Associations between maternal stressful life events experiences and risk of neural tube defects in offspring: a systematic review and meta-analysis

Figures & data

Figure 1. Selection of studies for inclusion in meta-analysis through searching PubMed, Springer Link, ScienceDirect, and Cochrane Library up to July 2022.

Table 1. Information of the studies included in the meta-analysis.

Study ID	Case population	Location	Design	Data collection period	Measures of stressful life events	Variables adjusted
Carmichael and Shaw [26]	127 spina bifida and 122 anencephaly from California Birth Defects Monitoring Program 1987–1989	USA	Case-control	One month before conception until the end of the third month of gestation	The interviewers asked women the following questions regarding stressful events during the periconceptional period: “Did anyone very close to you die during this period”? “Were you or was anyone to you separated or divorced during this period” and “Did you or anyone close to you lose a job during this period?” The exposure variable of interest was whether a woman reported any of these three events.	Race, ethnicity, nativity, mother’s education, cigarette smoking, binge drinking, vitamin use, folate consumption from cereals and vitamin supplements, obesity, mother’s age, maternal intake of corticosteroid medications or valium, presence of the uncommon allele for transforming growth factor-alpha.
Suarez et al. [27]	184 neural tube defects from Texas Department of Health’s Neural Tube Defect Project 1995–2000	USA	Case-control	One year or three month before conception	To measure maternal life-event stress, interviewers used the detailed residential and occupational histories for the year before conception, as well as responses to the questions about any accidents or injuries experienced during the periconceptional period. Injury information included the type of injury, circumstances, and month of occurrence. Reported injuries during the 3 months before conception included those resulting from car accidents, falls, and physical assaults. Interviewers calculated a life-event score for each woman by summing her number of residence moves, job changes, and major injuries.	Maternal age, maternal birthplace, annual household income, dietary folate intake, folic acid-containing vitamin supplementation during preconception, preconceptional cigarette smoking, preconceptional alcohol consumption, and obesity.
Carmichael et al. [28]	139 spina bifida and 186 anencephaly from Los Angeles, San Francisco, and Santa Clara counties 1999–2004	USA	Case-control	Two months before through the two months after conception	Mothers answered an 18-item inventory of stressful life events to assess the occurrence of specific events during the periconceptional period. Questions included only potentially major events, and responses were yes/no, to maximize ability to recall the events objectively. Each woman was asked whether she or her husband (or partner) had started a new job or lost a job; whether she or anyone close to her had had a serious illness or injury, serious legal or financial problems, problems with drinking or drugs, or had problems with immigration; whether she or anyone close to her had been a victim of violence or crime; whether anyone close to her had died; whether she was separated or divorced or had had serious difficulties with her husband or partner; whether she had moved; and whether she had had serious problems or disagreements with relatives, neighbors, or in laws.	Maternal race ethnicity, education, prepregnancy obesity, age at delivery, cigarette smoking, alcohol intake, and intake of folic acid-containing multivitamin/mineral supplement.
Li et al. [29]	285 anencephaly, 297 spina bifida, and 49 encephalocele from a population-based case-control study in Shanxi Province 2002–2007	China	Case-control	One month before pregnancy to two months after conception	Regarding severe life events, women were asked one question in the questionnaire: “During the period from one month before pregnancy to two months after conception, have you experienced any severe stressful events, including the death or life-threatening diseases in first degree relatives or partners, intense conflict with others, or other very severe life events that caused strong psychic trauma to you? (Yes/No).”	Maternal age, education, multiparity, multiple births, history of pregnancy affected by birth defects, meat, egg or milk, fresh vegetable, fresh fruit, legume, pickled vegetable, daily tea consumption, daily passive tobacco smoke, flu or fever, other inflammatory disease, anticonvulsant or sedatives use, antibiotics use, analgesics/antipyretics use, and other medication use.
Carmichael et al. [30]	552 neural tube defects from National Birth Defects Prevention Study 2006–2009	USA	Case-control	Three months before or first three months of pregnancy	Mothers were asked yes/no questions about whether they experienced five life events during the three months before or first three months of pregnancy (relationship difficulties; legal/financial problems; violence/crime; illness/injury; or a relative’s death). In a separate section of the interview, they reported their employment and residence history during that time period; we considered a change in employment or residence as two additional stressful life events, bringing the total to seven.	Maternal race-ethnicity, age, education, body mass index, smoking, drinking, and intake of vitamin supplements.
Ingstrup et al. [31]	1115 neural tube defects (85 anencephaly, 889 spina bifida, and 164 encephalocele) from a register-based cohort study	Denmark	Cohort	One year before conception and during the first trimester	Antenatal bereavement was defined as antenatal bereavement due to death of a close relative, which included relatives on the mother’s side including her parents, siblings, and children and also the registered (biological) father of the unborn child.	Maternal age, paternal age, parity, birth year, education, income, cohabitation, and place of residence

Figure 2. Effect of maternal stressful life events during periconceptional period on risk of neural tube defects in offspring. OR: odds ratio; CI: confidence interval. Diamond represents the pooled effects of the overall group of included studies.

Figure 3. Effect of maternal stressful life events during periconceptional period on risk of neural tube defects in offspring stratified by whether folic acid supplementation was adjusted for in each included study (1: yes, 0: no). OR: odds ratio, CI: confidence interval. Diamonds represent the pooled effects of the overall/each group of included studies.

Figure 4. Effect of maternal stressful life events during periconceptional period on risk of neural tube defects in offspring stratified by time window of exposure (1: three months preconception until three months post conception, 0: one year preconception until three months post conception). OR: odds ratio, CI: confidence interval. Diamonds represent the pooled effects of the overall/each group of included studies.

Figure 5. Begg’s funnel plot (with pseudo 95% confidence intervals) to detect any publication bias.

Carmichael SL, Shaw GM. Maternal life event stress and congenital anomalies. Epidemiology. 2000;11(1):30–35. doi: 10.1097/00001648-200001000-00008.

 PubMed Web of Science ®Google Scholar

Suarez L, Cardarelli K, Hendricks K. Maternal stress, social support, and risk of neural tube defects among Mexican Americans. Epidemiology. 2003;14(5):612–616. doi: 10.1097/01.ede.0000073270.39780.e9.

 PubMed Web of Science ®Google Scholar

Carmichael SL, Shaw GM, Yang W, et al. Maternal stressful life events and risks of birth defects. Epidemiology. 2007;18(3):356–361. doi: 10.1097/01.ede.0000259986.85239.87.

 PubMed Web of Science ®Google Scholar

Li Z, Zhang L, Li H, et al. Maternal severe stressful life events and risk of neural tube defects among rural Chinese. Birth Defects Res A Clin Mol Teratol. 2013;97(2):109–114. doi: 10.1002/bdra.23108.

 PubMed Web of Science ®Google Scholar

Carmichael SL, Ma C, Tinker S, et al. Maternal stressors and social support as risks for delivering babies with structural birth defects. Paediatr Perinat Epidemiol. 2014;28(4):338–344. doi: 10.1111/ppe.12123.

 PubMed Web of Science ®Google Scholar

Ingstrup KG, Wu CS, Olsen J, et al. Maternal antenatal bereavement and neural tube defect in live-born offspring: a cohort study. PLOS One. 2016;11(9):e0163355. doi: 10.1371/journal.pone.0163355.

 PubMed Web of Science ®Google Scholar

Data availability statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request.