Cesarean delivery is associated with an increased risk for autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), new research suggests. A review and meta-analysis of 61 studies conducted in 19 countries, encompassing 20.6 million deliveries, showed a 33% higher association with ASD and a 17% higher association with ADHD in offspring born via cesarean vs vaginal delivery. These findings remained whether the cesarean delivery (CD) was elective or prompted by a medical emergency during delivery. "It is well known that C-section should ideally only be undertaken when medically necessary [and] obstetricians should make every effort to provide C-section to women in need," lead author Tianyang Zhang, MSc, doctoral candidate in the Centre for Psychiatry Research at Karolinska Institutet in Stockholm, Sweden, told Medscape Medical News. "For women without medical indication to perform a C-section, recommending one may not be appropriate. Obstetricians should conduct a full evaluation on the status of the mother and the baby/babies to decide whether a C-section is necessary," said Zhang, who is also associated with the Department of Medical Epidemiology and Biostatistics at Karolinska. The findings were published online August 28 in JAMA Network Open. Negative Outcomes Births by cesarean delivery have previously been linked to several negative health outcomes in the children, such as obesity, asthma, allergy, and type 1 diabetes. "However, the association between C-section and neurodevelopmental and psychiatric disorders has been less studied," Zhang noted. "In addition, it is unclear whether the extent of this association is different if a cesarean section is planned in advance or performed urgently due to medical reasons during the delivery," she said. To investigate these questions, the researchers conducted a systematic review and meta-analysis of observational studies "to quantify the extent of the association between CD and a range of neurodevelopmental and psychiatric outcomes compared with vaginal delivery." They also assessed whether type of CD, elective vs emergency, or assisted vaginal delivery using vacuum or forceps were associated with neurodevelopmental and psychiatric outcomes in the offspring. The investigators identified 6953 studies. Of these, 61 studies comprising 67 independent samples (n = 20,607,935 deliveries) met their inclusion criteria. Studies were required to be observational and allow estimation of the associations between obstetric mode of delivery and neurodevelopmental/psychiatric disorders in offspring. They were also required to include formal outcome diagnoses, with self- or caregiver-reported outcomes excluded. Characteristics of the studies are listed below: Association of CD with ASD diagnosis: 27 studies (59,795 cases) Association with ADHD: 13 studies (92,718 cases) Association with intellectual disabilities: 3 studies (485 cases) Association with tic disorders: 3 studies (6181 cases) Association with eating disorders: 4 studies (4550 cases) Association with obsessive-compulsive disorder (OCD): 3 studies (7295 cases) Association with major depression or affective psychoses: 5 studies (8561 cases) Association with nonaffective psychoses: 7 studies (7195 cases) Of these, study quality was defined as "high" in 82% of cohorts and 50% of case-control studies. Increased Risk CD was found to be significantly associated with increased odds of a diagnosis of ASD in the offspring compared with birth by vaginal delivery (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.25 - 1.41). Similarly, there was a significant association with increased diagnosis of ADHD (OR, 1.17; 95% CI, 1.07 - 1.26). There were also increased odds for other neurodevelopmental and psychiatric outcomes in offspring delivered via CD vs those delivered vaginally. However, the associations did not reach statistical significance, "possibly because of the limited number of studies," the investigators write. When the researchers conducted a "leave-1-out" analysis, in which they omitted 1 study for each outcome, they found statistically significant associations between CD and intellectual disabilities, OCD, and tic disorders (ORs after exclusion, 2.61, 1.13, and 1.24, respectively). Elective as well as emergency CDs were associated with increased odds of ADHD and ASD but were not associated with tic disorders or affective and nonaffective psychoses. When comparing assisted vs unassisted vaginal delivery, the researchers found no associations with the outcomes of interest except for tic disorders (OR, 1.28; 95%CI, 1.17 - 1.41; I2 = 0.0%). Don't "Demonize" Cesarean Delivery Zhang suggested several possible reasons that CD might be associated with higher risk for neurodevelopmental or psychiatric problems in offspring. "Birth is complicated and there are numerous factors that can lead to different outcomes," she said. An emergency CD "usually occurs when something goes wrong during a delivery and a surgical intervention becomes necessary," she added. "It is not impossible that a child experiences injuries or asphyxia in a traumatic delivery, which later results in neurological or neurodevelopmental disorders." Moreover, "C-section is often recommended by obstetricians if the mother has diseases such as diabetes, hypertension, etc. Some of the diseases might already have had an effect on the child's brain development when he or she is still in the womb," Zhang noted. Factors related to the CD itself might further contribute to the risk. "For example, during a natural vaginal birth, specific bacteria from the mother's gut are passed on to the baby and stimulate the baby's immune response. This transmission is altered in children born by C-section," Zhang said. "We speculate that it is a combination of these and other factors, such as genetic predisposition to neuropsychiatric disorders, that result in increased risks in the offspring," she said. Therefore, she emphasized that "it would be wrong to demonize C-sections, and they should continue to be used when medically necessary." Reconsider Indications? Commenting on the study for Medscape Medical News, Xiawei Ou, PhD, associate professor of radiology and pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, said that the underlying mechanism linking cesarean delivery and these increased risks in offspring "is still unclear and will need further investigation." Still, the study has important take-home messages for clinicians, noted Ou, who is also the director of the Brain Imaging Laboratory at the Arkansas Children's Nutrition Center. "Elective C-section delivery without medical indications may need to be reconsidered in light of new scientific findings from this study and others. And additional consideration on risk-benefit ratio may need to be taken for planned C-section delivery with medical indications," said Ou, who was not involved with the study. Lead author Zhang cautioned that the study "does not provide irrefutable proof" that cesarean deliveries cause neurodevelopmental disorders. "Association is not causation," she emphasized. The study was supported by the China Scholarship Council. Zhang and Ou have disclosed no relevant financial relationships. Disclosures for the other study authors are listed in the original article. JAMA Network Open. Published online August 28, 2019. Full text Source
