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 < 28 weeks or weighing < 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.