BackgroundThe use of assisted reproductive techniques (ART) for treatment of infertility is increasing rapidly worldwide. However, various health effects have been reported including a higher risk of congenital malformations. Therefore, we assessed the risk of anorectal malformations (ARM) after in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).MethodsData of the German Network for Congenital Uro-REctal malformations (CURE-Net) were compared to nationwide data of the German IVF register and the Federal Statistical Office (DESTATIS). Odds ratios (95% confidence intervals) were determined to quantify associations using multivariable logistic regression accounting for potential confounding or interaction by plurality of births.ResultsIn total, 295 ARM patients born between 1997 and 2011 in Germany, who were recruited through participating pediatric surgeries from all over Germany and the German self-help organisation SoMA, were included. Controls were all German live-births (n = 10,069,986) born between 1997 and 2010. Overall, 30 cases (10%) and 129,982 controls (1%) were born after IVF or ICSI, which translates to an odds ratio (95% confidence interval) of 8.7 (5.9–12.6) between ART and ARM in bivariate analyses. Separate analyses showed a significantly increased risk for ARM after IVF (OR, 10.9; 95% CI, 6.2–19.0; P < 0.0001) as well as after ICSI (OR, 7.5; 95% CI, 4.6–12.2; P < 0.0001). Furthermore, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed strong associations with ART (ORs 4.9, 11.9 and 7.9, respectively). After stratification for plurality of birth, the corresponding odds ratios (95% confidence intervals) were 7.7 (4.6–12.7) for singletons and 4.9 (2.4–10.1) for multiple births.ConclusionsThere is a strongly increased risk for ARM among children born after ART. Elevations of risk were seen after both IVF and ICSI. Further, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed increased risks in each group. An increased risk of ARM was also seen among both singletons and multiple births.

Comparable histologic alterations of intramural nervous tissue were reported in various diseases of the small and large intestine. In 6 cases, an intestinal obstruction was present which led to secondary intramural inflammation. The obstruction was induced by the spastic segment in Hirschsprung’s disease (3 cases), by rectal atresia (2 cases) and by postoperative ischemic damage to the intestinal wall (1 case). In 4 other patients, the inflammation was predominant. The diseases considered were necrotizing enterocolitis (1 case), membranous enteritis (1 case) and Crohn’s disease (2 cases). On the one hand, inflammatory infiltration composed primarily of lymphocytes was observed histologically in various degrees proximal to the obstruction in all cases. On the other, comparable alterations were found in sputtering of nerve fibers and deterioration of nerve cells (degenerative alterations) in the plexus myentericus as well as hyperplasia and hyperchromasia of ganglion cells, Schwann cell proliferation and fibrosis in nerve fibers (reactive alterations). Until now such alterations were only observed in Chagas’ disease and in ulcerative colitis, especially complicated by toxic megacolon. It is suspected that the neurodegenerative alterations in these diseases are toxically induced.

This study provides evidence that assisted reproductive techniques such as in vitro fertilization and intracytoplasmic sperm injection are associated with a markedly increased risk of having a child born with exstrophy-epispadias complex. However, it remains unclear whether this finding may be due to assisted reproduction per se and/or underlying infertility/subfertility etiology or parent characteristics.

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