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\begin{document}

\title{Longitudinal assessment of maternal depression and later life childhood
asthma and wheeze: effect modification by child sex}



\author[1]{Cecilia Sara Alcala}%
\author[2]{Paloma Orozco Scott}%
\author[3]{Marcela Tamayo-Ortiz}%
\author[4]{Carmen Hernández}%
\author[5]{Lourdes Schnaas}%
\author[1]{Kecia N. Carroll}%
\author[1]{Megan Niedzwiecki}%
\author[1]{Robert O. Wright}%
\author[6]{Martha Maria Téllez-Rojo}%
\author[1]{Rosalind J Wright}%
\author[1]{Hsiao-Hsien Leon Hsu}%
\author[1]{Maria Jose Rosa}%
\affil[1]{Icahn School of Medicine at Mount Sinai Department of Environmental Medicine and Public Health}%
\affil[2]{Icahn School of Medicine at Mount Sinai Department of Medicine}%
\affil[3]{Occupational Health Research Unit Mexican Social Security Institute Mexico City Mexico}%
\affil[4]{National Institute of Perinatology Mexico City Mexico}%
\affil[5]{Department of Developmental Neurobiology National Institute of Perinatology Mexico City Mexico}%
\affil[6]{Center for Nutrition and Health Research National Institute of Public Health Cuernavaca Morelos Mexico}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Studies report associations between maternal mental
health and adverse respiratory outcomes in children; however, the impact
of timing and duration of maternal distress remains understudied. We
sought to longitudinally examine associations between maternal
depression and childhood asthma and wheeze, and explore sex differences.
\textbf{Methods:} Maternal depression (n=605) were assessed using the
Edinburgh Depression Scale questionnaire, dichotomized at a clinically
relevant cutoff (\textgreater{}12) a) during pregnancy, b) postpartum,
and c) postpartum and subsequent time points postnatally (recurrent
depression). Report of wheeze in the past 12 months (current wheeze) and
asthma were obtained using a validated survey at 48 and 72 months.
Associations were analyzed using a modified Poisson regression adjusted
for covariates, and in interaction models. \textbf{Results:} Both
postpartum and recurrent depression were associated with higher risk of
current wheeze (RR: 1.88, 95\% CI: 1.21, 2.92; RR: 2.39, 95\% CI: 1.52,
3.78) and asthma at 48 months (RR: 2.79, 95\% CI: 1.13, 6.87; RR: 3.14,
95\% CI: 1.26, 7.84). In interaction analyses, associations were
stronger in females. Postpartum and recurrent depression were associated
with higher risk of current wheeze at 48 months in females (RR: 3.06,
95\% CI: 1.48, 6.32; RR: 4.02, 95\% CI: 1.91, 8.46) when compared to
males RR: 1.47, 95\% CI: 0.84, 2.56; RR: 1.86, 95\% CI: 1.04, 3.34).
\textbf{Conclusions:} Postpartum and recurrent depression were
associated with higher risk of wheeze and asthma in children, and
associations were stronger in females than males. Understanding the
temporal- and sex-specific effects of maternal depression may better
inform prevention strategies.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Accumulating evidence has shown that prenatal and early life
psychological stress and stress correlates, like maternal depression and
anxiety, are linked to an increased risk of respiratory disorders
including wheeze and asthma\textsuperscript{1} in the offspring.
Psychological stress can affect the individual biology, progression, and
management of respiratory disease throughout the
lifespan\textsuperscript{2, 3}. Maternal psychological functioning has
been linked to the alteration of the immune system and lung
development\textsuperscript{4} prenatally and in early childhood. Both
prenatal and postnatal maternal psychological functioning is associated
with higher risk of allergy, asthma, and wheezing development in
infants\textsuperscript{5}. The effects of prenatal and postnatal
maternal stress have been examined independently from one another but
the influence of the timing of exposure during critical periods of
development has not been completely elucidated\textsuperscript{6-8}.

A few recent studies have examined the impact of prenatal and postnatal
maternal distress on childhood risk of atopic and respiratory
disease\textsuperscript{9-11}. Van der Leek et
al\textsuperscript{11}reported significant associations between maternal
prenatal, recurrent postpartum, and late onset postpartum distress and
higher risk of atopic dermatitis at age 5 years\textsuperscript{11}.
Prenatal maternal distress and late onset postnatal distress were also
associated with asthma at 7 years of age\textsuperscript{11}. Brew et
al\textsuperscript{9} examined the association between maternal
depression or anxiety during different exposure periods (pre-conception,
pregnancy, postnatal, or current) and childhood asthma development. They
did not identify a critical exposure period but rather reported that
chronic exposure to maternal depression and anxiety is associated with
offspring asthma. Ramratnam et al\textsuperscript{12} concluded that
maternal stress and depression in the first 3 years were positively
associated with respiratory illnesses and a
moderate-wheeze-low-atopy-phenotype\textsuperscript{12}.

Growing evidence has also demonstrated that critical windows of
vulnerability may differ by sex of the offspring\textsuperscript{10}.
Our group reported stronger associations between higher prenatal
maternal stress and childhood wheeze in males while the association
between postnatal maternal stress and wheeze was stronger among
females\textsuperscript{13}. Similarly, Lee and colleagues reported that
males were more vulnerable to stress during the prenatal period and
females were more impacted by postnatal and cumulative maternal stress
when examining asthma risk\textsuperscript{10}.

While the majority of these studies have been conducted in high-income
countries, maternal stress and depression is of particular concern in
low- and middle-income countries given its high prevalence and the
limited resources for its diagnosis and
management\textsuperscript{14-16}. Furthermore, studies have shown the
prevalence of asthma has increased worldwide, especially in
non-industrialized countries\textsuperscript{17, 18}. Understanding the
impact of timing and duration of symptoms of maternal psychosocial
distress during and post pregnancy and the development of childhood
respiratory disease would fulfill a research gap. We leveraged existing
data from an established population-based prenatally enrolled
longitudinal cohort in Mexico City. We examined the association between
maternal depression, assessed during pregnancy and postnatally, and the
risk of respiratory disease in early childhood. We also examined whether
these effects differed by child sex.

\textbf{Methods}

\emph{Study Population}

Between July 2007 and February 2011, pregnant women receiving health
service and prenatal care through the Mexican Social Security System
(Instituto Mexicano del Seguro Social --IMSS) were recruited into the
Programming Research in Obesity, Growth, Environment and Social
Stressors (PROGRESS) study. The inclusion criteria were: \textless{}20
weeks gestation, at least 18 years old, planned to stay in Mexico City
for the next 3 years, had telephone access, reported no medical history
of heart or kidney disease, no daily alcohol consumption, and no use of
any steroid or anti-epilepsy medications. Following birth, 681
mother-child dyads are actively followed, 605 completed the 48 month
visit and 569 completed the 72 month visits and has the necessary
covariates for analyses. The institutional review boards at the Harvard
School of Public Health, Icahn School of Medicine at Mount Sinai, and
the Mexican National Institute of Public Health approved the procedures
of the study. Women provided written informed consent.

\emph{Maternal Depression}

A trained psychologist administered the validated Spanish
version\textsuperscript{19, 20} of the Edinburgh Depression Scale
questionnaire (EDS) during the second or third trimester of pregnancy
(prenatal period), and the 1, 6, 12, 18, 24, and 48 month postnatal
study visits. The 10-item EDS asks about depression symptoms in the past
7 days, including: ``1: I have laughed and been able to see the funny
side of things,'' ``2: I have looked forward with enjoyment to things,''
``3: I have blamed myself unnecessarily when things went wrong,'' ``4: I
have been anxious or worried for no good reason,'' ``5: I have felt
scared or panicky for no very good reason,'' ``6: Things have been
getting on top of me,'' ``7: I have been so unhappy that I have had
difficulty sleeping,'' ``8: I have felt sad or miserable,'' ``9: I have
been so unhappy that I have been crying,'' and ``10: The thought of
harming myself has occurred to me.'' Participants rated the severity or
frequency of each item based on 4 levels scored from 0 (indicating the
most favorable condition) to 4 (indicating the least favorable
condition) for each item. Total scores can range from 0 to 30.

Maternal depression were examined as a dichotomous outcome using EDS
scores at a clinically-relevant cutoff (EDS score \textgreater{}
12)\textsuperscript{21}. Maternal depression was examined at three time
specific categories: a) depression only during pregnancy, b) postpartum
depression, and c) recurrent depression. Depression during pregnancy was
defined as depression during the second or third trimester of pregnancy
and at no other subsequent time point. Postpartum depression was defined
as depression during the first or sixth month postpartum. Lastly,
recurrent depression was defined as postpartum depression and depression
at any subsequent time point postnatally.

\emph{Respiratory outcomes}

The validated Spanish version of the International Study of Asthma and
Allergies in Childhood (ISAAC) questionnaire was administered at the 48
month and 72 month visit. The following outcomes were assessed during
both visits, ever wheeze, current wheeze, and asthma. Ever wheeze was
defined as caregiver report of ``Has your child ever had wheezing or
whistling in the chest at any time in the past?'' and current wheeze was
defined based on response to ``In the past 12 months, did your child
have wheezing or whistling in the chest?'' To measure asthma, caregivers
responded to the following question, ``Has your child ever had asthma in
their life?'' Repeated wheeze was defined as caregivers reporting wheeze
during both 48 month and 72 month visits. Any ever wheeze was defined as
caregiver reporting ever wheeze at 48 or 72 months and any current
wheeze was identified as wheeze in the past 12 months at 48 or 72
months. Lastly, ever asthma was defined as asthma at either 48 or 72
months.

\emph{Covariates}

Child's sex was obtained from delivery records. Mother's age at delivery
was calculated by subtracting child's birthdate from mother's birthdate
collected at enrollment. Caregiver's report of ever having asthma was
collected through questionnaires at enrollment (second or third
trimester). Maternal education was categorized into three levels: less
than high school, high school, or greater than high school.
Breastfeeding was assessed at 1 month postpartum and categorizes as,
never/ no attempt to breastfeed and attempted to breastfeed up to 1
month. Socioeconomic status (SES) was assessed utilizing 13 variables
derived from prenatal questionnaire results which were used to classify
study participant families into six levels based on the SES index
created by the Asociaci\selectlanguage{ngerman}ón Mexicana de Agencias de Investigación de
Mercados y Opinión Pública (AMAI)\textsuperscript{22}. These levels were
then collapsed into lower, medium, and higher socioeconomic status.
Exposure to particulate matter \textless{}2.5 microns in diameter
(PM\textsubscript{2.5}) was estimated at each participant's
residenceduring pregnancy and over the first two postnatal years using a
novel spatio- temporal model incorporating Moderate Resolution Imaging
Spectroradiometer (MODIS) satellite- derived Aerosol Optical Depth (AOD)
measurements at a 1x1km spatial resolution\textsuperscript{23}. These
remote sensing data are calibrated with municipal ground level monitors
of PM\textsubscript{2.5}, land use and meteorological data to yield
estimates of daily residential PM\textsubscript{2.5} levels for each
study participant\textsuperscript{23}. Daily particulate matter during
the first year of life was averaged for the entire gestational period
and over the first and second year postpartum\textsuperscript{13}.

\emph{Statistical Analyses}

Data were analyzed using a modified Poisson regression approach that
allowed for estimation of risk ratios instead of odds
ratios\textsuperscript{24}. Models were adjusted for child's sex,
maternal education level (\textless{}high school, high school,
\textgreater{}high school), mother's age, average PM\textsubscript{2.5}
during pregnancy, and average PM\textsubscript{2.5} during the first
year postpartum. We then examined effect modification by child sex
(male/female) for respiratory outcomes by including the relevant
interaction terms. Models with p-values \textless{}0.1 for interaction
terms were then stratified by child sex. In sensitivity analysis, we
also adjusted for average PM\textsubscript{2.5} during the first two
years postpartum, breastfeeding, and for SES instead of maternal
education. Analyses were performed in R Version 3.5.1 (R Development
Core Team) and SPSS version 24 (Chicago, IL).

\textbf{Results}

A total of 605 mother- child dyads from the PROGRESS cohort were
included in this study. Table 1 shows the distribution of exposure,
outcomes, and covariates of the study population as a whole and then
stratified by child sex. Child sex was evenly distributed within this
population. The average maternal age was 27 years of age. The majority
of participants had a lower SES (52\%), and no more than a high school
education (40\%). Only 8 women reported ever having asthma at
enrollment. Prenatal depression were observed in 16\% of mothers,
postpartum depression in 25\% of mothers, and recurrent depression in
17\% of mothers. Overall, at the 48 month assessment 26\%, 13\%, and 3\%
of the children had a caregiver report ever wheeze, current wheeze, and
asthma, respectively. The distribution of respiratory outcomes in
children at 72 months were as follows: a) ever wheeze in 16\%, b)
current wheeze in 6\%, and c) asthma in 4\%. Additionally, overall 29\%
of the study participant's caregivers reported any ever wheeze, 14\% any
current wheeze, and 5\% ever asthma.

\textbf{Table 1: Characteristics of mother--child dyads in the PROGRESS
cohort, n=605}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Characteristics}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Total Sample}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Male Children 304 (50\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Female Children} \textbf{301 (50\%)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Maternal age at enrollment (years), median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
27.00 (23.00, 31.00)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
27.00 (24.00, 31.00)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
27.00 (23.00, 31.00)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal breastfeeding, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal breastfeeding, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal breastfeeding, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal breastfeeding, n (\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Never/ no attempt to breastfed\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
33 (6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
8 (4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
14 (7\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Attempted to exclusively breastfed\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
542 (94\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
209 (96\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
200 (93\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal education at enrollment, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal education at enrollment, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal education at enrollment, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal education at enrollment, n (\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textless{} High school\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
242 (40\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
130 (43\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
112 (37\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
High school\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
221 (37\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
103 (34\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
118 (39\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textgreater{} High school\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
142 (23\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
71 (23\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
71 (24\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal ever asthma at enrollment, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal ever asthma at enrollment, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal ever asthma at enrollment, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal ever asthma at enrollment, n (\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Ever had asthma, yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
8 (4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7 (7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (1\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Socioeconomic status, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Socioeconomic status, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Socioeconomic status, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Socioeconomic status, n (\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Lower\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
314 (52\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
156 (51\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
158 (52\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Medium\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
230 (38\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
117 (38\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
113 (38\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Higher\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
61 (10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
31 (10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
30 (10\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Average PM\textsubscript{2.5} during pregnancy, median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
22.78 (20.58, 24.19)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
22.76 (20.65, 24.36)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
22.78 (20.38, 24.12)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Average PM\textsubscript{2.5} during the first year of life, median
(IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
22.73 (20.54, 23.88)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
22.73 (20.65, 23.95)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
22.76 (20.36, 23.83)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal Depression, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal Depression, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal Depression, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal Depression, n (\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Prenatal depression, yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
104 (17\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
57 (19\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
47 (16\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Postpartum depression, yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
145 (25\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
76 (26\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
69 (24\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Recurrent depression, yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
92 (16\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
49 (17\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
43 (15\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Respiratory Outcomes (48M), n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Respiratory Outcomes (48M), n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Respiratory Outcomes (48M), n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Respiratory Outcomes (48M), n (\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Ever wheeze, yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
150 (25\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
86 (28\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
64 (21\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Current wheeze, yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
72 (12\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
44 (14\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
28 (9\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Asthma, yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
20 (3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
11 (4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
9 (3\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Respiratory Outcomes (72M), n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Respiratory Outcomes (72M), n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Respiratory Outcomes (72M), n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Respiratory Outcomes (72M), n (\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Ever wheeze, yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
85 (15\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
47 (16\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
38 (13\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Current wheeze, yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
31 (5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
20 (7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
11 (4\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Asthma, yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
23 (4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
17 (6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6 (2\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Any ever wheeze\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
176 (29\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
96 (32\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
80 (27\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Any current wheeze\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
79 (14\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
47 (16\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
32 (11\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Any ever asthma\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
30 (5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
19 (6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11 (4\%)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2: Association of maternal depression and adverse
respiratory outcomes in children, n=605}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Outcome measures}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Maternal depression measures} \textbf{RR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Maternal depression measures} \textbf{RR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Maternal depression measures} \textbf{RR (95\% CI)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Prenatal depression\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Postpartum depression\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Recurrent depression\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Ever wheeze at 48M\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.00 (0.95, 1.06)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.24 (0.92, 1.67)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.48\emph{\textsuperscript{*}} (1.07, 2.03)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Current wheeze at 48M\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.02 (0.93 1.13)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.88\textsuperscript{+} (1.21, 2.92)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.39\textsuperscript{++} (1.52, 3.78)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Asthma at 48M\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.09 (0.80, 1.48)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.79\emph{\textsuperscript{*}} (1.13, 6.87)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3.14\emph{\textsuperscript{*}} (1.26, 7.84)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Ever wheeze at 72M\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.04 (0.95, 1.14)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.54\emph{\textsuperscript{*}} (1.02, 2.32)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.76\emph{\textsuperscript{*}} (1.12, 2.77)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Current wheeze at 72M\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.99 (0.87, 1.13)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.19 (0.55, 2.59)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.48 (0.63, 3.48)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Asthma at 72M\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.73 (0.81, 3.69)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.86 (0.79, 4.36)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.25 (0.91, 5.59)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Any ever wheeze\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.02 (0.97, 1.08)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.27 (0.97, 1.66)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.53\textsuperscript{+} (1.15, 2.03)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Any current wheeze\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.02 (0.93, 1.12)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.59\emph{\textsuperscript{*}} (1.03, 2.46)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.08\textsuperscript{+} (1.32, 3.28)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Ever asthma\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.12 (0.87, 1.45)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.15\emph{\textsuperscript{*}} (1.06, 4.39)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.46\emph{\textsuperscript{*}} (1.16, 5.21)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Models adjusted for child's sex, mother's age and educational level at
enrollment, average PM\textsubscript{2.5} exposure during pregnancy, and
average PM2.5 at 1st year postpartum. \emph{\textsuperscript{*}p}
\textless{} 0.05 \textsuperscript{+}\emph{p} \textless{} 0.01
\textsuperscript{++}\emph{p} \textless{} 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Models adjusted for child's sex, mother's age and educational level at
enrollment, average PM\textsubscript{2.5} exposure during pregnancy, and
average PM2.5 at 1st year postpartum. \emph{\textsuperscript{*}p}
\textless{} 0.05 \textsuperscript{+}\emph{p} \textless{} 0.01
\textsuperscript{++}\emph{p} \textless{} 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Models adjusted for child's sex, mother's age and educational level at
enrollment, average PM\textsubscript{2.5} exposure during pregnancy, and
average PM2.5 at 1st year postpartum. \emph{\textsuperscript{*}p}
\textless{} 0.05 \textsuperscript{+}\emph{p} \textless{} 0.01
\textsuperscript{++}\emph{p} \textless{} 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Models adjusted for child's sex, mother's age and educational level at
enrollment, average PM\textsubscript{2.5} exposure during pregnancy, and
average PM2.5 at 1st year postpartum. \emph{\textsuperscript{*}p}
\textless{} 0.05 \textsuperscript{+}\emph{p} \textless{} 0.01
\textsuperscript{++}\emph{p} \textless{} 0.001\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Table 2 shows the results of the modified Poisson regression analysis in
the overall population. We did not observe significant associations
between prenatal depression and childhood respiratory outcomes.
Postpartum depression was significantly associated with increased risk
of current wheeze (RR: 1.88, 95\% CI: 1.21, 2.92) and asthma (RR: 2.79,
95\% CI: 1.13, 6.87) at 48 months. We observed an association between
postpartum depression and any current wheeze (RR: 1.59, 95\% CI: 1.03,
2.46) and ever asthma (RR: 2.15, 95\% CI: 1.06, 4.39). Lastly, a
statistically significant association was observed between postpartum
depression and ever wheeze at 72 months (RR: 1.54, 95\% CI: 1.02, 2.32).

Maternal recurrent depression was associated with an increased risk of
ever wheeze at 48 months (RR: 1.48, 95\% CI: 1.07, 2.03) and 72 months
(RR: 1.76, 95\% CI: 1.12, 2.77). It was also associated with increased
risks of current wheeze (RR: 2.39, 95\% CI: 1.52, 3.78) and asthma at 48
months (RR: 3.14, 95\% CI: 1.26, 7.84). Additionally, we found that
recurrent depression was associated with increased risks of any ever
wheeze (RR: 1.53, 95\% CI: 1.15, 2.03), any current wheeze (RR: 2.08,
95\% CI: 1.32, 3.28), and ever asthma (RR: 2.46, 95\% CI: 1.16, 5.21).

In two-way interaction models, we found evidence for effect modification
by sex for postpartum (p\textsubscript{interaction}= 0.06) and recurrent
depression (p\textsubscript{interaction}= 0.06) on current wheeze at 48
months. As shown in figure 1, postpartum depression were associated with
higher risk of current wheeze at 48 months in females (RR: 3.04, 95\%
CI: 1.47, 6.27) when compared to males (RR: 1.53, 95\% CI: 0.87, 2.68).
We observed a similar pattern for recurrent depression, with females
having a higher risk of current wheeze (RR: 3.95, 95\% CI: 1.86, 8.36)
when compared to males (RR: 1.92, 95\% CI: 1.06, 3.46). We also found
interactions between child sex and postpartum depression
(p\textsubscript{interaction}= 0.05) on current wheeze at 72 months
(figure 2). Sensitivity analyses including additional adjustment for
average PM\textsubscript{2.5} in the first 2 postnatal years,
breastfeeding, and SES showed similar results (results not shown).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1:} Sex-stratified associations between postpartum and
recurrent depression and risk of current wheeze at 48 months. Models
adjusted for mother's age and educational level at enrollment, average
PM\textsubscript{2.5} exposure during pregnancy, and average
PM\textsubscript{2.5} at 1st year postpartum.

\par\null

\textbf{Figure 2:} Sex-stratified associations between postpartum
depression and risk of current wheeze at 72 months. Models adjusted for
mother's age and educational level at enrollment, average
PM\textsubscript{2.5} exposure during pregnancy, and average
PM\textsubscript{2.5} at 1st year postpartum.

\textbf{Discussion}

Our analyses leveraged longitudinal data to examine associations between
maternal psychological functioning and respiratory outcomes in
childhood. Our findings suggest that exposure to postpartum and
recurrent maternal depression are associated with higher risk of wheeze
and asthma in childhood. The observed associations remained significant
after adjustment for a number of important potential confounders and
covariates. We also found that child sex modified the association
between maternal depression and respiratory outcomes; the association
between postpartum and recurrent depression and higher risk of current
wheeze was stronger in females when compared to males.

Prospective birth cohorts examining maternal depression at different
time points in relation to wheeze and asthma development in childhood
have produced mixed results\textsuperscript{5, 9, 12}. A Canadian
population based birth cohort study found that continued exposure to
maternal anxiety or depression from birth into early childhood was
associated with a twofold increase in the risk of asthma at age 7
years\textsuperscript{5}. This is fairly consistent with the results our
study although we observed an association earlier at 48 months (4 years
of age)\textsuperscript{5}. Also in line with our results, Ramratnam et
al. assessed the associations between maternal stress and depression
during pregnancy and early life, and recurrent wheezing utilizing the
Urban Environment and Childhood Asthma (URECA) birth
cohort\textsuperscript{12} and found an association between cumulative
maternal depression in the first 3 years of life and recurrent
wheezing\textsuperscript{12}. However, we did not find any associations
between prenatal depression and any of our outcomes like previous
studies have reported\textsuperscript{9, 11}. Differences in our
findings may be attributable to our classification of depression (e.g.,
limited only to the prenatal period), the prevalence of our outcome and
sample size.

The assessment of maternal mental health in the first postnatal year
signifies an important critical window as the biological systems of
children are rapidly maturing within the first two years of life, and
may be compromised by exposure to more severe and enduring maternal
mental health problems beyond the first postnatal
year\textsuperscript{25}. A potential mechanism for the observed
relationships between postpartum and recurrent maternal depression and
respiratory outcomes in our study may be through dysfunction of the
hypothalamic pituitary adrenal (HPA) axis.~McLearn \emph{et al} reported
that depressed women had reduced odds of playing or talking with their
infants \textsuperscript{4, 26} and animal studies have reported that
decreased maternal attention enhanced hypothalamic-pituitary-adrenal
(HPA) axis stress response in their offspring\textsuperscript{4, 27,
28}. These interactions could be associated with symptoms of distress
and raised cortisol levels in infants\textsuperscript{4, 29} and
recurrent infections and asthma in preschool children\textsuperscript{4,
30}. Additionally, previous studies have reported that maternal
postnatal depression and anxiety strongly correlate with infant cortisol
levels\textsuperscript{31, 32}. HPA dysregulation and the production of
proinflammatory cytokines could increase children's susceptibility and
sensitivity to persistent maternal distress and other co-occurring
sources of chronic stress throughout the early childhood
period\textsuperscript{32, 33}. As a result, this could manifest as high
allostatic load or a blunted cortisol response, increasing children's
vulnerability for the development of asthma\textsuperscript{5, 34, 35}.

There is also growing evidence that the effects of maternal mental
health on children's health outcomes may differ by sex. Previous studies
have shown that the prenatal environment seems to impact males more than
females whereas, females may be more susceptible to the postnatal
environment. Lee et al. examined the associations between pre- and/ or
postnatal stress and children's asthma, along with their effect
modification by sex in a prospective cohort study utilizing the Asthma
Coalition on Community, Environment, and Social Stress (ACCESS)
project\textsuperscript{10}. Increased maternal stress during the
postnatal period was more strongly associated with higher odds of asthma
in females\textsuperscript{10}, which is in line with our study
findings. Previous studies have also shown that females may be more
adaptive in utero, though at a cost of adverse health effects later in
life\textsuperscript{10, 36}. As a result, the usual increase in stress
reactivity in females exposed to in utero stress could explain their
greater vulnerability to stress- induced health effects after
birth\textsuperscript{10, 36}. Alton et al concluded that wheeze at 3
years of age was nearly 5 times more likely in girls of mothers who
experienced postpartum depression, which is fairly similar to the
results seen in this paper\textsuperscript{4}.

Utilizing the PROGRESS cohort in Mexico City is an important
contribution to this growing body of work as the prevalence of postnatal
and recurrent depression varies widely across cultures and geographic
regions\textsuperscript{10}. This study has several strengths, which
include a prospective study design, large urban population and sample
size of participants, and validated methods for measuring maternal
depression and childhood respiratory health outcomes. Additionally, we
had the ability to adjust for important environmental factors, including
prenatal and early life exposure to PM\textsubscript{2.5}.

Our study also had some limitations. Asthma and wheeze outcomes are
based on caregiver report which might be subject to recall bias.
However, given the logistical and technical complexity of objectively
recording asthma and wheeze in children, caregiver-reported wheeze and
asthma is commonly utilized in moderate- to larger-sized population
level studies. The ISAAC survey has been validated internationally and
in Spanish-Speaking populations\textsuperscript{37}. Future work should
examine more objective respiratory outcomes, such as lung function as
these children continue to be followed. As with any observational study,
we cannot rule out residual confounding due to unmeasured factors that
may influence depression and wheezing/asthma in childhood. PROGRESS is
composed of urban, low-income families and our results may translate to
other populations who face similar rates of depression. Research into
the respiratory childhood health risks of maternal depression may be
particularly clinically relevant in countries with high maternal
depression such as the United States where 1/8 women experience symptoms
of postpartum depression\textsuperscript{23}.

\textbf{Conclusion}

Postpartum and recurrent depression were associated with higher risk of
wheeze and asthma in childhood. Our results, support the importance of
researching the critical windows of maternal mental health during
pregnancy and postnatally. Moreover, in order to more fully understand
the influence of maternal mental health childhood respiratory disease
risk, the modifying effects of child sex should be taken into account.
This enhanced knowledge may benefit prevention and intervention
strategies like maternal mental health surveillance programs.

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