Friday, September 6, 2019

Association of cesarean delivery with risk of neurodevelopmental and psychiatric disorders in the offspring

Zhang T, Sidorchuk A, Sevilla-Cermeño L, Vilaplana-Pérez A, Chang Z, Larsson H, Mataix-Cols D, Fernández de la Cruz L. Association of Cesarean Delivery With Risk of Neurodevelopmental and Psychiatric Disorders in the Offspring: A Systematic Review and Meta-analysis. JAMA Netw Open. 2019 Aug 2;2(8):e1910236.


Birth by cesarean delivery is increasing globally, particularly cesarean deliveries without medical indication. Children born via cesarean delivery may have an increased risk of negative health outcomes, but the evidence for psychiatric disorders is incomplete.

To evaluate the association between cesarean delivery and risk of neurodevelopmental and psychiatric disorders in the offspring.

Ovid MEDLINE, Embase, Web of Science, and PsycINFO were searched from inception to December 19, 2018. Search terms included all main mental disorders in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition).

Two researchers independently selected observational studies that examined the association between cesarean delivery and neurodevelopmental and psychiatric disorders in the offspring.

Two researchers independently extracted data according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines and assessed study quality using the Newcastle-Ottawa Scale. Random-effects meta-analyses were used to pool odds ratios (ORs) with 95% CIs for each outcome. Sensitivity and influence analyses tested the robustness of the results.

The ORs for the offspring with any neurodevelopmental or psychiatric disorder who were born via cesarean delivery compared with those were born via vaginal delivery.

A total of 6953 articles were identified, of which 61 studies comprising 67 independent samples were included, totaling 20 607 935 deliveries. Compared with offspring born by vaginal delivery, offspring born via cesarean delivery had increased odds of autism spectrum disorders (OR, 1.33; 95% CI, 1.25-1.41; I2 = 69.5%) and attention-deficit/hyperactivity disorder (OR, 1.17; 95% CI, 1.07-1.26; I2 = 79.2%). Estimates were less precise for intellectual disabilities (OR, 1.83; 95% CI, 0.90-3.70; I2 = 88.2%), obsessive-compulsive disorder (OR, 1.49; 95% CI, 0.87-2.56; I2 = 67.3%), tic disorders (OR, 1.31; 95% CI, 0.98-1.76; I2 = 75.6%), and eating disorders (OR, 1.18; 95% CI, 0.96-1.47; I2 = 92.7%). No significant associations were found with depression/affective psychoses or nonaffective psychoses. Estimates were comparable for emergency and elective cesarean delivery. Study quality was high for 82% of the cohort studies and 50% of the case-control studies.

The findings suggest that cesarean delivery births are associated with an increased risk of autism spectrum disorder and attention-deficit/hyperactivity disorder, irrespective of cesarean delivery modality, compared with vaginal delivery. Future studies on the mechanisms behind these associations appear to be warranted.

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...
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.

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