P–776 Singleton pregnancies conceived with infertility treatments and the risk of neonatal and infant mortality

Study question Is maternal infertility treatment associated with an increased risk of neonatal and infant mortality when compared to natural conception? Summary answer Infertility treatment is associated with a 70% increased adjusted risk of neonatal mortality. This association is strongly mediated by preterm delivery. What is known already The number of assisted reproduction technology (ART) cycles performed in the United States (US) increased by 39% from 142,435 cycles in 2007 to 197,737 in 2016. Within this growing experience, several studies described an increased risk of preterm delivery, low birth weight, congenital malformations, neonatal intensive care unit admission, stillbirth, and perinatal mortality among singletons conceived through ART compared to those conceived naturally. Experts have called for ART patients to be advised of potential increased risk for adverse perinatal outcomes and for obstetricians to manage these pregnancies as high risk. Study design, size, duration This is a cross-sectional study of 11,289,466 pregnancies in the United States (US) from 2015–2017 that resulted in a non-malformed singleton live birth. The exposure group includes births resulting from any infertility treatment method, including ART and fertility-enhancing drugs. The control group includes births resulting from natural conceptions. The primary outcomes measured were neonatal (within 1 month), post-neonatal (1 month to a year), and infant (up to 1 year) mortality. Participants/materials, setting, methods Pregnancies (n = 11,289,466) resulting in a non-malformed singleton live birth in the US from 2015–2017. Associations were estimated from log-linear Poisson regression models with robust variance. Risk ratio (RR) and 95% confidence interval (CI) were derived as the effect measure with adjustments for confounders. The impact of exposure misclassification and unmeasured confounding biases were assessed. A causal mediation analysis of the infertility treatment-mortality association with preterm delivery (<37 weeks) was performed. Main results and the role of chance Any infertility treatment was documented in 1.3% (n = 142,215) of singleton live births during the study period. Any infertility treatment was associated with a 70% increased adjusted risk of neonatal mortality (RR 1.70, 95% CI 1.54–1.88), with an even higher risk for early neonatal (RR 1.82, 95% CI 1.63–2.05) than late neonatal (RR 1.37, 95% CI 1.11–1.69) mortality. These risks were similar among pregnancies conceived through ART and treatment with fertility-enhancing drugs. The mediation analysis showed that 68% (95% CI 59–81) of the total effect of infertility treatment on neonatal mortality was mediated through preterm delivery. In a sensitivity analysis, following corrections for exposure misclassification and unmeasured confounding biases, these risks were higher for early neonatal (bias-corrected RR [RRbc] 2.94 95% CIbc 2.16–4.01), but not for late neonatal (RRbc 1.04, 95% CIbc 0.68–1.59) mortality. Limitations, reasons for caution Limitations of the study include the potential underreporting of infertility treatment on birth certificates and potential confounding from sociodemographic characteristics that were not accounted for in this study. Wider implications of the findings: Pregnancies conceived with infertility treatment are associated with increased neonatal mortality and this association is mediated by the increased risk of preterm delivery. Knowledge of this risk should be shared with prospective couples consulting for fertility care in order to best provide adequate informed consent. Trial registration number Not applicable

Η επίδραση του τοκετού στη δραστικότητα των ενζύμων ακετυλοχολινεστεράση, (Νa+,Κ+)-ΑΤΡάση και Mg2+-ΑΤΡάση στις ερυθροκυτταρικές μεμβράνες μητέρων-παιδιών

Reactive oxygen species (ROS) are chemical molecules, that contain an atom of oxygen and are highly reactive. In vivo, they are being produced through the cellular metabolism and in conditions of ischemia and reperfusion. The ROS react with various cellular elements and damages them, causing changes in the DNA sequence or lipid and aminoacid oxidation. The organism possesses various defense mechanisms that inactivate these oxidative agents. There are situations, however, that these mechanisms are being overpowered by the ROS and a stress situation is being created, which is called oxidative stress. There are various studies that show a connection between exercise and oxidative stress, because of the increased oxygen consumption and catecholamines. As in exercise so in labor, several muscle groups and the myometrium participate, with concomitant increase of the metabolism and periods of ischemia and reperfusion.With these in mind, it is only natural to ask ourselves, if there is oxidative stress during labor and how the method of delivery (normal labor versus caesarean section) affects the TAS and the newborns. Another point of interest is the effect of the ROS on the term and preterm newborn, since its widely acknowledged that prematurity is worldwide the first cause of perinatal morbidity and mortality and that in situations of hypoxia like dystocia or complicated labor the nervous system of the newborn is most often affected.Acetylocholinestrase and Na+-K+ ATPase on the erythrocyte membranes are indicators of oxidative stress and can be used to estimate the TAS. It is also known that these enzymes are also situated in the synaptic cleft and are implicated in the neurotransmission.In this inquiry the activity of these enzymes were measured from the blood of mother that gave birth naturally and by caesarean section (CS), in order to evaluate the effect of the way of delivery on the oxidative stress. Additionally we aimed to evaluate the total antioxidant status of term and preterm newborns and how the mode of delivery affected them.Method: Serum samples were collected from mothers at the beginning of labor (pre-delivery), 3-4 min after membranes rupture, at the end of delivery (post-delivery), and from the cord blood (CB) of the newborn infants. The mothers were divided into two categories depending on the gestational age and newborns weight. The first category (N=30) consisted of women that gave birth to full term babies according to the following criteria: (1) singleton live birth, (2) gestational age between the beginning of the 37th week and the end of the 41st week, (3) body weight of the newborn between 2,500 and 4,000 g, and (4) Apgar scores of ≥9 at the first–fifth minute. The second categories (N=26) consisted of women that gave birth to premature infants, fulfilling the following criteria: (1) singleton live birth, (2) gestational age before the 37th week, (3) body weight of the newborn under 2,500 g, and (4) Apgar scores of ≥9 at the first–fifth minute. The control group consisted of 20 non-pregnant students of similar age.A history of the pregnancies and deliveries was obtained from the notes in the records made by obstetricians and pediatricians, according to the strict routine ―follow-up‖ practice of the First Department of Obstetrics and Gynecology of Athens University in the ―Alexandra‖ Maternity Hospital. Gestation age was determined based on the menstrual history and ultrasound obstetrical findings. The participants were divided into four groups according to the mode of labor and delivery as well as to the week of gestation and birth weight: Group A1 (n=16) women with normal labor and vaginal delivery, Group B1 (n=14) with scheduled cesarean section (CS).Group A2 (n=12) women with preterm labor and vaginal delivery and Group B2 (n=14) with cesarean section. CSs were performed with spinal anesthesia without oxygen administration. Twenty (N=20) non-pregnant medical students of comparable age were the controls. Blood was obtained for the evaluation of Total Antioxidant Status (TAS) and the erythrocyte membrane AChE, Na+, K+-ATPase and Mg2+ -ATPase activities in mothers pre-delivery. Immediately after delivery, blood from the umbilical cord and from the mothers (post-delivery) was also collected. Sera, plasma or erythrocytes were separated and kept frozen (−70°C) until analysis for the same biochemical parameters within a maximum of 72 h. The controls underwent the above laboratory investigations once and three determinations.Results: The mothers‘ blood biochemistry did not reveal any significant difference between the groups, except from the creatinine kinase levels, which as expected were higher in the normal labor because of the physical activity that involves.The TAS levels in the blood of mothers that gave birth naturally were lower than the TAS levels from the CS groups. Accordingly the TAS levels in the cord blood of natural born infants were lower than the levels from the CS groups.The maternal AChE activity was higher in the natural labor groups (A1 and A2) in comparison to the CS groups (B1and B2). It is worth noticing that, the AChE activity in the cord blood from preterm infants was lower, independent of the mode of delivery.Furthermore, the (Na+,K+)-ATPase activity was higher in mothers that gave birth naturally and unaltered in the CS groups. In the cord blood, the activities of AChE and (Na+,K+)-ATPase was lower