Infertility. Semin Reprod Med, May;35(3):304-310.
19. Sunkara, S. K., LaMarca, A., Polyzos, N. P., Seed, P. T., & Khalaf, Y. (2016). Live birth and perinatal outcomes following stimulated and unstimulated IVF: analysis of over two decades of a nationwide data. Hum Reprod, Oct;31(10):2261-7.
20. Kamath, M. S., Kirubakaran, R., Mascarenhas, M., & Sunkara, S. K. (2018). Perinatal outcomes after stimulated versus natural cycle IVF: a systematic review and meta-analysis. Reprod Biomed Online, Jan;36(1):94-101.
21. Ferraretti, A. P., Nygren, K., Andersen, A. N., de Mouzon, J., Kupka, M., Calhaz-Jorge, C., Wyns, C., Gianaroli, L., Goossens, V., & the European IVF- Monitoring Consortium (EIM), for the European Society of Human Reproduction and Embryology (ESHRE). (2017). Trends over 15 years in ART in Europe: an analysis of 6 million cycles. Hum Reprod Open, Aug; 2017(2): hox012.
22. Davies, M. J., Moore, V. M., Willson, K. J., Van Essen, P., Priest, K., Scott, H., Haan, E. A., & Chan, A. (2012). Reproductive technologies and the risk of birth defects. N Engl J Med, May 10;366(19):1803-13.
23. Boulet, S. L., Kirby, R. S., Reefhuis, J., Zhang, Y., Sunderam, S., Cohen, B., Bernson, D., Copeland, G., Bailey, M. A., Jamieson, D. J., Kissin, D. M., & the States Monitoring Assisted Reproductive Technology (SMART) Collaborative. (2016). Assisted Reproductive Technology and Birth Defects Among Liveborn Infants in Florida, Massachusetts, and Michigan, 2000-2010. JAMA Pediatr, Jun 6;170(6):e154934.
24. Tandulwadkar, S., Lodha, P., & Vineeta Kharb. (2012). Congenital malformations and assisted reproductive technique: Where is assisted reproductive technique taking us? J Hum Reprod Sci, Sep;5(3):244-7.
25. Eggermann, T., de Nanclares, G. P., Maher, E. R., Temple, I. K., Tümer, Z., Monk, D., Mackay, D. J. G., Grønskov, K., Riccio, A., Linglart, A., & Netchine, I. (2015). Imprinting disorders: a group of congenital disorders with overlapping patterns of molecular changes affecting imprinted loci. Clin Epigenetics, Nov 14;7:123.
26. Hattori, H., Hiura, H., Kitamura, A., Miyauchi, N., Kobayashi, N., Takahashi, N. S., Okae, H., Kyono, K., Kagami, M., Ogata, T., & Arima, T. (2019). Association of four imprinting disorders and ART. Clin Epigenetics, Feb 7;11(1):21.
27. Qin, J., Pang, L., Li, M., Xu, J., & Zhou, X. (2013). Risk of Chromosomal Abnormalities in Early Spontaneous Abortion after Assisted Reproductive Technology: A Meta-Analysis. PLoS One, Oct 10;8(10):e75953
28. Maymon, R., & Shulman, A. (2002). Serial first- and second-trimester Down’s syndrome screening tests among IVF-versus naturally-conceived singletons. Hum Reprod, Apr;17(4):1081-5.
29. Strömberg, B., Dahlquist, G., Ericson, A., Finnström, O., Köster, M., & Stjernqvist, K. (2002). Neurological sequelae in children born after in-vitro fertilisation: a population-based study. Lancet, Feb 9;359(9305):461-5.
30. Zhu, J. L., Hvidtjørn, D., Basso, O., Obel, C., Thorsen, P., Uldall, P., & Olsen, J. (2010). Parental infertility and cerebral palsy in children. Hum Reprod, Dec; 25(12): 3142–3145.
31. Sakka, S. D., Malamitsi-Puchner, A., Loutradis, D., Chrousos, G. P., & Kanaka-Gantenbein, C. (2009). Euthyroid hyperthyrotropinemia in children born after in vitro fertilization. J Clin Endocrinol Metab, Apr;94(4):1338-41.
32. Ceelen, M., van Weissenbruch, M. M., Vermeiden, J. P. W., van Leeuwen, F. E., & van de Waal, H. A. D. (2008). Pubertal development in children and adolescents born after IVF and spontaneous conception. Hum Reprod, Dec;23(12):2791-8.
33. Ceelen, M., van Weissenbruch, M. M., Vermeiden, J. P.W., van Leeuwen, F. E., & van de Waal, H. A. D. (2008). Cardiometabolic differences in children born after in vitro fertilization: follow-up study. J Clin Endocrinol Metab, May;93(5):1682-8.
34. Basatemur, E., Shevlin, M., & Sutcliffe, A. (2010). Growth of children conceived by IVF and ICSI up to 12years of age. Reprod Biomed Online, Jan;20(1):144-9.
35. Källén, B., Finnström, O., Lindam, A., Nilsson, E., Nygren, K., & Olausson, P. O. (2010). Cancer risk in children and young adults conceived by in vitro fertilization. Pediatrics, Aug;126(2):270-6.
36. Williams, C. L., Bunch, K. J., Stiller, C. A., Murphy, M. F. G., Botting, B. J., Wallace, W. H., Davies, M., & Sutcliffe, A. G. (2013). Cancer risk among children born after assisted conception. N Engl J Med, Nov 7;369(19):1819-27.
37. Reigstad, M. M., Oldereid, N. B., Omland, A. K., & Storeng, R. (2017). Literature review on cancer risk in children born after fertility treatment suggests increased risk of haematological cancers. Acta Paediatr, May;106(5):698-709.
38. Wainstock, T., Walfisch, A., Shoham-Vardi, I., Segal, I., Harlev, A., Sergienko, R., Landau, D., & Sheiner, E. (2017). Fertility treatments and pediatric neoplasms of the offspring: results of a population-based cohort with a median follow-up of 10 years. Am J Obstet Gynecol, Mar;216(3):314.e1- 314.e14.
39. Karama, S., Colom, R., Johnson, W., Deary, I. J., Haier, R., Waber, D. P., Lepage, C., Ganjavi, H., Jung, R., & Evans, A. C. (2011). Brain Development Cooperative Group. Cortical Thickness Correlates of Specific Cognitive Performance Accounted for by the General Factor of Intelligence in Healthy Children Aged 6 to 18. Neuroimage, Apr 15; 55(4): 1443–1453.