Hua-Jie Zhai,Gui-Fang Wang,Min Chen,Yi Ling,Hong-Yu Zhang*
1Department of obstetrics,Dongchang maternal and child health hospital in Shandong liaocheng city,Shandong,China.
2Department of obstetrics,Center hospital of Xindu district of Xingtai city of Hebei,Hebei,China.
3Hainan Medical University,Haikou,Hainan,China.
#Hua-Jie Zhai and Gui-Fang Wang contributed equally to this work.
Abstract Autism spectrum disorder (ASD) is a high genetic heterogeneity neurodevelopmental disorder characterized by social, communicative, and behavioral deficits. However, there are very few studies thus far addressing risk factors for ASD in China children. This case-control study aims to investigate whether various risk factors especially cesarean section, epidural analgesia during labor, immediate cord clamping at birth were associated with the risk of having an offspring with ASD. There were 50 children with ASD (age 34.76±7.78 months) and 150 normal children (age 33.76±6.73 months)enrolled in this study. The risk of developing ASD in these children included cesarean section (RR=3.512, 95% confidence interval (CI)=1.162–10.620), anesthesia for pain relief (RR=3.387, 95%CI=1.160–9.891), early cord clamping (RR=19.062,95%CI=3.894–93.0304), gender of boy (RR=3.530, 95%CI=1.223–10.188). Further research is needed to determine whether such factors have a causal link to ASD.
Keywords:Autism spectrum disorder, Delayed cord clamping, Anesthetic labor analgesia
Autism spectrum disorder (ASD) is a high genetic heterogeneity neurodevelopmental disorder characterized by social, communicative,and behavioral deficits. According to the WHO, on a worldwide basis,it is estimated that 1 in 160 children exhibit ASD [1]. Although the prevalence of autism is increasing [2-3], a pharmaceutical has not been developed for the treatment of the core symptoms of ASD.
The etiologic factors related to ASD is remained unclear. Several factors including genetic, disorder of endocrine system, maternal infection during pregnancy,obesity,food,chemical solvent play a role in the pathogenesis of ASD.Recent studies demonstrated that cesarean section, oxytocin induction during labor may be the high-risk factors.The study by Curran confirmed that babies born by cesarean section had higher risk of ASD compared to normal vaginal birth [4, 5].Recent years, the possibility of brain protection of delaying umbilical cord clamping(DCC)had drawn more attention.Rao R,et al.reported an additional benefit of DCC in full-term infants; compared with immediate cord clamping (ICC), DCC is associated with better hemodynamic stability,a decreased need for transfusions,and a lower risk of intraventricular hemorrhage and necrotizing enterocolitis in preterm infants; in full-term infants, DCC is associated with higher hemoglobin levels after birth, improved iron status at 4-6 months of age,and better neurodevelopment,especially in boys,at 4 years of age[6]. But whether DCC can reduce the incidence of ASD is unknown.This study was designed by cohort study to compare diagnosed ASD children with normal children to explore the factors in prenatal period that may relate to the prevalence of ASD.
Fifty children (age 34.76±7.78 months) diagnosed as ASD were recruited from Janary 2021 to June 2022 at Dongchang maternal and child health hospital, Liaocheng, Shandong. The random method selected normal babies from the clinical record in hospital information system. Contact the child"s parents by phone, follow up the child"s condition, and make an appointment to come to the hospital for free routine examination,so as to exclude the possibility of inquiring about some diseases. After the check up, one hundred-fifty children (age 33.76±6.73 months) without any neurodevelopmental or behavioral disruptions related to ASD were arranged to be control group. All parents of the children signed the informed consent form. This study This study was approved by hospital ethics committee (No.20210001).
Inclusive criteria
The child was born in our hospital and has a complete record about birth condition. The parents of participant signed informed consent.
Exclusive criteria
Children suffered from malformation, mental illness or other serious diseases; parents or children refused to participate in the study.
Research tools and observation indicators
Research tools.The ASD risk factor questionnaire was developed according to the possible autism risk factors in the literature.According to the parents" interview outline, the mother"s mental state,family relations, pregnancy and childbirth related events, and postpartum breast milk, et al.were asked.
Observation indicators
General data indicators.Birth date of children, birth weight, birth condition, parent healthy condition, genetic disease of family,perinatal condition, whether epidural analgesia was used during labor, whether oxytocin is used, whether other drugs are used in the perinatal period, DCC or not, normal birth or cesarean section, breast feeding time and relationship between couples and family.
Statistical analysis
Data distributions are reported as mean ± standard deviation for continuous variables and as number (percentage) for categorical variables. The chi-square test was used to measure the statistical differences between classes of categorical data. Continuous data between the two groups were compared by the student’sttest.Factors with statistical significance in single factor analysis are included in conditional multifactor logistic regression analysis to evaluate the comprehensive effect of each factor. All statistical analyses were performed using SPSS 22.0 with a cutoff p-value ＜0.05 was used for all tests of statistical significance.
In the overall sample, the mean age of fathers of control group were significantly older than those with ASD (32.46±5.43vs28.82±4.91,P＜0.001); This finding was also observed for the mean age of the mothers between the two groups (30.66±4.29vs27.88±4.21,P＜0.001). Cesarean section, epidural analgesia during labor, baby gender, early cord clamping at birth, and whether the relationship between husband and wife is harmonious were among potential risk factors that tended to be associated with ASD in the offspring. There were no statistic difference in history of diabetes or hyperglycemia of parents, father smoking or not, oxytocin induction during labor,babies birth condition, and breast feeding time between two groups.(Table 1).
The potential risk factors mentioned above were chosen for further evaluation of the association with ASD in the multiple Logistic regression analysis presented in Table 2. The results had shown cesarean section (RR=3.512, 95%CI=1.162-10.620), anesthesia for pain relief (RR=3.387, 95%CI=1.160-9.891), early cord clamping was risk factors to autism (RR=19.062, 95%CI=3.894-93.0304) and and gender (RR=3.530, 95%CI=1.223-10.188) were the risk factors to autism. Pregnant weeks at birth (RR=0.526, 95%CI =0.372-0.744) and babies transfer to neonatal intensive care unit(NICU) (RR=0.179, 95%CI =0.050-0.636) have shown to be the protective factors.
Table 1 Analysis of single indicators between groups
Table 2 Multiple factors may related to autism by logistic regression
Many factors influenced the newborns healthy and contributed to ASD, such as infection in uterus, complications during pregnant,contact to chemical materials and environment pollution, labor and postpartum conditions, etc. Hultman and Wilkerson reported that mother’s emotional compression during pregnant, smoking, virus infection, fever, history of drug abuse, cesarean section, preterm, low birth weight, labor related injury, and asphyxia at birth and genetic defect all may put the baby at risk of ASD [7,8]. CMV infection of uterus is the known high risk to autism; it is related to immune dysfunction due to inflammatory reaction caused by virus infection.Exposure to 2-valproate during pregnancy and childbirth may also increase the risk of ASD in offspring, especially in the first three months of pregnancy. A large sample epidemiological study analyzed the prenatal use of valproate by mothers of 5437 children with ASD in Denmark from 1996 to 2006; it was found that taking this drug significantly increased the risk of ASD in offspring [9]. In this study,no mother took valproate during labor. There was no statistical significance between the two groups in smoking history.
Curran EA, et al. conducted a systematic review and found delivery by caesarean section is associated with a increased odds of ASD,when compared to vaginal delivery [4]. Another investigation in 5 nations covered 5 million pregnant women with singles fetus had discovered that cesarean section increase the potential of ASD; when analyzed by subgroup of pregnant weeks, the results remain on rising trend [5].This is consistent with our research results. Our study found the potential risk of cesarean section to ASD increased risk 3.512. times than babies by normal virginal birth. This highlights the style of birth worth attention. Besides, our study showed that application of epidural analgesia during labor is the risk factors of ASD. In single factor analysis, the application of epidural analgesia during labor process in ASD group is 70.0%(35/50),which was higher than that of control group 25.3% (38/150).
This study focuses on the impact of DCC on ASD. DCC for at least 30-60 seconds after birth is recommended in preterm and full-term births [10, 11]. Our results showed that the proportion of ECC in control group is higher than that in ASD group. Multivariate regression analysis showed that ECC was a risk factor for ASD. Few literatures study the relationship between DCC and ASD. However,relevant studies have proved that the pH value of umbilical artery blood of neonates in the DCC group during neonatal asphyxia rescue is significantly higher than that in the control group, and the absolute values of PaCO2 and BE are significantly lower than those in the control group; this study confirms that for asphyxiated neonates, DCC can alleviate metabolic acidosis and respiratory acidosis [12].Whether DCC at birth can protect the brain is worthy of further attention.
Our study found male sex was a signifcant risk factor for ASD. This signifcant association between male sex and ASD was also reported by Davidovitch et al.[13-15].With one proposal that ASD is an extreme presentation of the typical male brain [16]. In this study, the mother and fathers age at birth of the baby had shown younger in the ASD group than that control group. Nevertheless some previous studies showed that advanced maternal age conferred a significant risk of ASD in the offspring [17-20]. Therefore, the association between advanced maternal age and ASD still needs further research.
Some study suggested breastfeeding modal may influence the flora in intestine that may be contributed to developing of ASD. Breastfeeding may transfer normal flora from mother to baby in the process while the bottle feeding can block this transfer link between mother and baby. In this study, the breast feeding time in two groups was not of statistic difference; the influence of feeding patterns should be observed in further study. In this study, there is no statistical difference in oxytocin application between the two groups. This may be bleared by too much oxytocin used in clinical seeting even on low risk women. The effect of oxytocin on babies long term life quality should be observed further.
This study focused on the prenatal factors may relate to ASD.Cesarean section, analgesics during labor and early cord clamping, gender of boy were risk factors of ASD. Longer pregnant weeks and baby transfer to NICU had shown the protective factors. Further study should be paid on attention on clinical protocols to reduce the rate of cesarean section and the use of analgesics during labor. This study proposes for the first time that early umbilical cord clamping at birth is an important risk factor for autism.