Gian Carlo Di RenzoGynecology and women health, Santa Maria della Misericordia University Hospital of Perugia
- Santa Maria della Misericordia University Hospital of Perugia
ART, INFANT DEATHS AND DEFECTIVE PLACENTATION. A CALL FOR PROLONGING PROGESTERONE SUPPLEMENTATION
The evidence is now compelling that the mortality rate of singletons conceived through Assisted Reproduction Technology (ART), both following transfer of frozen and thawed embryos, is higher, both late in pregnancy and in the early neonatal period. In this connection, the recent report by Rodriguez-Wallberg et al.  has provided essential new information on children conceived through assisted reproduction technologies (ART). True that the study, by its very nature, could not evaluate whether the increased risk is due to the ART, confounding but unmeasured parental characteristics, or underlying infertility. Nonetheless, the study provided details that may help delineating plausible causes for the increase in early infancy mortality. At the same time, the nearly two-fold increased risk of early neonatal death after transfer of blastocysts is in line with the finding of Källén et al  that the risk of preterm birth among singleton is significantly greater after blastocyst-stage than after cleavage-stage transfer. Clearly the issue warrants further evaluation and monitoring. In addition, the incidence of children who were born preterm, or with a low-birth weight for gestational age, was higher in ART-conceived children.
It must be stressed that in absolute terms the increase in risk is very small. Reassuring for clinicians, parents and their offspring is also the finding that beyond the first year of life there is no increased mortality rate among children conceived from ART.
The leading causes of infant mortality among children conceived from ART included respiratory distress syndrome, pulmonary hypoplasia in preterm infants, infections, and neonatal hemorrhage and a higher early mortality risk may be linked to the higher prevalence of preterm births and the adverse outcomes associated with prematurity .
It seems therefore that, on the one hand we face an increase of pregnancy-related problems in ART-conceived pregnancies; on the other there is good evidence that women conceiving through the ample spectrum of fertility treatments are at increased risks of adverse perinatal and obstetric outcomes, such as preterm birth and small for gestational age, which are associated with neonatal mortality [3-7]. A recent comprehensive review on this topic called for research “to determine which aspects of ART poses most risk and how this risk can be minimized” .
We believe that a tentative answer to this pivotal question can be suggested. First, the fact that increased morbidity and mortality seem confined to the first year of life supports the hypothesis that – with the possible exception of blastocyst transfers – the increased risk may not be due to impact of in vitro fertilization process on the embryo, as epigenetic changes are predicted to act before and after the first 12 months of life. Second, a recent Japanese study concluded that “women who conceived by ART had a higher risk of maternal/perinatal complications necessitating advanced obstetric care” . It seems therefore reasonable to assume that a maternal factor accounts for the increased risk of adverse pregnancy outcome in ART.
One such factor may be a less than complete decidualization process, which in turn increases the risk of defective deep placentation. The process of decidualization starts with a transient cellular stress response and release of inflammatory mediators, coinciding with the putative implantation window [10, 11]. Specialized anti-inflammatory decidual cells then emerge, and first engage in embryo biosensing and quality control before cooperating with innate immune cells, foremost uterine NK cells, to accommodate the deeply invading placenta [11, 12]. It has been suggested that the interplay between decidual and immune cells imposes a ‘clock’ mechanism that determines the length of gestation and onset of parturition . The question arises whether the increased risk of preterm birth or small for gestational age associated with ART can be attributed to a less than optimal decidual response. Since endometrial maturation in most ART procedures is “artificial”, the hypothesis seems plausible.
These considerations lead to the conclusion that, in the event of pregnancy following an ART procedure, there is a need to consider the opportunity to prolong the progesterone support for more than just up to 8 or 12 weeks as recommended in the most protocols around the world. This is because the process of placentation lasts for the entire first trimester and there is now compelling evidence that natural micronized progesterone can prevent premature labor in high risk patients [14-15].
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2 Källén B, Finnström O, Lindam A, Nilsson E, Nygren KG, Olausson PO Blastocyst versus cleavage stage transfer in in vitro fertilization: differences in neonatal outcome? Fertil Steril. 2010;94:1680-3.
3. Ceelen M, van Weissenbruch MM, Vermeiden JP, van Leeuwen FE, Delemarre-van de Waal HA. Growth and development of children born after in vitro fertilization. Fertil Steril. 2008;90:1662-73.
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6. Kalra SK, Molinaro T A. The association of in vitro fertilization and perinatal morbidity. Semin Reprod Med. 2008;26:423-35.
7. Pastore LM, Williams CD. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol. 2004;104:411. Authors reply. 411-2.
8. Pandey S, Shetty A, Hamilton M, Bhattacharya S, Maheshwari A. Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update. 2012;18:485-503.
9. Nagata C. Yang L, Yamamoto-Hanada K, Mezawa H, Ayabe T, Ishizuka K, Konishi M, Ohya Y, Saito H, Sago H; Japan Environment & Children’s Study Group. Complications and adverse outcomes in pregnancy and childbirth among women who conceived by assisted reproductive technologies: a nationwide birth cohort study of Japan environment and children's study. BMC Pregnancy Childbirth. 2019;19:77.
10. Brighton PJ, Maruyama Y, Fishwick K, Vrljicak P, Tewary S, Fujihara R, Muter J, Lucas ES, Yamada T, Woods L, Lucciola R, Hou Lee Y, Takeda S, Ott S, Hemberger M, Quenby S, Brosens JJ. Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium. Elife. 2017;6: e31274.
11. Lucas E S, Vrljicak P, Muter J, Diniz-da-Costa MM, Brighton PJ, Kong CS, Lipecki J, Fishwick KJ, Odendaal J, Ewington LJ, Quenby S, Ott S, Brosens JJ.. et al. Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window. Commun Biol. 2020;3:37.
12. Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev. 2014;35:851-905.
13. Norwitz ER, Bonney EA, Snegovskikh VV, Williams MA, Phillippe M, Park JS, Abrahams VM. Molecular Regulation of Parturition: The Role of the Decidual Clock. Cold Spring Harb Perspect Med. 2015;5: a023143.
14. Coomarasamy A, Devall AJ, Brosens JJ, Quenby S, Stephenson MD, Sierra S, Christiansen OB, Small R, Brewin J, Roberts TE, Dhillon-Smith R, Harb H, Noordali H, Papadopoulou A, Eapen A, Prior M, Di Renzo GC, Hinshaw K, Mol BW, Lumsden MA, Khalaf Y, Shennan A, Goddijn M7, van Wely M, Al-Memar M, Bennett P, Bourne T, Rai R, Regan L, Gallos ID. Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence. Am J Obstet Gynecol. 2020; 223:167-76.
15. Di Renzo GC, Tosto V, Tsibizova V. Progesterone: History, facts and artifacts. Best Pract Res Clin Obstet Gynaecol. Online ahead of print. 02 Sep 2020, DOI: 10.1016/j.bpobgyn.2020.07.012 PMID: 32943346.
Faculty of Medicine and Surgery, Sapienza University of Rome, Rome, Italy
Gian Carlo Di Renzo
Department of Obstetrics and Gynaecology and Centre for Perinatal and Reproductive Medicine, University of Perugia, Perugia, Italy
Tel. +39 075 5783829, +39 075 5783231
Fax +39 075 5783829
Jan J. Brosens
Division of Biomedical Sciences, University of Warwick Medical School, Warwick, UK
Tel: +024 7696 8704