Mood Symptoms and Other Maternal Factors in Pregnancy and Adverse Neonate Outcomes

Background Antenatal women experience a higher level of mood symptoms, which have negative effects on mothers’ mental and physical health and their newborns. The relation of maternal moods including depression and anxiety and other maternal factors in pregnancy and neonate outcomes are well-studied with inconsistent ndings. Although antenatal women experience a higher level of mood instability (MI), the association between antenatal MI and neonatal outcomes has not been investigated. We aimed to address this gap and to contribute to the pregnancy-neonate outcomes literature by examining the relationship between antenatal mood symptoms and other maternal factors and neonatal outcomes. Methods A prospective cohort of women (n = 555) participated in this study at early pregnancy (T1, 17.4 ± 4.9 weeks) and late pregnancy (T2, 30.6 ± 2.7 weeks). The Edinburgh Postnatal Depression Scale (EPDS) was used to assess antenatal depressive symptoms, the EPDS anxiety subscale was utilized to measure anxiety symptoms, and mood instability was measured using a visual analogue scale. These mood states together with stress, social support, as well as healthy and unhealthy behaviours were also examined in relation to neonatal outcomes using chi-square tests and logistic regression models. Results Depression and MI were unrelated to adverse neonatal outcomes and anxiety was related to Apgar score with marginal statistical signicance. Higher stress, lack of partner support, smoking, and primiparous status were associated with some adverse outcomes. Conclusions The current study identied no associations between antenatal mood symptoms and neonatal outcomes. Our ndings further support and extend previous evidence on smoking abstinence or cessation, and the provision of resources for stress management and social support that could help prevent or alleviate adverse neonatal outcomes.

divergent ndings could result from differences in the measuring tools, gestational ages, and sample characteristics. Although signi cant correlations between MI and an array of psychiatric disorders including depression and anxiety have been reported in clinical and general populations (19,20), and a strong link between MI and depression in perinatal women has been documented (21), the relation of antenatal MI to neonatal outcomes has been less studied, which can partly be explained by the transdiagnostic nature of MI or because MI is seen to be a normal part of women's pregnancy that resolves itself (22).
Maternal mental health and their association with infant outcomes may be related to psychosocial factors and lifestyle in pregnancy. For example, Nylen and colleagues found that women with unsupportive partners had babies with lower Apgar scores compared to those with supportive partners (23). The perception of partner support, they found, partly offsets the adverse effect of maternal depression. Other studies have shown that stress in pregnancy is associated with lower birth weight and pre-term birth (17,24,25). These stressors tended to be major life events, disasters, or chronic conditions such as poverty, but not the usual daily hassles (25). Behaviors in pregnancy such as smoking and alcohol use are associated with childhood cognitive and emotional regulation de cits (26), but relatively few studies have reported neonatal outcomes. Alcohol use in pregnancy is associated with lower birth weight (LBW), pre-term birth (PBW) (27,28), and small for gestational age (SGA) (28). Cotinine levels collected in pregnancy showed an inverse associated with birth weight (29,30). Generally, no relation between exercise and infant outcomes has been found (31) but there is evidence for positive maternal outcomes, such as cardiovascular health and prevention of gestational diabetes (32,33).
In this study, we examined the association of antenatal mood symptoms and other maternal factors with ve neonate outcomes measured shortly after birth.

Methods
Participants and procedure The current study was a secondary data analysis of the Feelings in Pregnancy and Motherhood Study (FIP). The FIP is a longitudinal cohort study of maternal mental health and the associated factors from 2006 to 2014. Women were recruited in the early pregnancy from a variety of community settings including doctors' o ces, prenatal classes, maternity stores, and responders to radio and newspaper advertisements. The inclusion criteria were English speaking women in early pregnancy (gestation ≤ 20 weeks), and having a residence in one of two health regions in Saskatchewan. Data were collected by trained research assistants in a face-to-face interview at two-time points during pregnancy: T1 (early pregnancy: 17.4 ± 4.9 weeks), and T2 (late pregnancy: 30.6 ± 2.7 weeks). Information regarding children's neonatal outcomes was obtained from the mothers and linked with hospital discharge records, with permission. If a woman screened positive for depression, she was referred with her permission to her family doctor and given information about local mental health services. If she was deemed at risk of self-harm or harming others, immediate help was provided. Our sample size for this analysis was 555 mothers and the same number of infants.
Ethics approval for the research protocol was obtained from the Behavioural Research Ethics Board at the University of Saskatchewan. All participants gave written informed consent.

Measures
We assessed the symptoms of three constructs known in the literature to be closely related: depression, anxiety, and mood instability (34,35), making use of thresholds for clinical relevance.
Depression. Depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS) at T1 and T2 (36). The EPDS is the most widely used self-report measure for screening postnatal depression (37). Respondents select one of four possible responses (0-3) to each of ten questions to indicate how they felt in the previous week. Ratings for each item are summed for a possible maximum score of 30 (range 0-30; 0 = not depressed, 30 = highest score for depressive mood). Validation studies of the EPDS have been conducted in different cultures, languages, and settings, including in Saskatchewan (38, 39). The EPDS has been found to have a sensitivity of 80% and speci city of 87% (40). In this study, attaining a score ≥ 12 at either T1 or T2 was indicative of clinically signi cant depression (41)(42)(43). In our sample, EPDS had a Cronbach alpha of .83 Anxiety. Anxiety symptoms were measured at T1, and T2 using the EPDS anxiety subscale (items 3, 4, and 5) (44-47) with a range of 0 to 9. Jomeen and Martin (48) found that the anxiety subscale has an acceptable internal consistency (Cronbach α = .77) (49). In our sample, the anxiety subscale had Cronbach alpha of .72. We followed the recommended cut-off score of ≥ 6 for community samples (50). As with the total EPDS score, women were categorized in the high anxiety group if they met the cut-off at either T1 or T2.
Mood instability. Mood instability was measured using ve questions that were answered on a Visual Analogue Scale (VAS): 1 "mood frequent ups and downs", 2 "mood swings occur for no reason", 3 "other people complain about your mood swings", 4 "having trouble following through with plans because of mood swings", and 5 "not making commitments because moods might change". Women were asked to mark an "X" on a 10 cm line to indicate their level of MI. The length of the segment from the origin to the X mark was measured by a trained research assistant, randomly audited by another. This length of the segment was then translated into a score that ranged from 0 to 50. We dichotomized MI scores into above and below the mean. This was done by calculating the average of T1 and T2 scores separately. If a woman scored above the mean in either period, her MI symptom was coded 1 "High MI" and 0 "Low MI" otherwise.
Other maternal variables. Demographic, psychosocial, and pregnancy-related variables were also assessed. These included age (< 25 vs ≥ 25 yrs), education attainment (< Grade 12 vs ≥ Grade 12), marital status (with or without a partner), ethnicity (aboriginal or not aboriginal), and annual family income (≤ 40K vs >40K). The psychosocial variables were sources of social support (1 or less vs 2 or more), the number of stressors (0-2 vs >2), partner support (yes or no), maternal smoking (yes or no), alcohol consumption (yes or no), and physical activity status (yes or no) during pregnancy were assessed. As we did with the mood variables, we classi ed a woman as having a risk factor if these were reported at either T1 or T2. We also used parity (primiparous vs multigravida) as a maternal variable.
Neonatal outcome variables. Neonatal outcome variables included one-and ve-minute Apgar scores, LBW, SGA, and PTB. We dichotomized the Apgar scores based on previous studies [41][42][43][44]. Apgar scores re ect a baby's wellbeing at birth by assessing ve areas: activity, pulse, grimace, appearance, and respiration (51). Each area is rated from 0 to 2 with a possible score of 10 (scores 7 or above indicate that the baby is doing well). Apgar scores were dichotomized into below normal < 7 or normal ≥ 7 (51). Birth weight was measured in grams (g) and dichotomized into two levels: low < 2500 g or normal ≥ 2500 g (52). SGA was de ned as being in the 10 th percentile for gestational age (53). Preterm birth is based on the duration of pregnancy in completed weeks from the rst day of the last normal menstrual period to birth. The variable was dichotomized into two levels: preterm birth (PTB) (< 37 weeks) and normal term birth (≥ 37 weeks) (54).

Data Analysis
We cross-tabulated nine maternal variables in pregnancy with the ve neonatal outcomes. Chi-square or Fisher's exact test was used to examine the association of each maternal variable and each baby outcome (45 tests in all).
For each result that was signi cant at an α level of 5%, we created a logistic regression model that adjusted for maternal age category and marital status. Each logistic regression model was performed rst, with complete cases and then with multiple imputations. Coe cients in logistic regression models were exponentiated to yield odds ratios (OR), and their 95% con dence intervals (CI) were calculated accordingly. Multiple imputation was necessary because ve variables (SGA, Apgar 1 minute, Apgar 5 minute, LBW, pregnancy stress, and maternal age category) had missing values that ranged from less than 1 to 17 percent. Multiple imputation is a principled way of avoiding biased estimates that can result from non-random missingness and overly narrow con dence intervals (55).
Statistical analyses were performed using Stata and imputation was carried out using multiple imputation with chained equations (MICE) (56). We created 20 imputed datasets following the recommendation of White and colleagues (57).

Characteristics of the mothers and babies
Mothers had a mean age of 29.0 years (SD =4.85), and 38% (n = 212) were rst-time mothers. Most of the women lived with a partner, had a Grade 12 or higher education, and had a family income of at least $40,000. Sixty-eight babies (12%) had a 1-minute Apgar score < 7, while 15 (3%) babies had a 5-minute Apgar of <7. Only 20 (4%) of the baby's birth weight was <2500g, while 39 babies (7%) were SGA. Thirtytwo babies were born preterm (6%). The complete demographic, psychosocial, and neonatal outcomes are presented in Table 1. Higher anxiety in pregnancy was associated with a higher proportion of Apgar (5-minute) scores below 7 (X 2 =3.78, p = .05) while a higher level of stress was associated with low Apgar (1-minute) scores (X 2 =5.09, p = .02). Smoking, lack of partner support, and primiparous status were each associated with SGA (X 2 =10.05, p = .002; X 2 = 7.63, p = .006; X 2 = 13.25, p < .001 respectively). In addition, primiparous status was associated with LBW (X 2 = 4.50, p = .03). Depression, mood instability, alcohol use, and exercise during pregnancy were not associated with any of the neonatal outcomes. PTB was not associated with any maternal mood symptoms and other maternal factors in pregnancy. The complete crosstabulation of maternal variables and neonate outcomes is presented in Table 2. When we adjusted these associations for maternal age category and marital status, ve maternalneonate outcomes remained signi cant. Smoking, lack of partner support, and primiparous status were associated with SGA. Higher stress was associated with a low Apgar score (1-minute) while being primiparous was linked to LBW. When using complete cases, data analyses results agreed with those using imputed data except for primiparous status and LBW. The results are presented in Table 3.

Discussion
In this study, we examined maternal mood symptoms, and psychosocial and behavioral factors in pregnancy with ve neonate outcomes. The rst main nding is that mood symptoms are not signi cantly related to neonatal outcomes, or marginally related as in the case of anxiety and low Apgar score at 5 minutes. The second nding is that psychosocial and behaviors factors as well as primiparous status are strongly associated with neonatal outcomes, especially SGA.
We found that antenatal depression is not related to SGA/PTB/LBW/low Apgar score that is in agreement with prior studies (16, 18, 58, 59), but in contrast to others (12,60,61). The major reasons for the divergent ndings may be related to differences in the measurement of depression, gestational age, settings, and the samples. For example, a study with 791 women in the US assessed depression using the Center for Epidemiological Studies Depression Scale (CESD) in their early pregnancy (around 10 weeks gestation) (61). Studies found that CESD tends to produce higher scores and more false-positive results in symptomatic pregnant and postpartum women (62-64). In this diverse sample of 38.1% Caucasian, 28.6% Asian or Paci c Island, 21.0% Hispanic, and 6.8% African American women, a positive association between depression and PTB was found. Similar ndings were reported in a study including 959 Chinese women in late pregnancy using the Beck Depression Inventory to assess women's depressive status (65). Holland, and found a positive relationship between perinatal depression and neonatal outcomes. Furthermore, in a study by Nasreen et al. (11), 720 women from two rural subdistricts of the developing country of Bangladesh were assessed in their third trimester using the EPDS to determine depressive status, and a signi cant relationship between antenatal depression and LBW was found while controlling for poverty and maternal nutritional status. The mechanism of impact of antenatal depression on neonatal outcomes is not well understood, and more research is required.
Among the mood symptoms, elevated anxiety was associated with low Apgar score at 5-minutes although this did not survive sign cance when adjusting for maternal age and marital status. Anxiety is closely related to stress, and a higher level of stress was associated with low Apgar score (1-minute) in our study. Potential causal pathways through which prenatal anxiety and stress may lead to adverse neonatal outcomes have been proposed. One potential mechanism was identi ed as changes in maternal hypothalamic-pituitary-adrenal (HPA) axis activity. Increased maternal HPA axis activity has been observed during the perinatal period (69). However, experiencing elevated levels of anxiety and stress during pregnancy may contribute to an increase in stress hormones, such as cortisol and catecholamines (70). The release of stress hormones has also been found to cause changes in immunologic functioning and uterine blood ow during human pregnancy, thus increasing vulnerability to preterm birth, SGA, and low BW (71-76). However, not all studies found such an association (16, 58), which might be related to the timing of when antenatal anxiety and stress were measured in pregnancy, and what instruments were utilized (77,78) while others suggest that the mechanisms of the association between stress and neonatal outcomes need to be further investigated (79,80).
To the best of our knowledge, this is the rst study to report the relationship between antenatal MI and neonatal outcomes, and we did not nd a signi cant relationship. It may be that MI affects neonatal outcomes through depression, anxiety, or stress since MI is related to depression, anxiety, and stress as reported in clinical samples (19,81) and perinatal women (21,82). To date, the possible role of antenatal MI in fetal intrauterine development remains unexplored. More studies are required in order to understand the relationship between antenatal MI and neonatal outcomes.
The association between lack of social support during pregnancy and poor neonatal outcomes has been documented according to a systematic review (83). Our ndings further support and extend previous evidence on the effect of low social support on the occurrence of adverse neonatal outcomes. During early pregnancy, women experience tremendous changes physically and psychologically which require major adjustments, and social support plays a crucial role to help women cope with the transition to motherhood (84, 85). Lack of social support from partner, family and/or friends can be re ected on lack of social stability and social participation, which has a very negative impact on the psychological wellbeing of pregnant women (86, 87). While the mechanism of the association between antenatal social support and neonatal outcomes is not fully understood, some proposed that effects of social support on neonatal outcomes maybe by increasing maternal stress, probably via the pathway of biological stress systems including HPA axis activity (88, 89).
Smoking was a risk factor for SGA in the current study, which replicated previous studies (90)(91)(92).
Antenatal cigarette smoking leads to fetal exposure to nicotine, which crosses the placenta and leads to a 15% higher concentration than in maternal blood (93,94). Nicotine interferes with normal placental function, and reduces uterine blood ow by an average of 30 to 49%, which causes a deprivation of nutrients and oxygen, resulting in fetal hypoxia and malnutrition, and may lead to intrauterine growth restriction (93,95).
Our study found that being primiparous was associated with LBW and SGA, which is consistent with some studies (96). A meta-analysis of 41 studies found that being primiparous increased a woman's risk of having a baby with LBW and SGA (96). Parity in uences the growth of the placenta and its e ciency, which is related to uterine blood ow, oxygen availability, nutrient exchange, and endocrine regulation of the fetus (97, 98).
There were several limitations to the current study. First, although this is a relatively large sample, the participants were predominantly Caucasian, married, with post-secondary education, and higher family income, which limits the generalization of the ndings. According to the 2016 Census of Canada (99)

Conclusion
The current study identi ed no associations between antenatal mood symptoms and neonatal outcomes. However, our ndings further support and extend previous evidence on smoking abstinence or cessation, and the provision of resources for stress management and social support that could help prevent or alleviate adverse neonatal outcomes. Ethics approval for the research protocol was obtained from the Behavioural Research Ethics Board at the University of Saskatchewan (Beh # 16-267). Written informed consent was obtained from women before they participated in the study.

Consent for publication
Not applicable Availability of data and materials The datasets used and analyzed in this study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
This work was supported by the Canadian Institutes of Health Research (Grant # 145179). The funding agency had no role in the design, data collection, analysis, interpretation, and writing of the study.