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\begin{document}

\title{Forced Expiratory Flows and Diffusion Capacity in Infants Born from
Mothers with Pre-eclampsia}



\author[1]{Clement Ren}%
\author[2]{James Slaven}%
\author[2]{David Haas}%
\author[3]{Laura Haneline}%
\author[3]{Christina Tiller}%
\author[2]{Graham Hogg}%
\author[2]{Jeffrey Bjerregaard}%
\author[2]{Robert Tepper}%
\affil[1]{The Children's Hospital of Philadelphia}%
\affil[2]{Indiana University School of Medicine}%
\affil[3]{James Whitcomb Riley Hospital for Children}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Rationale: Animal models suggest pre-eclampsia (Pre-E) affects alveolar
development, but data from humans are lacking. Objective: Assess the
impact of Pre-E on airway function, diffusion capacity, and respiratory
morbidity in preterm and term infants born from mothers with Pre-E.
Methods: Infants born from mothers with and without Pre-E were recruited
for this study; term and preterm infants were included in both cohorts.
Respiratory morbidity in the first 12 months of life was assessed
through monthly phone surveys. Raised volume rapid thoracoabdominal
compression and measurement of diffusion capacity of the lung to carbon
monoxide (DLCO)) were performed at 6 months corrected age. Results:
There were 146 infants in the Pre-E cohort and 143 in the control
cohort. The Pre-E cohort was further divided into non-severe (N=41) and
severe (N=105) groups. There was no significant difference in DCLO and
DLCO/aveolar volume amongst the three groups. Forced vital capacity was
similar amongst the three groups, but the non-severe Pre-E group had
significantly higher forced expiratory flows that the other two. After
adjusting for multiple covariates including prematurity, the severe
Pre-E group had a lower risk for wheezing in the first year of life
compared to the other two. Conclusions: Pre-E is not associated with
reduced DLCO, lower forced expiratory flows, or increased wheezing in
the first year of life. These results differ from animal models and
highlight the the complex relationships between Pre-E and lung function
and respiratory morbidity in human infants.%
\end{abstract}%



\sloppy


\textbf{Title:} Forced Expiratory Flows and Diffusion Capacity in
Infants Born from Mothers with Pre-eclampsia

\textbf{Authors:} Clement L. Ren MD MBA\textsuperscript{1,2}, James E.
Slaven MS\textsuperscript{3}, David M. Haas MD\textsuperscript{4}, Laura
S. Haneline MD\textsuperscript{5}, Christina Tiller
RRT\textsuperscript{6}, Graham Hogg BS\textsuperscript{4}, Jeffrey
Bjerregaard RRT\textsuperscript{6}, and Robert S. Tepper MD
PhD\textsuperscript{6}

\textsuperscript{1} Division of Pulmonary and Sleep Medicine, Children's
Hospital of Philadephia, Philadelphia, PA, USA

\textsuperscript{2} Department of Pediatrics, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, PA, USA

\textsuperscript{3} Department of Biostatistics, Indiana University
School of Medicine, Indianapolis, IN, USA

\textsuperscript{4} Department of Obstetrics and Gynecology, Indiana
University School of Medicine, Indianapolis, IN, USA

\textsuperscript{5} Division of Neonatal-Perinatal Medicine, Department
of Pediatrics, Indiana University School of Medicine, Indianapolis, IN,
USA

\textsuperscript{6} Division of Pulmonary, Allergy, and Sleep Medicine,
Department of Pediatrics, Indiana University School of Medicine,
Indianapolis, IN, USA

\textbf{Corresponding Author:} Robert S. Tepper, MD, PhD

Riley Hospital for Children 705 Riley Hospital Drive Indianapolis, IN
46202 Email: rtepper@iu.edu Phone: 317-948-7180 FAX: 371-944-7427

\textbf{Funding:} NIH R01HL122215 (RST, LSH)

\textbf{Running Title:} PFTs and DLCO in Infants born from Pre-clamptic
Mothers

\textbf{Total word count:} 3,486



\textbf{Abstract}

Rationale:

Animal models suggest pre-eclampsia (Pre-E) affects alveolar
development, but data from humans are lacking.

Objective:

Assess the impact of Pre-E on airway function, diffusion capacity, and
respiratory morbidity in preterm and term infants born from mothers with
Pre-E.

Methods:

Infants born from mothers with and without Pre-E were recruited for this
study; term and preterm infants were included in both cohorts.
Respiratory morbidity in the first 12 months of life was assessed
through monthly phone surveys. Raised volume rapid thoracoabdominal
compression and measurement of diffusion capacity of the lung to carbon
monoxide (DLCO)) were performed at 6 months corrected age.

Measurements and Main Results:

There were 146 infants in the Pre-E cohort and 143 in the control
cohort. The Pre-E cohort was further divided into non-severe (N=41) and
severe (N=105) groups. There was no significant difference in DCLO and
DLCO/alveolar volume amongst the three groups. Forced vital capacity was
similar amongst the three groups, but the non-severe Pre-E group had
significantly higher forced expiratory flows that the other two. After
adjusting for multiple covariates including prematurity, the severe
Pre-E group had a lower risk for wheezing in the first year of life
compared to the other two.

Conclusions:

Pre-E is not associated with reduced DLCO, lower forced expiratory
flows, or increased wheezing in the first year of life. These results
differ from animal models and highlight the the complex relationships
between Pre-E and lung function and respiratory morbidity in human
infants.

Word count: 242



\textbf{Introduction}

Pre-eclampsia (Pre-E) is a serious complication of pregnancy that occurs
in approximately 5\% of pregnancies in the USA {[}1{]}. Pre-E is
characterized by maternal hypertension and systemic vascular endothelial
dysfunction. Although the pathogenesis of Pre-E is not well-defined,
several studies have demonstrated that women with Pre-E have increased
circulating levels of anti-angiogenic factors such as soluble FMS-like
Tyrosine Kinase-1 (sFlt-1) {[}2, 3{]}. Infants born from mothers with
Pre-E have a reduced risk for retinopathy of prematurity, a condition
caused by excess retinal angiogenesis and neovascularization {[}4{]}. In
addition, infants born from hypertensive women have reduced skin
capillary density {[}5{]}. These observations suggest that the
anti-angiogenic milieu of pregnant women with Pre-E affects vascular
development in the fetus. Recent evidence from a murine model of the
early onset immune-mediated subtype of Pre-E suggests that the placenta
plays a key role in mediating the effects of Pre-E on fetal lung
development {[}6, 7{]}.

Disruption of pulmonary vascular development is linked to impaired
alveolar growth, a hallmark feature of bronchopulmonary dysplasia (BPD).
Increased cord blood sFlt-1 is also associated with an enhanced risk of
BPD in preterm infants {[}8-11{]}. A rat model of Pre-E utilizing
intra-amniotic injection of sFlt-1 demonstrated decreased alveolar
number and reduced pulmonary vessel density at 14 days of age, which
corresponds to 1 year of human life {[}10{]}. Furthermore, a history of
maternal Pre-E is associated with increased rates of asthma, allergy,
and eczema {[}12, 13{]}. Taken together, these clinical and animal data
suggest that the effect of Pre-E on angiogenesis may affect respiratory
function in infants with Pre-E. However, there are limited data on
airway function and, to our knowledge, no data on gas transfer of
off-spring with a history of maternal Pre-E.

The objective of our study was to assess the impact of Pre-E on
respiratory outcomes in early infancy, which included lung function and
respiratory morbidity. We hypothesized that the \emph{in
utero}anti-angiogenic environment of pre-E would result in impaired lung
growth and development with decreased parenchymal and airway function,
as well as increased respiratory morbidity in infants born of pregnant
women with Pre-E. To test this hypothesis, we recruited a cohort of
pregnant women with Pre-E and a cohort of normotensive pregnant women
with similar gestational ages (GA) that included preterm and term
infants. We evaluated parenchymal function with measurements of
diffusion capacity of the lung and lung volume and airway function with
measurements of forced expiratory flows. Infant pulmonary function tests
(IPFTs) were performed at approximately 6 months corrected-age, and
their respiratory status was followed through 12 months corrected age.

\textbf{Methods}

\emph{Study Population and Design}

This was a single center, prospective, observational cohort study
(NCT02639676). Potential study participants were recruited from 3 local
hospitals in Indianapolis, IN USA. Inclusion criteria for the study
cohort included a clinical diagnosis of Pre-E (using definitions
contained in the American College of Obstetrcis and Gynecology Task
Force on Hypertension in Pregnancy 2013 report) with anticipated
delivery between 26-40 weeks GA determined by best obstetrical dating
(last menstrual period confirmed by ultrasound) {[}14{]}. We also
recruited a comparison cohort of infants born from normotensive pregnant
women with anticipated delivery between 26-40 weeks GA determined by
best obstetrical dating. Exclusion criteria included multiple gestation
pregnancy, prenatally identified fetal cardiopulmonary defects, known
fetal chromosomal disorders, women with diabetes mellitus, and women
with chronic or gestational hypertension. Prematurity was not an
exclusion criterion for either cohort, and the final cohorts were
comprised of term and preterm infants. Prior to initiation of this
study, we received approval from the Indiana University Institutional
Review Board. The mothers of infant study participants all provided
written informed consent.

We used the electronic medical record to obtain maternal clinical
information, such as maternal medications (e.g. antenatal steroids,
magnesium sulfate, other anti-hypertensive therapies), tobacco use, and
family history of asthma. We also obtained neonatal clinical information
such as birth weight and length, gestational age at birth, sex, race,
and need for interventions such as exogenous surfactant therapy,
positive pressure ventilation, and supplement oxygen use.

Following discharge from the hospital, we performed monthly telephone
surveys to track episodes of wheezing, respiratory medication use (e.g.
inhaled bronchodilators and inhaled corticosteroids), and
hospitalizations for respiratory related illness.

\emph{Infant Pulmonary Function Tests (IPFT)}

Parenchymal and airway function were assessed using previously described
methods {[}15, 16{]}. In brief, infants were first sedated with oral
chloral hydrate (85 mg/kg) and measurements of the alveolar volume (VA)
and diffusion capacity of the lung to carbon monoxide (DLCO) were
performed. In addition, forced expiratory flows (FEFs) using the raised
volume rapid thoraco-abdominal compression technique were measured and
quantified by forced vital capacity (FVC), forced expiratory flows
between 25\% and 75\% expired FVC (FEF25-75), forced expired flow at
50\% and 75\% expired FVC (FEF50, FEF75), as well as forced expired
volume in 0.5 seconds (FEV0.5). Data quality was determined using
published guidelines {[}17{]}, and only research quality data were used
for analysis.

\emph{Statistical Analysis}

The Pre-E cohort was evaluated as a single group, as well as divided
into 2 groups, non-severe Pre-E and severe Pre-E, using the American
College of Obstetrics and Gynecology criteria for Pre-E with severe
features {[}18{]}. Basic clinical and demographic comparisons were
performed using Chi-Square tests for categorical variables and Students
t-tests and Wilcoxon rank-sum tests for continuous variables, depending
on the linearity of the data. Pairwise comparisons were made using a
Bonferroni correction. To analyze wheezing outcomes, a participant level
variable of ever/never wheezed was created for participants who had at
least one survey response in the the first six months of surveys, as
well as after 6 months. We then analyzed all the survey data from
infants meeting this criterion. For each of the main outcomes, simple
bivariate analyses were first performed and those variables with
significance of P[?]0.10 were included in a multivariable model. In
addition to these variables, we included clinically relevant ones, e.g.
sex, race, etc. For the outcome of wheezing, using the dichotomous
wheezing outcome as described above, logistic regression analysis was
performed using multivariable model including Pre-E group, sex, GA,
mother's smoking history, family history of asthma, and antenatal
steroid use. IPFT outcomes were analyzed with raw data adjusting for
race, sex, and body length at testing in multivariable models. Simple
t-tests were used for the bivariate analyses and ANCOVA models were
performed for the adjusted models, with the covariates sex, race,
length, and GA. Fetal growth restriction, antenatal steroid use, and
family history of asthma were also included as covariates based on the
results of the bivariate analysis. All analytic assumptions were
verified, collinearity was assessed for multivariable models, and
analyses were performed using SAS v9.4 (SAS Institute, Cary, NC).

\textbf{Results}

A total of 430 infants were screened, and 289 were enrolled, 146 in the
Pre-E group and 143 in the normotensive comparison cohort. Figure 1
illustrates the derivation of the study cohort. The demographic and
clinical features of the Control and Pre-E (non-severe and severe)
cohorts are summarized in Table 1. There were no differences among
groups for sex and maternal race; however, as expected, GA, birth
weight, and birth length of the Severe Pre-E infants were significantly
lower compared to infants in the Control and Non-severe Pre-E groups.
Severe Pre-E infants were also more likely to have fetal growth
restriction (FGR), to be small of gestional age (SGA), and to be born to
women treated with antenatal steroids (ANS). No significant differences
were observed among the groups in terms of need for mechanical
ventilation, surfactant therapy, development of bronchopulmonary
dysplasia, history of maternal smoking, and second-hand smoke exposure.
A similar pattern of clinical features was seen when comparisons were
restricted to the infants who had IPFT obtained (data not shown).

IPFTs were performed at a mean corrected-age of 7.99 months (SD 2.69,
range=4.14-19.53), and the results are summarized in Table 2.{[}add
information to address Laura's comment of drop out{]} DLCO, DLCO/VA, and
VA were not different for the Control and Pre-E group, even when the
latter was divided into the Non-Severe and Severe Pre-E groups. In
addition, Hemoglobin (Hb) concentration did not differ among the 3
groups (11.5\selectlanguage{ngerman}±1.2, 11.3±1.4, and 11.7±1.2; p \textgreater{} .3728). While
FVC did not differ among any of the groups, the forced expiratory flows
(FEF50; FEF25-75) tended to be higher in the Pre-E group compared to
Controls, but didn't reach statistical significance (FEF50: 483 vs. 445,
p \textless{} 0.057; FEF25-75: 442 vs. 413, p \textless{} 0.098 ).
However, when Pre-E was divided by severity, the Non-severe Pre-E cohort
had significantly higher FEFs compared to the Controls and Severe Pre-E
infants (Table 2). In addition, FEV0.5 was higher in the Non-severe
Pre-E group, although the difference did not reach statistical
significance (p = 0.058)

There were 234 infants (Control N=108; Pre-E N = 126) whose caregivers
responded to at least one survey in the first 6 months of life, and
again after 6-months of life. The demographics and clinical features of
this group were similar to those of the entire cohort and the proportion
of respondents was similar in both the control group and pre-E groups.
Among all infants with respiratory quesstonairres, 98 (42\%) had at
least 1 episode of wheezing reported in the first year of life. To
determine potentially significant confounding covariates, we initially
performed bivariate analysis of wheezing outcomes (No Wheeze vs Wheeze)
(Table 3). There were 81 out of a total of 126 Pre-E infants with no
wheezing (64\%), and this was significantly greater than that of the
Control group (55 out of 108, 51\%, P=0.039). When the Pre-E subjects
were divided by severity, there was not a significant difference in the
proportion of subjects with No Wheeze among the three groups (Control,
Non-Severe Pre-E, and Severe Pre-E). Preterm birth, lower birth weight,
lower birth length, and lower GA, maternal smoking and history of asthma
were also associated with a higher prevalence of wheezing. An analysis
restricted to only those infants who also had IPFT revealed a similar
pattern. Using covariates related to risk of wheeze selected from the
bivariate analysis (Table 3) and additional variables based on clinical
relevance (listed in the Methods), we then performed multi-variable
logistic regression modeling for the outcome of Wheeze vs No Wheeze. The
odds ratio (OR) of Wheeze was significantly lower in the combined Pre-E
group compared to Controls (0.47; p \textless{} 0.009). When the Pre-E
group was divided into Non-Severe and Severe Pre-E, each of the Pre-E
groups had OR for Wheeze of less than 1.0; however, compared to the
Control group, only the Severe Pre-E group, which composed the majority
of Pre-E subjects, had significantly lower risk for wheeze (Table 4).
Family history of asthma, maternal smoking, and antenatal steroids were
all included in the logistic model based upon their associated increased
risk of Wheeze in the bivariate analysis (Table 3), only antenatal
steroids, which was more frequent in the Severe Pre-E group, was
statistically significant, while family history of asthma and maternal
smoking were still associated with an increased risk of wheeze with p
values \textless{} 0.10 (Table 1). Very few infants were hospitalized
for respiratory illness following discharge, precluding a detailed
analysis of this respiratory outcome.

With all subjects grouped together(Control, non-severe and severe
Pre-E), higher FEF25-75 was associated with lower risk of wheeze (OR =
0.74 (0.55, 1.00); p = 0.048); however, when analyzed as 3 separate
groups (Control, Non-Severe, Severe Pre-E), the relationships between
FEF25-75 and the risk of wheeze (OR: 0.61 (0.35, 1.05), 1.57 (0.63,
3.92), 0.73 (0.47, 1.14)) were not significant for any of the groups (p
values: 0.076, 0.339, 0.164).

\textbf{Discussion}

In this single-center prospective cohort study of infants born from
mothers with Pre-E, no differences were detected in the lung parenchymal
function of gas exchange and lung volume, as assessed by DLCO, DLCO/VA,
or VA, when compared to control infants born from normotensive mothers.
This finding does not support our hypothesis nor agree with animal
models of pre-eclampsia, which suggest impaired alveolar development in
the offspring of mothers with Pre-E. However, we did find that airway
function, assessed by FEFs, were actually higher in the non-severe Pre-E
group compared to Control and severe Pre-E groups. Although the
non-severe Pre-E group had higher FEFs, the severe Pre-E group, which
did not have higher FEFs, had a lower risk for wheeze in the first year
of life when adjusted for covariates including GA. These findings
highlight the complex relationships among prematurity, lung function and
respiratory morbidity in infants born from mothers with Pre-E.

We are not aware of other studies that have assessed DLCO as a
respiratory outcome in offspring of mothers with Pre-E. The majority of
infants born following maternal pre-eclampsia are preterm because labor
is either induced or a Cesarean section is performed at a premature GA
to protect the mother with severe Pre-E. Therefore, preterm birth, which
is associated with impaired alveolar development and increased
respiratory morbidity, becomes an important confounder in the assessment
of respiratory outcomes of lung function and respiratory morbidity. We
therefore used a control group from normotensive pregnancies that
included preterm and term births. Our findings that DLCO and VA did not
differ between Pre-E (Non-Severe and Severe) and normctentsive Control
group suggests that Pre-E did not significantly impair alveolar
development when evaluated at a mean corrected-age of 7-8 months.

Our findings related to parenchymal function do not support our initial
hypothesis and are not consistent with current animal models of
Pre-eclampsia. Tang et al reported that the amniotic administration of
the anti-angiogernic factor FLT-1 to pregnant rats 2 days prior to
delivering pups via caesarian section resulted in decreased alveolar
number, reduced pulmonary vessel density, and right ventricular
hypertrophy {[}10{]}. More recently, Taglauer et al used a heme
oxygenase-1 null mouse model of pre-eclampsia to demonstrate disrupted
alveolar formation and altered airway development. This model was also
associated with a down-regulation of angiogenic and epithelial pathways,
as well as an up-regulation of inflammatory and extra-cellular matrix
pathways, suggesting multiple molecular pathways contributing to the
observed pulmonary phenotype. It is possible that the Pre-E infants we
evaluated may have demonstrated impaired alveolar development if
evaluated during the neonatal period and subsequently exhibited catch-up
in alveolar development prior to our evaluation. However, the animal
models of Pre-E that demonstrated impaired alveolar development often
evaluated animal offspring at human developmental age equivalent to our
study in human infants {[}19{]}. In addition, there are currently no
longitudinal data in humans to indicate that there is catch-up lung
growth following preterm birth or maternal pre-E. Therefore, it remains
unclear how well the current animal models of Pre-E reflect clinical
Pre-E, and the various subtypes, which may result from multiple
differing factors and be associated with multiple co-morbidities, such
as fetal growth restriction and prematurity, which can affect lung
development.

In contrast to no differences in DLCO and VA, we did find higher FEFs in
infants of mothers with Non-severe Pre-E. This finding is consistent
with the higher FEFs reported in older children born of mothers with
Pre-E, although that study of older children was restricted to subjects
born preterm with GA \textless{} 28 weeks or weighing \textless{} 1000g
{[}20{]}. In both that study and ours, FVC did not differ between Pre-E
and control groups, suggesting that the higher FEFs were related to
differences in airway function rather than to differences in lung
volume. In our study, we also found that VA did not differ between Pre-E
and Control groups, again suggesting that differences in FEFs were
secondary to differences in airway function rather than differences in
lung volumes. The only previous study evaluating infants born to women
with Pre-E was by Stokholm, et al {[}13{]}. These investigators reported
that at 1-month of age, FEV0.5 and FEF50 were not significantly
different comparing infants from Pre-E and non-PreE mothers; however, in
that study, all infants were from mothers with asthma, which may also
have an effect upon the airway function of offspring. The mechanism for
our observed higher FEFs in offspring of PreE mothers is unclear and
future studies might include a more direct assessment of airway size,
such as high resolution computed tomography.

The increased risk of wheeze we found related to preterm birth, maternal
smoking, family history of asthma, and antenatal steroids is consistent
with previous reports in the literature {[}21, 22{]}. The lower risk for
wheeze in the Pre-E group, after adjusting for other covariates related
to wheeze (Table 3), was primarily driven by the severe Pre-E group
(OR=0.42) (Table 4). Although the non-severe Pre-E group tended to have
a lower risk of wheeze compared to Controls (OR=0.61), this was not
statistically significant, which may be related to the fewer Non-Severe
compared to Severe Pre-E infants evaluated (41 vs 105).

In prior studies of airway function among full-term infants without
Pre-E, higher airway function during infancy was associated with lower
risk for subsequent wheezing in the first year of life {[}23{]}. We
found a similar relationship between higher FEFs and lower risk of
wheeze only when all subjects were evaluated as a single group, but not
for the individual groups (Control, Non-Severe and Severe Pre-E). Our
Non-Severe Pre-E group had significantly higher FEFs; however, their
lower risk of wheeze did not reach statistical significance. The Severe
Pre-E group had a significantly lower risk of wheeze compared to
Controls, even after adjusting for several covariates that increase the
risk of wheeze and more frequent in the severe Pre-E group; however,
this group did not have significantly higher FEFs. These inconsistencies
may relate to differences in these two very different respiratory
outcomes, the limited number of infants in the non-severe Pre-E group,
as well as as the multiple factors that can contribute to wheeze.
Spirometry is assessed while infants are sleeping and without any
intercurrent respiratory illness, making FEFs a reproducible objective
measurement of airway function when not symptomatic. In contrast, wheeze
is determined from parental questionnaire as a sign of airways
obstruction when the infant is ill. The mechanisms that contribute to
wheeze are complex and can include the baseline airway function, as well
as the inflammatory responses to stimuli, such as viruses and allergen.
In addition, molecular pathways that contribute to Non-severe and Severe
Pre-E may not be a continuous spectrum, but rather may represent
differing pulmonary phenotypes. It is also possible that Non-Severe and
Severe Pre-E, as well as prematurity, differ in their effects upon
baseline airway development and function, as well as immune development
and responses to stimuli. Therefore the relationship between airway
function and wheezing previously observed in full-term infants may be
more indirect and may not apply in our populations of infants.

Our study has several strengths and limitations. One of the strengths of
our study was the ability to obtain a detailed assessment of lung
function in infants. We were able to address the effect of Pre-E upon
the lung parenchyma development, as well as airway function.
Importantly, we evaluated Control subjects from normotensive pregnancies
with a balanced mix of GA and sex, as these factors can contribute to
alterations in lung growth and development. Preterm infants with chronic
lung disease of infancy (CLDI) have lower DLCO, but normal VA compared
to fullterm infants{[}24{]}. However, the effect of Pre-E upon alveolar
development may be less than that observed with CLDI. Our study also had
limitations. All of the infants were recruited from a single health
system, which could have led to bias in the study population or
treatment of Pre-E. Although our cohort size was large for an IPFT
study, the number of infants evaluated was still relatively small,
potentially rendering us underpowered to detect some associations.
Although we accounted for multiple covariates in our analysis, we were
unable to adjust for all potential confounders, such as respiratory
viral infections. The number of very low GA infants was small, and it is
possible that the impact of Pre-E on pulmonary outcomes in extremely low
GA neonates would be different from our observations. Lastly, our DLCO
measurement was obtained in infants sleeping, which may have limited our
ability to detect smaller differences of impaired alveolar development,
which may only be present under conditions of increased cardiac output,
such as exercise {[}25{]}.

In summary, the results of our study do not support the hypothesis that
in utero Pre-E exposure leads to impaired lung parenchymal development
in humans. The differences between our findings in humans and those
reported from animal models may be due to differences in the impact of
anti-angiogenic factors on lung development or the ability of the human
lung to rapidly compensate for in utero anti-angiogenic factors.
However, we separately found better airway function and decreased
wheeze, but not in the same severity group of Pre-E offspring.
Therefore, differing Pre-E severity may represent differing molecular
pathways, which could result in differing pulmonary phenotypes. Further
research is needed to obtain a more comprehensive understanding of the
effect of Pre-E on lung development and respiratory morbidity.



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study. \emph{Am J Hypertens} 2012; 25: 848-853.

6. Taglauer ES, Fernandez-Gonzalez A, Willis GR, Reis M, Yeung V, Liu X,
Prince LS, Mitsialis SA, Kourembanas S. Antenatal Mesenchymal Stromal
Cell Extracellular Vesicle Therapy Prevents Preeclamptic Lung Injury in
Mice. \emph{American Journal of Respiratory Cell and Molecular Biology}
; 0: null.

7. Thébaud B. Preempting Bronchopulmonary Dysplasia: Time to Focus on
the Placenta? \emph{American Journal of Respiratory Cell and Molecular
Biology} ; 0: null.

8. Jakkula M, Le Cras TD, Gebb S, Hirth KP, Tuder RM, Voelkel NF, Abman
SH. Inhibition of angiogenesis decreases alveolarization in the
developing rat lung. \emph{Am J Physiol Lung Cell Mol Physiol} 2000;
279: L600-607.

9. Le Cras TD, Markham NE, Tuder RM, Voelkel NF, Abman SH. Treatment of
newborn rats with a VEGF receptor inhibitor causes pulmonary
hypertension and abnormal lung structure. \emph{Am J Physiol Lung Cell
Mol Physiol} 2002; 283: L555-562.

10. Tang J-R, Karumanchi SA, Seedorf G, Markham N, Abman SH. Excess
soluble vascular endothelial growth factor receptor-1 in amniotic fluid
impairs lung growth in rats: linking preeclampsia with bronchopulmonary
dysplasia. \emph{American Journal of Physiology-Lung Cellular and
Molecular Physiology} 2012; 302: L36-L46.

11. Yang WC, Chen CY, Chou HC, Hsieh WS, Tsao PN. Angiogenic Factors in
Cord Blood of Preterm Infants Predicts Subsequently Developing
Bronchopulmonary Dysplasia. \emph{Pediatr Neonatol} 2015; 56: 382-385.

12. Mirzakhani H, Carey VJ, McElrath TF, Qiu W, Hollis BW, O'Connor GT,
Zeiger RS, Bacharier L, Litonjua AA, Weiss ST. Impact of Preeclampsia on
the Relationship between Maternal Asthma and Offspring Asthma. An
Observation from the VDAART Clinical Trial. \emph{Am J Respir Crit Care
Med} 2019; 199: 32-42.

13. Stokholm J, Sevelsted A, Anderson UD, Bisgaard H. Preeclampsia
Associates with Asthma, Allergy, and Eczema in Childhood. \emph{Am J
Respir Crit Care Med} 2017; 195: 614-621.

14. Hypertension in pregnancy. Report of the American College of
Obstetricians and Gynecologists' Task Force on Hypertension in
Pregnancy. \emph{Obstet Gynecol} 2013; 122: 1122-1131.

15. Castillo A, Llapur CJ, Martinez T, Kisling J, Williams-Nkomo T,
Coates C, Tepper RS. Measurement of single breath-hold carbon monoxide
diffusing capacity in healthy infants and toddlers. \emph{Pediatr
Pulmonol} 2006; 41: 544-550.

16. Feher A, Castile R, Kisling J, Angelicchio C, Filbrun D, Flucke R,
Tepper R. Flow limitation in normal infants: a new method for forced
expiratory maneuvers from raised lung volumes. \emph{J Appl
Physiol}1996; 80: 2019-2025.

17. ATS/ERS statement: raised volume forced expirations in infants:
guidelines for current practice. \emph{Am J Respir Crit Care Med} 2005;
172: 1463-1471.

18. Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin,
Number 222. \emph{Obstetrics \& Gynecology} 2020; 135: e237-e260.

19. Sengupta P. The Laboratory Rat: Relating Its Age With
Human's.\emph{Int J Prev Med} 2013; 4: 624-630.

20. Doyle LW, Ranganathan S, Haikerwal A, Cheong JLY, Victorian Infant
Collaborative Study G. Associations of Preeclampsia with Expiratory
Airflows in School-Age Children Born Either at \textless{}28 Weeks or
Weighing \textless{}1000 g. \emph{J Pediatr} 2019; 209: 39-43 e32.

21. Nixon PA, Washburn LK, O'Shea TM. Antenatal steroid exposure and
pulmonary outcomes in adolescents born with very low birth
weight.\emph{Journal of Perinatology} 2013; 33: 806-810.

22. Pole JD, Mustard CA, To T, Beyene J, Allen AC. Antenatal steroid
therapy for fetal lung maturation: is there an association with
childhood asthma? \emph{J Asthma} 2009; 46: 47-52.

23. Martinez FD, Morgan WJ, Wright AL, Holberg CJ, Taussig LM.
Diminished lung function as a predisposing factor for wheezing
respiratory illness in infants. \emph{N Engl J Med} 1988; 319:
1112-1117.

24. Balinotti JE, Chakr VC, Tiller C, Kimmel R, Coates C, Kisling J, Yu
Z, Nguyen J, Tepper RS. Growth of lung parenchyma in infants and
toddlers with chronic lung disease of infancy. \emph{Am J Respir Crit
Care Med} 2010; 181: 1093-1097.

25. Fitzgerald NM, Kennedy B, Fitzgerald DA, Selvadurai H. Diffusion
capacity of carbon monoxide (DLCO) pre- and post-exercise in children in
health and disease. \emph{Pediatr Pulmonol} 2014; 49: 782-789.

\textbf{Figure Legend}

\textbf{Figure} . Derivation of the study cohorts. The numbers in the
screening box represent approximate monthly values. Abbreviations: RQ,
respiratory questionnaire; PFT, pulmonary function test; DLCO, diffusion
capacity of the lung to carbon monoxide; RVRTC, raised volume rapid
thoracoabdominal compression.

\textbf{Table 1.} Clinical features of the cohort. Abbreviations: Pre-E,
pre-eclampsia; GA, gestational age.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Control\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Non-severe Pre-E\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Severe Pre-E\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
P value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
N\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
143\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
41\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
105\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Sex Female Male\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
61 (43.0) 81 (57.0)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
19 (46.3) 22 (53.7)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
56 (53.3) 49 (46.7)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
.2695\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Maternal Race Black White Multi Unknown\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
67 (47.2) 67 (47.2) 7 (4.9) 1 (0.7)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
17 (41.5) 20 (48.8) 4 (9.8) 0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
57 (54.3) 43 (41.0) 4 (3.8) 1 (1.0)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
.6416\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Preterm Delivery\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
55 (38.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (19.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
66 (62.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}.0001 \textsuperscript{bc}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Gestational age Mean (SD)\\
Median (95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
37.11 (3.55) 38.4 (35.1, 39.9)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
37.66 (2.46) 37.6 (37.0, 39.3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
35.32 (3.49) 36.3 (33.6, 37.3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textless{}.0001\textsuperscript{bc}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Birth weight (kg) Mean (SD)\\
Median (95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2.8559 (0.7389) 2.98 (2.52, 3.36)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2.9978 (0.8205) 3.19 (2.66, 3.51)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2.3184 (0.7744) 2.41 (1.78, 2.89)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textless{}.0001\textsuperscript{bc}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Birth length (cm) Mean (SD)\\
Median (95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
47.87(5.20) 49.0(46.0, 51.0)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
48.48 (4.95) 49.0 (48.3, 52.0)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
45.19 (5.07) 47.0 (43.0, 48.5)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textless{}.0001\textsuperscript{bc}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Fetal growth restriction\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16 (11.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5 (12.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27 (25.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
.0081\textsuperscript{b}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Family history of asthma\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
31 (21.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11 (26.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
28 (26.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
.6273\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Size for GA Small for GA Appropriate for GA Large for GA\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
14 (9.9) 119 (84.4) 8 (5.7)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
5 (12.2) 32 (78.1) 4 (9.8)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
26 (24.8) 79 (75.2) 0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
.0014 \textsuperscript{bc}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Antenatal steroids\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
55 (39.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
12 (29.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
63 (60.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
.0004 \textsuperscript{bc}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Values in parentheses represent percentages except as noted.
Superscripted letter indicate which pairwise comparison was made
(a=control vs. non-severe preE; b=control vs. severe PreE, c=non-severe
PreE vs. severe PreE).

\textbf{Table 2.} Infant Lung Function Results. The total numbers for
each group are shown in the table. Values are means (standard errors)
for each group with 95\% CI for difference between means and p-value
from ANCOVA models. Abbreviations: DLCO, diffusion capacity of the lung
to carbon monoxide; VA, alveolar volume; FVC, forced vital capacity;
V\textsubscript{50}, flow at 50\% of FVC; V\textsubscript{75}, flow at
75\% of FVC; FEF\textsubscript{25-75}, forced expiratory flow between
25-75\% of FVC; FEV\textsubscript{0.5}, forced expiratory volume in 0.5
second.\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
PFT Measure & Control (n=108) & Non-severe Pre Eclampsia (n=34) & Severe
Pre Eclampsia (n=92) & Mean difference (95\% CI) (control vs.
non-severe) & Mean difference (95\% CI) (control vs. severe) & Mean
difference (95\% CI) (non-severe vs. severe) & Omnibus
p-value\tabularnewline
\midrule
\endhead
DLco (ml/min/mmHg) & 2.6 (0.1) & 2.6 (0.1) & 2.5 (0.1) & -0.0 (-0.3,
0.3) & 0.1 (-0.2, 0.3) & 0.1 (-0.2, 0.4) & .7786\tabularnewline
DLco/VA (ml/min/mmHg/ml) & 6.9 (0.2) & 7.1 (0.3) & 7.1 (0.2) & -0.2
(-0.8, 0.4) & -0.2 (-0.6, 0.2) & -0.0 (-0.6, 0.6) & .6103\tabularnewline
VA (ml) & 410.6 (12.6) & 397.8 (19.3) & 389.2 (13.0) & 12.8 (-27.3,
52.8) & 21.5 (-7.6, 50.5) & 8.7 (-33.4, 50.8) & .3391\tabularnewline
FVC (ml) & 271.4 (6.5) & 275.2 (9.8) & 265.4 (7.1) & -3.8 (-24.3, 16.7)
& 6.0 (-8.9, 20.9) & 9.8 (-12.1, 31.8) & .6102\tabularnewline
V\textsubscript{50} (ml/s) & 444.6 (17.8) & 537.0
(26.8)\textsuperscript{b} & 457.9 (19.3) & -92.4 (-148.6, -36.2) & -13.3
(-54.2, 27.6) & 79.1 (18.9, 139.3) & .0061\tabularnewline
FEF\textsubscript{25-75}(ml/s) & 412.0 (16.2) & 495.0
(24.4)\textsuperscript{b} & 418.5 (17.6) & -83.0 (-134.1, -31.9) & -6.5
(-43.6, 30.7) & 76.5 (21.8, 131.3) & .0062\tabularnewline
V\textsubscript{75} (ml/s) & 252.0 (12.5) & 289.1 (18.8) & 251.0 (13.5)
& -37.1 (-76.4, 2.3) & 1.0 (-27.6, 29.6) & 38.1 (-4.0, 80.2) &
.1525\tabularnewline
FEV\textsubscript{0.5} (ml) & 211.7 (5.4) & 231.2
(8.1)\textsuperscript{b} & 210.5 (5.8) & -19.5 (-36.4, -2.5) & 1.2
(-11.2, 13.5) & 20.6 (2.5, 38.8) & .0578\tabularnewline
\bottomrule
\end{longtable}

Superscripted letters indicate which pairwise comparison was made
(a=control vs. non-severe preE; b=control vs. severe PreE, c=non-severe
PreE vs. severe PreE).

\textbf{Table 3.} Wheezing outcomes in the study cohort.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
No Wheezing\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Wheezing\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
P value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
N\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
136\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
98\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Group Control PreEclamptic\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
55 (40.4) 81 (59.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
53 (54.1) 45 (45.9)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.0389\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Group Control PreEclamptic (low severity) PreEclamptic (high
severity\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
55 (40.4) 22 (16.2) 59 (43.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
53 (54.1) 12 (12.2) 33 (33.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.1184\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Sex Female Male\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
68 (50.0) 68 (50.0)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
43 (43.9) 55 (56.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.3548\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Race White Other\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
62 (45.6) 74 (54.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
46 (46.9) 52 (53.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.8380\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Term Full Term Pre-Term\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
81 (59.6) 55 (40.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
45 (45.9) 53 (54.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.0389\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Gestational age\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
36.89 (3.30); 37.29 (35.79, 39.29)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
35.73 (3.84); 36.43 (34.00, 38.86)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.0215\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Birth weight (kg)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.7443 (0.7662); 2.79 (2.04, 3.13)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.5366 (0.8622); 2.63 (2.04, 3.13)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.0732\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Birth length\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
47.49 (5.39); 48.50 (47.00, 50.50)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
45.89 (5.32); 46.75 (43.50, 49.53)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.0064\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Surfactant treatment No Yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
127 (93.4) 9 (6.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
89 (90.8) 9 (9.2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.4674\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Mechanical Ventilation No Yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
127 (93.4) 9 (6.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
88 (89.8) 10 (10.2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.3217\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Bronchopulmonary dysplasia No Yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
133 (97.8) 3 (2.2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
93 (94.9) 5 (5.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.2290\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Fetal growth restriction No Yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
116 (85.3) 20 (14.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
82 (83.7) 16 (16.3)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.7346\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Secondhand smoke exposure No Yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
131 ( 5 (55.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
94 (41.8) 4 (44.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.8737\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Mother smoked during pregnancy No Yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
111 (81.6) 25 (18.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
69 (70.4) 29 (29.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.0447*\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Family history of asthma No Yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
107 (78.7) 29 (21.3)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
67 (68.4) 31 (31.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.0748\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Size for gestational age (GA) Small for GA Appropriate for GA Large for
GA\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
22 (16.2) 108 (79.4) 6 (4.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
15 (15.3) 80 (81.6) 3 (3.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.8469\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Antenatal steroids No Yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
85 (62.5) 51 (37.5)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
41 (41.8) 57 (58.2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
.0018\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Values are means (standard deviations); medians (IQRs) for continuous
variables and frequencies (row percentages) for categorical variables,
with p-values from Wilcoxon and Chi-Square tests, respectively.

\textbf{Table 4.} Logistic regression model for reported wheeze.\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
Odds Ratio (95\% CI)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Group Non-severe PreEclampsia vs. Control\\
Severe PreEclamptic vs. Control\\
Non-severe PreEclamptic vs. Severe PreEclampsia\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
0.61 (0.26, 1.41) P=.2439 0.42 (0.22, 0.70) P=.0074 1.45 (0.59, 3.57)
P=.4235\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Sex Female Male\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
0.81 (0.46, 1.42) Reference P=.4683\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Gestational age\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
0.96 (0.86, 1.07) P=.4396\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Mother smoked during pregnancy\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
1.88 (0.99, 3.60) P=.0556\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Family history of asthma\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
1.71 (0.91, 3.21) P=.0952\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Antenatal steroids\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
2.23 (1.04, 4.79) P=.0387\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Values are reported as odds ratios (95\% CI). The model includes
independent variables selected from Table 3 with P\textless{}0.10.
Comparisons of dichotomous variables are for ``yes'' compared to ``no''

\textbf{Hosted file}

\verb`Figure.docx`  available at \url{https://authorea.com/users/471667/articles/563029-forced-expiratory-flows-and-diffusion-capacity-in-infants-born-from-mothers-with-pre-eclampsia}

\selectlanguage{english}
\FloatBarrier
\end{document}

