Impact of pregnancy-related anxiety on preschoolers' emotional and behavioral development: Gender specificity, critical time windows and cumulative effect

Maternal mental health during pregnancy is of special concern because of its potential impact on the developing fetus. Anxiety disorders are mental disorders characterized by anxiety and fear, mainly manifested in excessive worry about certain events or a highly sustained fear response. Pregnancy-related anxiety (PrA) is a specific anxiety than can be experienced by expectant mothers. This anxiety is defined as concerns about the mother's health, baby's health and childbirth (Rini et al., 1999). Similarly, Orr et al. (2007) defined PrA as worries and concerns related to pregnancy. The prevalence of PrA in high-income countries is approximately 29 % (Arch, 2013). In India, as many as 55.7 % of pregnant women suffer from severe PrA at <24 weeks gestation (Nath et al., 2019). The prevalence of PrA shows significant variability in different regions, and varies as high as 12.4 % to 31.6 % in China (Haihua, 2017; Yahui et al., 2021; Wang et al., 2021).

Huizink et al. (2004) found that only 8 % to 27 % of PrA can be explained by general anxiety and depression in the first and second trimesters. Researchers have proposed that PrA is a relatively unique syndrome that differs from general anxiety. PrA may be more closely associated with maternal and fetal outcomes than general anxiety, and assessment of maternal anxiety by the general anxiety scales may underestimate pregnancy-specific anxiety (McMahon et al., 2013). PrA is reported to be associated with preterm birth (Gimenez et al., 2019), low birth weight (Nasreen et al., 2019), and poor executive function in children (Buss et al., 2011). It is shown that PrA is superior to general anxiety in predicting birth outcomes and children's development, as PrA can more accurately describe maternal particular psychological states related to pregnancy (Sandman et al., 2012).

Emotional and behavioral development are critical dimensions that reflects brain function. Children's emotional and behavioral problems have drawn much attention in the field of neurodevelopment because they are associated with long-term social adaptation and can be intervened in early life. Many researchers have revealed that PrA may be related with children's emotional and behavioral problems. (Buss et al., 2011; Sun et al., 2016; Mudra et al., 2022; Gordon Green et al., 2022) Studies have confirmed that development of emotional and behavioral problems in children is gender-specific (Ma et al., 2022). Current evidence on the gender-specific effect of PrA on children's brain function is limited. A prospective cohort study found that PrA in late pregnancy was associated with only emotional symptoms in girls and hyperactivity in boys (Liu et al., 2021). Wang et al. (2021) suggested that PrA in early and late pregnancy may be associated with externalizing problems in preschool boys and that PrA in early pregnancy increased the risk of internalizing problems in girls. This gender-specific effect of PrA might be due to differences in placental response to increased glucocorticoid by maternal anxiety (Clifton and Murphy, 2004; Mueller and Bale, 2008).

Attention should also be paid to critical time windows during which maternal anxiety impacts children's neural development. The different time points at which PrA occurs may have different influence. A study from California suggested that PrA in early pregnancy had a unique impact on children, causing children to show more negative effect in temperament at two years of age (Blair et al., 2011). Buss et al. (2010) firstly provided evidence of gray matter volume reduction in prefrontal cortex, the premotor cortex, the medial temporal lobe in children at 6 to 9 years of age born of mothers who reported high-level PrA in the second trimester of pregnancy. But the association was not found in the third trimester, and data from the first trimester was lack. Similar studies have investigated the effect of PrA in the first and second trimesters on children's emotional and behavioral development (Wang et al., 2021). Most of the current studies have been performed primarily within one or two trimesters of pregnancy, and few studies examined PrA throughout the entire gestation.

From what has mentioned above, studies on the gender-specific effect of PrA on children's emotional and behavioral development are limited. Lack of PrA data on the entire pregnancy had caused difficulties in identifying the key time window that PrA would affect, and also limited the feasibility of understanding the cumulative effects of PrA on emotional and behavioral development in offspring. Therefore, in this study, based on a population-based birth cohort, we repeatedly assessed PrA in all three trimesters and aimed to answer the following three scientific questions: 1) What is the gender specificity in the association between PrA and children's emotional and behavioral development? 2) Which trimester is the potential critical time window when PrA impacts children's emotional and behavioral development? 3) Whether there exists dose-response relationship between maternal PrA and children's emotional and behavioral development?

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