CONCLUSIONS
Although births at 34+0 – 36+6 are
usually considered as a homogeneous population under the definition of
LP, this large prospective, observational study demonstrated significant
differences in neonatal outcomes based on gestational age at delivery.
We found that approximately one third of newborns at 34 weeks
experienced neonatal morbidities, when compared to < 10% of
the 36 weeks births (Table 4). Moreover, after controlling for
confounding, adverse outcomes were 2-4 folds more common when delivery
took place at 34 instead of 36 weeks’ gestation (Tables 5, 6). As also
shown by the Consortium on Safe Labor [22], we identified a
continuum of neonatal morbidities that inversely correlated with timing
of delivery; therefore, when maternal, fetal or obstetric complications
develop between 34+0 and 36+6 weeks’
gestation, obstetricians need to carefully balance the risks and
benefits of birth at a specific gestational age with the consequences of
pregnancy continuation beyond that time point [23].
As metabolic acidosis and the need for neonatal resuscitation reflect
the fetus’ exposure to hypoxia and increased metabolic demands, we found
an association with pregnancy complications rather than gestational age
at delivery (Table 5, 6). De Almeida et al. [24] initially
demonstrated that LP babies were at substantially increased risk for
neonatal resuscitation when compared to term counterparts. Our
multivariate analyses confirmed among LP newborns known risk factors for
resuscitation at birth, such as delivery prompted by maternal or fetal
disorders (i.e. indicated deliveries, Table 5), vaginal bleeding from
placenta abruption/abnormal placentation, and non-reassuring fetal
status (Table 6) [25]. These findings may help develop strategies to
prepare for circumstances requiring advanced neonatal resuscitation
skills, and to organize in utero transfer to Tertiary Care Centers.
In our cohort, indicated deliveries were associated with worse immediate
neonatal outcomes when compared with spontaneous LP labor (Table 5), as
also indicated in previous reports [8, 9]. The process of labor
itself likely facilitates fetal lung maturation and improves clearance
of pulmonary fluid, reducing the risk of neonatal respiratory
morbidities and the need for resuscitation [26], while the
underlying condition that prompted delivery may also account for poorer
outcomes. Interestingly, expectantly managed pPROM had outcomes similar
to spontaneous LP labor, suggesting that prompt induction of labor may
not represent the only option available when rupture of membranes
complicates LP gestations, as also stated in the PPROMEXIL [14] and
PPROMEXIL2 [27] trials.
Our study also showed that an adverse intrauterine environment may
significantly contribute to neonatal morbidity. The association between
infection, inflammation and adverse neonatal outcomes may be explained
by the ability of pro-inflammatory cytokines to produce the “fetal
inflammatory response” [28]. Intrauterine inflammation has been
demonstrated in pregnancies complicated by preeclampsia [29],
maternal obesity [30], polyhydramnios [31], rupture of
membranes, and chorioamnionitis [32]. Diabetes mellitus not only
creates a pro-inflammatory intrauterine environment [33], but it
also accounts for the damaging effects of fetal hyperglycaemia and
hypoxia [34]. Accordingly, our multivariate analyses confirmed the
correlation between pregestational diabetes and increasing maternal BMI
with both the composite adverse neonatal outcome, and the need for
respiratory support, while polyhydramnios was linked to both the
composite adverse neonatal outcome and resuscitation at birth. We also
showed how pregestational diabetes relates to neonatal metabolic
complications, while pPROM was confirmed as a risk factor for the
composite of neonatal morbidities (Table 6). Surprisingly, preeclampsia
had a protective effect on neonatal complications (Table 6), suggesting
that the increased antepartum surveillance once preeclampsia is
diagnosed may counterbalance the risks associated with an adverse
intrauterine environment
Placental ischemia and hypoxia are characterized by impairment of
placental blood flow, which results in reduced delivery of oxygen and
nutrients to the fetus [35]. According to our multivariate analyses,
placental abruption or bleeding from abnormal placentation were
associated with the composite adverse neonatal outcome, with metabolic
acidosis and/or resuscitation at birth, and respiratory support as they
may compromise fetal supply of oxygen and nutrients to the fetus (Table
6). Similarly, increased metabolic demands may lead to non-reassuring
fetal status, that was also correlated with resuscitation at birth, the
composite metabolic outcome, and respiratory support (Table 6).
Insufficient intrauterine growth has been attributed to hypoxemia from
placental under perfusion [36, 37], and it was found to have
increased neonatal risks among preterm births [10, 11]. Our
multivariate analyses confirmed such finding also in the LP population,
since IUGR babies had more metabolic complications (Table 6).
It has been speculated that spontaneous onset of preterm labor may be a
consequence of an earlier idiopathic activation of the normal labor
process in an attempt to protect the fetus. Therefore, labor may enable
the fetus to exit a potentially “hostile” in-utero environment
[38]. Accordingly, our multivariate analysis showed a protective
effect of spontaneous preterm labor on the risk of developing the
composite metabolic outcome, as opposed to other maternal, fetal or
obstetric complications.
Strengths of this study include the large sample size and multicenter
nature of the cohort: both characteristics increase the generalizability
of our findings. The prospective design of the survey, along with
predefinition of standardized chart abstraction forms completed by
Obstetricians and Pediatricians, and periodically audited by research
associates, limit misclassification bias and assures data validity. We
acknowledge also some limitations. The study did not classify neonatal
complications according to specific obstetric, maternal or fetal
indications for delivery. We deliberately chose to analyze together the
outcomes of all indicated deliveries, as some disease processes such as
hypertensive disorders, diabetes mellitus or intraamniotic infections
may affect both mothers and babies. Moreover, we focused on specific
disorders, rather than delivery indications, as those may be indirectly
responsible for LP deliveries; for example, IUGR may account for
non-reassuring fetal status that prompts emergent delivery, or also
preeclampsia may cause placental abruption that then leads to delivery.
Although inconsistencies in antenatal corticosteroids administration may
reflect different opinion leaders’ viewpoints prior to the publication
of the ALPS trial, we considered bethamethasone treatment among the
potential confounders in our multivariate analyses.
In conclusion, gestational age at delivery, circumstances at
parturition, and specific maternal, fetal, as well as obstetric
complications have a significant impact on neonatal outcomes. Therefore,
the decision to deliver or not during LP period should be based on the
underlying conditions affecting the mother and/or the fetus, and a
careful assessment of the risks of preterm delivery versus the potential
benefits of expectant management should be performed. Our findings can
be helpful when counselling mothers at risk of LP delivery, and can be
used to plan interventions for their newborns.
DISCLOSURE OF INTERESTS : Each author declares to have no
conflicts of interest.
CONTRIBUTION TO AUTHORSHIP: each author contributed
significantly: FM and MB in writing paper and collecting data, GC in
statistical analysis and writing paper, GG, DB, AC in the conception of
the study and FF in scientific conception and principal investigator of
the study.
DETAILS OF ETHICS APPROVAL: The study was approved from the
Institution Review Board of the 9 Emilia Romagna Counties (n 24512 _
25/9/2014)
FOUNDING: The study was financed by the Emilia Romagna County
Grent (n 417149 _ 2014)
* Late Preterm Emilia Romagna Group: Vittorio Basevi
(Health facilities, Emilia-Romagna Region, Bologna, Italy), Frusca
Tiziana (Obstetrics and Gynaecology Unit, University of Parma, Parma,
Italy ), Giuseppe Battagliarin (Health facilities, Emilia-Romagna
Region, Bologna, Italy) , Marinella Lenzi (Maternal and Pediatrics
Department, Maggiore Hospital, Bologna, Italy)., Gina Ancora (Neonatal
Intensive Care Unit, Azienda Sanitaria Romagna, Infermi Hospital Rimini,
Rimini, Italy ), Luigi Corvaglia (Pediatric unit, Ospedale S.
Orsola- Malpighi di Bologna).
Acknowledgments: we are indebted to all collegues and research
fellows for their contributions to data collection: