Our results show that children born to women with perinatal depression had a 40% increased rate of GI infections and a 27% increased rate of LRTIs compared with children born to women without perinatal depression. For more severe, antibiotic-treated infections, the observed effects increased slightly for GI infections to 47% but decreased slightly for LRTIs to 19%. Our observed absolute differences in rates suggest that over a one year period there were about 97 more GI infections and 19 more LRTIs among every 1000 children born to women with perinatal depression than among 1000 children born to women without perinatal depression. Moreover, the near identical timing of the first polio vaccination among both groups provides no evidence to support the possibility that higher rates of GI infections and LRTIs in children of mothers with perinatal depression may be explained by differential levels of diagnosis due to increased healthcare-seeking behavior among this group.
Strengths and limitations
We have conducted a large population-based cohort study of the association between maternal perinatal depression and childhood infections using primary care data in the UK. Our considerable sample size means that our findings are unlikely to be due to chance. The data we used were obtained from a national database and prospectively recorded by GPs, thus excluding the possibility of recording or recall bias in both our exposure and outcome.
Full 4-year follow-up data were not available for 19.5% of children. Such drop-outs occur due to death or patients deregistering from GP practices. There was no evidence of an increased risk of death in either cohort. In the UK registration with a general practitioner is continuous unless a patient actively requests removal from the practice list, or makes an application to join another practice (typically due to a change of address, or the opening of a new practice). Drop-out rates were similar in both cohorts and we feel they are unlikely to have had a substantial impact on our results.
Although the inclusion of postpartum depression in the exposure definition meant that there could be potential for reverse causation due to some overlap between postpartum depression and childhood infections in the first six months of a child's life, such overlap could not affect the observations at age 1, 2, and 3 years. As we found that the increased risk of childhood infections in mothers with perinatal depression was consistent throughout the first four years of the child's life, we believe it is unlikely that our results were due to reverse causality.
There was a legitimate weakness in our exposure measurement as a certain proportion of mothers with perinatal depression are neither diagnosed nor treated in primary care. The prevalence of diagnosed maternal perinatal depression found in our study (about 9.1%) was in general 4-6% lower than some previous studies conducted in high-income countries [2–4, 23]. However, these studies were based in research settings where selected populations were screened for depression mostly using self-administered questionnaires and their samples were much smaller than ours. On restricting to diagnosed depression using a standardized interviewing schedule, two previous studies (including a meta-analysis) [4, 22] found fairly similar prevalence figures to ours. Although we acknowledge that existing depression does remain undiagnosed in the population, during pregnancy and in the first few months after delivery, women typically have more frequent contact with health professionals than they would usually do because of antenatal/postnatal check-ups. This would tend to reduce under-diagnosis of depression this period. Nevertheless, the presence of under-diagnosis in this population would only result in an underestimation of the risk of childhood GI infections and LRTIs in children associated with perinatal depression, since such misclassification would produce a bias towards the null-hypothesis (of no association between perinatal depression in mothers and childhood infections in offspring).
We defined childhood infections as children having been diagnosed with GI infections or LRTIs in primary care, which primarily relied on mothers bringing their children to see their GPs, so they most likely represented the more severe end of the spectrum of these infections. We supposed that, if women with perinatal depression felt more anxious or less capable to take care of their children, they may take children to see their GPs more often than women without perinatal depression and the increased risk of childhood infections in mothers with perinatal depression therefore could be an overestimate due to biased ascertainment. The first childhood polio vaccination is a routine appointment common to both cohorts of children and mothers and one might expect the timing to be earliest and uptake the greatest amongst children of mothers with high levels of healthcare-seeking behaviour. Although timing and uptake of polio vaccination were all but identical in both cohorts we accept that this is only an indirect, measure of mothers' health seeking behaviour and we cannot conclusively exclude the possibility of biased ascertainment.
Although we considered other factors related to maternal perinatal depression in our analysis, the records of a substantial number of individuals did not provide information about factors such as household socioeconomic status (44% missing), maternal smoking (26.4%) and maternal BMI (40% missing). We were also unable to adjust for some other factors, such as the period of breastfeeding and the child's birth weight which have previously been linked to childhood infections [13, 24, 25] in low-income countries, because birth weight and breastfeeding status are seldom recorded in THIN. It could be argued, however, that these factors may form part of a causal pathway linking maternal perinatal depression to childhood infections. After adjusting for these factors, one previous study  (carried out in Pakistan) still found a statistically significant association between maternal postpartum depression and childhood GI infections, suggesting that incomplete adjustment for confounding is unlikely to completely explain the observations of our study.
Interpretation in context of previous studies
Although to our knowledge there are only three previous studies [9–11] examining the potential association between maternal perinatal depression and childhood infections, all have found an increased risk of childhood infections in children born to women with perinatal depression. For example, in a recent American cross-sectional study of 194 mothers and their children at 4-6 weeks postpartum, Groer and Morgan found that children of mothers with postpartum depression experienced more physical illness (including diarrhoeal illness) since birth compared with children of mothers without postpartum depression (p = 0.03) . This study, however, did not provide any measure of effect and did not adjust for potential confounding factors.
In our study, we combined the period of antenatal and postnatal depression together and therefore we did not examine whether the increased risk of childhood infections was independently associated with antenatal depression or early postnatal depression. Rahman et al carried out a similar cohort study  of 265 mothers (130 mothers with perinatal depression) in Pakistan and found an increased risk of diarrhoea and a slightly increased, but not statistically significant, risk of ARIs in children of mothers with antenatal or postnatal depression compared with children of mothers without depression (OR = 2.4; 95% CI 1.7-3.3 and OR = 1.1; 95% CI 0.9-1.4, respectively), although they did not adjust for any confounding factors. A subsequent study by the same authors  which focused only on the relationship between postnatal depression and childhood diarrhoeal illness showed a similar result to the first, although the risk of diarrhoea in children of mothers with postnatal depression compared with children of mothers without postnatal depression was much stronger once adjusted for important maternal and child factors (unadjusted OR = 2.3; 95% CI 1.6-3.1 and adjusted OR = 3.1; 95% CI 1.8-5.6). The latter study used data from the same cohort of women and only about 5% of women with antenatal depression did not also have postnatal depression .
Compared with our study, Rahman et al found a larger effect on GI infections but a slightly smaller one on respiratory infections. Their study population was from a rural area of Pakistan where childhood infections were much more common than in our study population. Furthermore, they used only binary outcomes of more or fewer than five childhood diarrhoeal episodes and more or fewer than six ARI episodes per year, while our outcomes were incidence rates of individual episodes of GI infections and LRTIs. Consequently, our results are not directly comparable. In spite of different study populations and different measures of outcome, we both found an increased risk of GI infections (and also a similar magnitude of respiratory infection risk) in children born to women with perinatal depression compared with those born to women without perinatal depression.
There could be several potential explanations for the association between perinatal depression in mothers and childhood infections in offspring. First of all, previous research [6, 9] has found that mothers with depression during the perinatal period have a dysregulated hypothalamic pituitary adrenocotical axis resulting in decreased levels of salivary cortisol and potentially depressed cellular immunity. This may have a direct impact on the child's immune and neuroendocrine development. Secondly, perinatal depression can have a considerable impact on mothers' childcare abilities. Previous studies [9, 26] reported that mothers with postpartum depression were less likely to breastfeed their children and more likely to give up exclusive breastfeeding than mothers without depression. Breastfeeding can strengthen the immune system of the child and it has been shown that children who are not breastfed have more acute respiratory infections than those who are not . Likewise, children of mothers with perinatal depression have been found to be less well nourished than those of mothers without depression [27, 28], which will increase susceptibility to infection.
In addition, postpartum depression in mothers can lead to child neglect and poorer childcare practices, especially in high-income countries [5, 29, 30]. Children may thus be more exposed to unsanitary and dangerous environments, increasing the potential for exposure to sources of infection.