P re t e r m L a b o r

Approach to Decreasing Complications of

Prematurity

Anna Locatelli, MDa, Sara Consonni, MD

a
,
Alessandro Ghidini, MDb,*

KEYWORDS
 Prematurity  Tocolysis  Antibiotics  Corticosteroids  In utero transfer
 Magnesium sulfate  Mode of delivery  Delayed cord clamping

KEY POINTS
 Implementation of certain obstetric practices in women in preterm labor can significantly
improve the prognosis for the premature neonate.
 Tocolytic agents can delay preterm birth for at least 2 days, thus allowing the administra-
tion of antenatal corticosteroid and in utero transfer to appropriate neonatal health care
settings; these two interventions reduce perinatal mortality.
 Antepartum administration of magnesium sulfate in preterm delivery reduces the risk of
cerebral palsy.
 In preterm birth, cesarean delivery offers survival advantage in nonvertex presentation.
 In preterm infants, delayed cord clamping is associated with a reduced risk of blood trans-
fusion, intraventricular hemorrhage, necrotizing enterocolitis, and mortality (<32 weeks).

INTRODUCTION

The rate of mortality and sequelae in preterm neonates has been decreasing over the
years worldwide. In great part, this is caused by improvements in neonatal care. How-
ever, the obstetricians also play a relevant role, as implementation of certain proce-
dures in women in preterm labor (PTL) can significantly affect the prognosis for the
premature neonate. The authors review the best-evaluated practices and, whenever
possible, assess them in terms of effect on clinically relevant outcomes (eg, neonatal
mortality or morbidity) rather than surrogate outcomes (eg, pregnancy prolongation).

The authors have nothing to disclose.

a
Department Obstetrics and Gynecology, University of Milano-Bicocca, Carate-Giussano,
Milano-Bicocca 20841, Italy; b Inova Alexandria Hospital, Alexandria, VA 22304, USA
* Corresponding author. Antenatal Testing Center, 4320 Seminary Road, Alexandria, VA 22304.
E-mail address: [email protected]

Obstet Gynecol Clin N Am - (2015) -–-

http://dx.doi.org/10.1016/j.ogc.2015.01.004 obgyn.theclinics.com
0889-8545/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
2 Locatelli et al

TOCOLYTICS

The pathophysiology leading to PTL is multifactorial, with initiating factors including

intrauterine infection, inflammation, ischemia, uterine overdistension, and hemor-
rhage. Contractions are not the starting point of most preterm births, as they are usu-
ally preceded by cervical ripening and decidual activation; this is important to
understand why therapy for PTL targeting only contractions has been modestly effec-
tive and it has not been shown to reduce the incidence of preterm birth.1
The methodology of many randomized clinical trials (RCTs) on tocolytics is limited
by the lack of sufficient numbers of patients enrolled and lack of comparison with a
placebo. Such limitations in the individual studies make it difficult to evaluate the effi-
cacy of classes of tocolytics using meta-analysis.
The current evidence suggests that tocolytic agents can delay preterm birth for at
least 2 days, thus allowing the administration of antenatal corticosteroid (ACS) and
in utero transfer to appropriate neonatal health care settings. There is no convincing
evidence that tocolytic agents improve substantive perinatal outcomes (such as rates
of perinatal death or neonatal morbidities associated with prematurity, like respiratory
distress syndrome or intraventricular hemorrhage) or provide long-term benefits
compared with no tocolytic therapy.
Several tocolytic agents can inhibit uterine contractility (Table 1).2–7 The decision as
to which tocolytic agent should be used as first-line therapy for an individual patient
should be based on multiple factors, including efficacy, gestational age, presence
of maternal comorbidities, and the frequency and severity of side effects.
Betamimetics, Cox inhibitors, and calcium channel blockers seem beneficial in delay-
ing birth for more than 48 hours when compared with no tocolytic treatment, whereas for
other tocolytics there is no evidence of benefit for pregnancy prolongation. Most toco-
lytics are associated with side effects that often depend on their class and mechanism of
action. Such side effects can be very frequent and serious, such as with betamimetics,
but they can be considerable also for calcium channel blockers, oxytocin receptor an-
tagonists, and nitric oxide donors. The Food and Drug Administration has issued a warn-
ing against prolonged maintenance tocolysis (beyond 48–72 hours) for betamimetics.
Some trials have compared different types of tocolytics among themselves. Table 2
displays the results of the meta-analyses of such trials.3–7

Type of Tocolytic
The best tocolytic should maximize safety and efficacy. Calcium channel blockers,
oxytocin receptor antagonists, and Cox inhibitors are all associated with fewer
maternal side effects compared with betamimetics and magnesium sulfate, which
have significantly higher rates of side effects requiring a change of medication. More-
over magnesium sulfate administered for longer than 5 to 7 days can lead to fetal and
neonatal bone demineralization and fractures; thus only short-term (usually <48 hours)
use of magnesium sulfate is advocated in obstetric care.8
In terms of pregnancy prolongation for at least 48 hours, it is highest with prosta-
glandin inhibitors compared with placebo (odds ratio [OR] 5.39), followed by calcium
channel blockers (OR 2.71) and the oxytocin receptor blocker atosiban (OR 2.02).9
In terms of reduction of neonatal morbidity, particularly respiratory distress syn-
drome, no class of tocolytic has been significantly superior to placebo, with the limi-
tation that larger studies were conducted at a time when steroids were not routinely
administered to patients.
Cox inhibitors and calcium channel blockers may, thus, be the best tocolytics in
terms of pregnancy prolongation, improvement of neonatal outcome, and risk of
 Table 1
Tocolytic drug versus placebo or no treatment

Drug Patients Pregnancy Outcomes Adverse Drug Reactions Neonatal Outcomes Source
Betamimetics vs placebo or 1367 Reduced risk of birth <48 h Palpitation, chest pain, No benefit Neilson et al,2 2014
no treatment (RR 0.68) headache, hyperglycemia,
No reduced risk of delivery hypokalemia, dyspnea,
<37 wk nausea or vomiting,
tremor, nasal stuffiness,
cessation of treatment
Calcium channel blocker vs 173 Reduced risk of birth <48 h Flushing, headache, and Not reported Flenady et al,3 2014
placebo or no treatment (RR 0.30) vertigo
No reduced risk of delivery
<37 wk
Cox inhibitors vs placebo or 36 Reduced risk of delivery Could not be adequately No benefit King et al,4 2005
no treatment <37 wk (RR 0.21) assessed because of

Obstetric Interventions in Preterm Labor

insufficient data
Magnesium sulfate vs 449 No differences for birth <48 h No significant differences for Borderline increased risk of Crowther et al,5 2014
placebo or no treatment maternal adverse events perinatal death (RR 4.56,
severe enough to stop 95% CI 1.00–20.9)
treatment
Oxytocin receptor 854 No reduced delivery <48 h Increased side effects No benefit Flenady et al,6 2014
antagonists vs placebo or requiring cessation of
no treatment treatment (RR 4.02)
Nitric oxide donors vs 336 No reduced delivery <48 h Increased adverse reactions No benefit Duckitt et al,7 2014
placebo or no treatment (RR 1.49) and headache (RR
1.95)

Abbreviations: CI, confidence interval; RR, relative risk.

Data from Refs.2–7

3
 4
Locatelli et al
Table 2
Comparisons among classes of tocolytics

Drug Patients Pregnancy Prolongation Adverse Drug Reactions Neonatal Outcomes Source
Calcium channel blockers 1926 Reduced birth <34 wk in the Lower risk of discontinued No differences for perinatal Flenady et al,3 2014
vs betamimetics calcium channel blockers treatment caused by side mortality
group (RR 0.78) effects (RR 0.22) and adverse Reduced RDS, necrotizing
Reduced birth <37 wk (RR 0.89) reactions in general (RR 0.36) enterocolitis, and IVH in the
in the calcium channel calcium channel blockers
blockers group group
Calcium channel blockers 226 No differences for preterm No difference in No differences for perinatal Flenady et al,3 2014
vs oxytocin receptor birth <28 or <34 wk or birth discontinuation of therapy mortality, serious infant
antagonists within 48 h because of side effects morbidity, or NICU admission
Women receiving atosiban had
increased rates of preterm
birth <37 wk (RR 1.56)
Calcium channel blockers 943 No differences in preterm birth Maternal side effects less No differences for perinatal Flenady et al,3 2014
vs magnesium sulfate <34 or 37 wk or birth within frequent for calcium channel mortality or infant morbidity
48 h blockers
Calcium blockers vs Cox 301 Reduced birth within 48 h in No differences in maternal No differences for mortality or Flenady et al,3 2014
inhibitors calcium blockers (RR 0.42) adverse drug reactions serious infant morbidity
Oxytocin receptor 1402 No differences for birth Atosiban: fewer adverse drug No differences for mortality or Flenady et al,6 2014
antagonists vs <28 wk, birth within 48 h reactions requiring cessation serious infant morbidity
betamimetics of treatment
 Cox inhibitors vs any 168 Reduced birth <37 wk (RR 0.53) Cox inhibitors: less risk of No differences in infant King et al,4 2005
other tocolytic adverse effects leading to mortality and morbidity but
treatment cessation or any insufficient data
adverse drug reaction
Magnesium sulfate 1375 No differences for preterm Magnesium was more likely to No differences in infant Crowther et al,5 2014
vs betamimetics birth <37 wk, birth within lead to treatment mortality and morbidity
48 h discontinuation than
betamimetics
Nitric oxide donors 691 No reduced preterm birth <32, Betamimetics were associated No differences in infant Duckitt et al,7 2014
vs betamimetics 34, 37 wk, birth within 24 with increased rates of side mortality and morbidity
and 48 h and 7 d effects: tachycardia, chest
pain, palpitations, shortness
of breath, and nausea

Abbreviations: IVH, intraventricular hemorrhage; NICU, neonatal intensive care unit; RDS, respiratory distress syndrome; RR, relative risk.
Data from Refs.3–7

Obstetric Interventions in Preterm Labor

5
6 Locatelli et al

maternal side effects. In patients at less than 32 weeks’ gestation, indomethacin may
be a reasonable first choice based on its efficacy, ease of administration, and minimal
side effects. At 32 to 34 weeks, nifedipine may be a reasonable first choice because it
does not carry the risks of oligohydramnios and premature closure of ductus arterio-
sus observed with indomethacin.
The use of maintenance therapy with a tocolytic agent following an initial treatment
of threatened PTL is not recommended. The use of a combination of tocolytic agents
for delaying preterm birth is not recommended.
Optimal Dosage
Little evidence is available on the optimal dosage. For calcium channel blockers, one
small study compared 20 mg/L repeated in 30 minutes followed by 120 to 160 mg
slow-release nifedipine daily for 48 hours versus lower doses (10 mg repeated every
15 minutes for a maximum of 4 doses, followed by 60–80 mg slow release daily for
48 hours). There were no significant differences between groups for birth within
48 hours, before 28, 34, or 37 weeks, in mean interval from trial entry to delivery,
maternal side effects, perinatal mortality, and morbidity.10

ANTIBIOTICS

Given the known association of PTL with increased frequency of subclinical intra-
amniotic infection, several RCTs have evaluated the benefit of antibiotics in PTL. A va-
riety of antibiotics have been studied (including ampicillin or amoxicillin with or without
sulbactam or clavulanic acid; erythromycin, clindamycin, mezlocillin, ceftizoxime, or
metronidazole) for durations ranging from 3 to 10 days. Compared with placebo, there
is no clear neonatal benefit from prophylactic antibiotic treatment of PTL with intact
membranes. Evidence from a Cochrane systematic review of 14 RCTs involving more
than 7800 women with PTL and no clinical signs of infection revealed some maternal
benefit in terms of lower risk of infection but increased risk of neonatal death (Table 3).11
At 7 years of age, there was no significant difference between children whose
mothers had received antibiotics compared with those who received placebo with
respect to moderate or severe functional impairment (relative risk [RR] 1.07, 95%

Table 3
Antibiotics for PTL

Outcome Benefit (RR) Significance (95% CI)

Maternal infection 0.74 0.63–0.86
Birth within 48 h 1.04 0.89–1.23
Birth before 36 or 37 wk 0.98 0.92–1.05
Perinatal death 1.22 0.88–1.69
Stillbirth 0.73 0.43–1.26
Neonatal death 1.57 1.03–2.40
Infant death after 28 d 1.06 0.68–1.67
Infant respiratory distress syndrome 0.99 0.84–1.16
Necrotizing enterocolitis 1.06 0.64–1.73
Neonatal sepsis 0.86 0.64–1.16
Intraventricular hemorrhage 0.76 0.48–1.19

Abbreviations: CI, confidence interval; RR, relative risk.

Data from Flenady V, Hawley G, Stock OM, et al. Prophylactic antibiotics for inhibiting preterm
labour with intact membranes. Cochrane Database Syst Rev 2013;(12):CD000246.
 Obstetric Interventions in Preterm Labor 7

confidence interval [CI] 0.89–1.28).12 However, subgroup analysis showed that cere-
bral palsy (CP) was significantly more frequent among infants of women allocated to
macrolide and beta-lactam antibiotics combined compared with placebo (RR 2.83,
95% CI 1.02–7.0). Further, exposure to any macrolide antibiotics versus no macrolide
antibiotics increased neonatal death (RR 1.52, 95% CI 1.05–2.19) and CP (RR 1.90,
95% CI 1.20–3.01). Exposure to any beta-lactam antibiotics versus no beta-lactam
antibiotics resulted in more neonatal deaths (RR 1.51, 95% CI 1.06–2.15) and CP
(RR 1.67, 95% CI 1.06–2.61).
Taken together, the evidence of a reduction in maternal infection associated with
antibiotic prophylaxis in PTL comes at a cost of an increase in neonatal death and
poorer long-term outcomes in children.

Special Consideration
In women who are known to be group-B streptococcus (GBS) colonized, prophylaxis
with penicillin is recommended until imminent delivery is excluded; in women with un-
known GBS status, rectovaginal cultures are recommended at diagnosis of PTL and
GBS prophylaxis should be administered until culture results are available as well
as to known carriers. The recommended antibiotic is penicillin (5 million units intrave-
nously and then 2.5 million units every 4 hours or, if unavailable, ampicillin 2 g intrave-
nously and then 1 g every 4 hours). In the presence of allergy to penicillin, the
treatment should be based on sensitivity to erythromycin and clindamycin. Until sensi-
tivity results, vancomycin should be used for prophylaxis.

CORTICOSTEROIDS

A single course of ACS is recommended for PTL before 34 weeks. Such treatment de-
creases the risk of neonatal death by 31% (95% CI 19%–42%), of respiratory distress
syndrome by 34% (95% CI 27%–41%), of intraventricular hemorrhage by 46% (95%
CI 31%–57%), of necrotizing enterocolitis by 54% (95% CI 26%–71%), and of
neonatal infection in the first 48 hours by 44% (95% CI 15%–62%).13,14 As for long-
term outcomes, treatment was associated with a 51% reduction in developmental
delay in childhood (95% CI 0%–76%) and a trend toward a lower risk of CP (RR
0.60, 95% CI 0.34–1.03).13,14 ACS is safe and reduces the risk of adverse neonatal
outcomes for all types of preterm birth; it is beneficial even in the presence of cho-
rioamnionitis, where it has not been shown to increase potential harms, such as
neonatal sepsis.15
Both betamethasone (2 doses of 12 mg given intramuscularly 24 hours apart) and
dexamethasone (4 doses of 6 mg given intramuscularly 12 hours apart) have demon-
strated similar efficacy.

Gestational Ages
The benefits of ACS demonstrated in the trials included in the systematic review were
not consistent across all gestational ages because the sample sizes particularly at
the 2 extremes of prematurity were underpowered to detect differences in the out-
comes. The administration of ACS is recommended between 24 and 34 weeks’
gestation. However, under particular circumstances, it may be beneficial even at
23 weeks.16,17

Repeated Courses
Benefits of ACS therapy have been established for infants born between 24 hours and
7 days after treatment. Two different approaches have been evaluated for patients
8 Locatelli et al

undelivered after 7 days from the first course and who remain at increased risk for pre-
term delivery: (1) a single rescue dose or course if the risk of preterm birth represents
at more than 1 week from the first ACS course (A single course before 33 weeks when
administered at least 2 weeks after the first course is associated with reduced respi-
ratory and composite morbidity [RR 0.65, 95% CI 0.44–0.97])18 and (2) multiple
courses of ACS. The results of 10 RCTs on this topic, involving 4730 women and
5650 neonates, have been summarized recently in a Cochrane review.19 Treatment
of women who remained at risk of preterm birth 7 or more days after an initial course
of ACS with repeat doses compared with no repeat treatment reduced the risk of in-
fant respiratory distress syndrome (RR 0.83, 95% CI 0.75–0.91). In addition, serious
infant morbidity included a composite of death, respiratory distress syndrome, severe
intraventricular hemorrhage, periventricular leukomalacia, and necrotizing enteroco-
litis was reduced by repeat doses (RR 0.84, 95% CI 0.75–0.94). Treatment with repeat
doses was associated with a reduction in mean birth weight (mean difference
75.79 g, 95% CI 117.63 to 33.96). Four of the trials included reported data from
an early childhood follow-up. No statistically significant differences were seen for chil-
dren in the repeat corticosteroid group as compared to with controls. The authors in-
vestigators concluded that short-term benefits support the use of repeat dose(s) of
antenatal corticosteroids ACS for women who have received an initial course and
remain at risk for preterm birth 7 or more days later. However, there is no proof of
long-term benefit either. In addition, there are no data on overall health, neurodevelop-
ment, and cardiovascular and metabolic function later in childhood or in adulthood af-
ter exposure to repeat dose(s). Recently a gestational age–based decisional model
observed that at more than 29 weeks, there is a suggestion of more risk than benefit
for this policy.20

AMNIOCENTESIS

Since the original study by Miller and colleagues21 in 1980, amniocentesis has been
used in women with PTL to evaluate for the presence of microbial invasion of the am-
niotic cavity. Several large cohort studies have shown that the prevalence of positive
amniotic fluid cultures (including those for mycoplasma species) in patients with PTL
averages 12.7%, and it is inversely related to the gestational age at sampling and
directly related to the degree of cervical dilation.22 The microorganisms usually follow
an ascending route from the lower genital tract. While waiting for amniotic fluid culture
results, several fast screening tests have been proposed for the detection of intra-
amniotic infection: presence of microorganisms at a gram stain, white blood cell count
of 50 cells/mm3 or greater, and glucose level less than 14 mg/dL.22 Proteomic profiling
has also been proposed to predict intra-amniotic infection.23,24 However, clinical use
has been limited by lack of confirmation by enzyme-linked immunosorbent assay anal-
ysis for altered expression patterns; moreover, results cannot be combined because
of the heterogeneity in the type of sample and analytical platform.25
Because cultures may yield negative results despite the presence of intrauterine
infection (eg, if the inoculum size is small, the bacterium is fastidious to grow, patients
have been receiving antibiotics, or the infection is predominantly located within the
chorion rather than intra-amniotic), several cytokines have been proposed as surro-
gate markers of intra-amniotic infection. Such sterile intra-amniotic inflammation
carries increased risks of spontaneous prematurity and shorter interval to delivery.26
Moreover, adverse pregnancy and neonatal outcomes have been observed more
frequently in the presence of intrauterine inflammation, independently from bacterio-
logic culture results and gestational age.22,27,28
 Obstetric Interventions in Preterm Labor 9

Among patients in PTL, biomarkers for increased risk of preterm delivery have been
identified with proteomic profiling, transcriptomics, and metabolomics, both in amni-
otic fluid and maternal serum.29,30 Characterization of the identified compounds has
shown that different pathologic pathways are involved in PTL besides acute
inflammation.29

Benefits
Amniocentesis can establish whether an intrauterine infection is present and, thus,
assist the clinician in the counseling of patients, expediting delivery, initiation of guided
antibiotic therapy, and alerting the neonatologist to the increased risk of an infected or
compromised neonate. Such information may be particularly desired when PTL is
associated with uterine tenderness, elevated maternal white blood cell count, or fetal
tachycardia.

Risks
Although second trimester amniocentesis in women with PTL has not been shown to
increase the risk of preterm delivery, information gained by the procedure may lead to
a shortened interval to delivery without evidence of a benefit. Indeed there have been
no case control, cohort, or RCT studies in which amniocentesis results have been
used to guide the clinical management of patients with PTL. Of interest, among pre-
term infants, cord serum levels of interleukin-6, interleukin-8, interleukin-1 beta, tumor
necrosis factor alpha, and C-reactive protein were not independently predictive of
adverse newborn outcomes, CP, or neurodevelopmental delay at 2 years of age.31,32

TRANSFER TO APPROPRIATE FACILITY LEVEL

The only 2 interventions that have been able to reduce perinatal mortality in preterm
birth are antenatal administration of corticosteroids and maternal transfer to facilities
that provide the required level of specialized care. Neonatal outcomes of infants
requiring neonatal intensive care unit management are better for those transferred
in utero than those transferred as neonates, especially for preterm infants born at
less than 30 weeks’ gestation.33–36 Out-born infants are at significantly higher risk of
death (adjusted OR [aOR] 1.7), grade III or IV intraventricular hemorrhage (aOR 2.2),
patent ductus arteriosus (aOR 1.6), respiratory distress syndrome (aOR 4.8), and
nosocomial infection (aOR 2.5).37–39

Organization
In order to guarantee a reliable communication policy between referring hospitals, a
network of assistance, based on a 24-hour availability transport system, should be
established (Table 4). Each region should be responsible for developing transport
protocols for specific clinical situations. The creation of a transfer network allows
registering, by electronic databases, the requests for transport and how they are
managed, for purposes of quality audit, education and research programs, and
follow-up of clinical cases.40
All perinatal care providers must be familiar with the mechanisms for initiating trans-
port and verifying the ability of the receiving institution to provide the necessary care.
The reason for a maternal transport may be related to either the woman or the fetus or
both.
Communication between the referring physician and the accepting physician before
transport is essential to the provision effective care. Indeed one of the main causes of
10 Locatelli et al

Table 4
Principles for a good transfer network

Principles Tools
Communications between professionals Electronic database, informatics tools, maternal
transfer form
24-h availability transport system Link to territorial emergency facilities
(ambulance or helicopter service)
Transport protocols Clinical guidelines shared between different
facilities
Good knowledge of transport system Meeting and audit of cases in the network
Continuum of care During transport an adequate level of assistance
must be maintained; close monitoring of vital
sign and clinical conditions
Back transport to referring hospital Good distribution of sanitary resources
when problems are resolved

substandard care in preterm delivery is lack of communication between professionals,

resulting in poor care management and adverse clinical outcomes.41
Contraindications to maternal transport include the following:
 The woman’s condition is insufficiently stable.
 The fetus’ condition is unstable or may deteriorate rapidly.
 The birth is imminent.
During interhospital transfer, a continuum of care with adequate level of assistance
must be maintained. The care of the woman during transport is the responsibility of the
referring institution, and both mother and fetus need to be monitored. Assessments
should include uterine activity, maternal vital signs, and fetal heart rate. A transfer
network usually also provides a return transport, namely, when a woman or her
neonate, after receiving intensive or specialized care at a referral center, is returned
to the original referring hospital for continuing care after the problems that required
the transfer have been resolved.

MAGNESIUM SULFATE

Prematurity is the leading risk factor for CP, which is the most common and costly
form of chronic motor disability in childhood. It has been reported that more than
30% of cases of CP occur in infants delivered at less than 32 weeks or weighing
less than 1500 g.42 Possible human benefit from administration of magnesium sulfate
was first shown in a case control study, which showed that children with CP were less
likely to have been exposed to magnesium sulfate than control subjects (OR 0.14;
95% CI 0.05–0.51).43 Subsequently, several RCTs have evaluated the efficacy of mag-
nesium sulfate for prevention of CP. Table 5 displays the characteristics of the studies
in which magnesium sulfate was administered for neuroprotection of the fetus.44–48
A meta-analysis of the findings concluded that magnesium sulfate significantly re-
duces the risk of any CP (RR 5 0.71, 95% CI 0.55–0.91), moderate or severe CP
(RR 5 0.64, 95% CI 0.44–0.92), as well as death or CP (RR 5 0.85, 95% CI 0.74–
0.98).44 There was significant homogeneity among the studies. All studies included twins.
In addition to the dose of magnesium sulfate and the gestational age at inclusion, the
RCTs differed for several inclusion criteria (such as clinical presentation: PTL, premature
rupture of membranes, chorioamnionitis, preeclampsia, or severe fetal growth restriction)
 Obstetric Interventions in Preterm Labor 11

Table 5
Characteristics of the RCTs on magnesium sulfate in preterm birth analyzed in reference to
occurrence of perinatal death or CP

Number Gestational Regimen of MgSO4: RR of CP or Perinatal

Study, Author, Year of Subjects Age Load/Maintenance Death (95% CI)
Mittendorf et al,45 2002 59 <34 wk 4 g then 2–3 g/h 4.83 (0.60–38.90)
Crowther et al,46 2003 1255 <30 wk 4 g then 1 g/h 0.82 (0.66–1.02)
Marret et al,47 2006 688 <33 wk 4 g then none 0.80 (0.58–1.10)
Rouse et al,48 2008 2444 <32 wk 6 g then 2 g/h 0.90 (0.73–1.10)
Overall — — — 0.85 (0.74–0.98)

Abbreviation: MgSO4, magnesium sulfate.

Data from Refs.45–48

and timing of magnesium administration before birth. (In the largest trial of Rouse and col-
leagues,48 women received magnesium as late as 20 minutes before delivery.)
It has been calculated that with the implementation of such prophylaxis in women at
risk for delivery at less than 32 weeks, only 63 women would need to be treated to pre-
vent one case of neonatal CP; the number would be higher if more inclusive criteria were
used (eg, gestational age <34 weeks), whereas it would be lower if a more strict gesta-
tional age cutoff was used (eg, <30 weeks).49 Magnesium sulfate administration did not
significantly affect the risk of adverse maternal outcome (in terms of death, cardiac
arrest or respiratory arrest, pulmonary edema, or severe postpartum hemorrhage).
Similar conclusions were reached by 2 other meta-analyses on the subject.50,51 Despite
such evident benefits, a 2013 study showed that only 40% of candidate patients receive
magnesium sulfate prophylaxis.52
The optimal treatment protocol (doses and duration) needed for maximal neuropro-
tection remains unknown. For practical purposes, each institution should develop a
specific magnesium sulfate protocol, specifying inclusion criteria, treatment regimens,
concurrent tocolysis, and monitoring.8 Box 1 displays the protocol used in the largest
of the randomized trials.48 In the absence of evidence for an optimal dose of magne-
sium sulfate, and the borderline increased risk of perinatal death associated with mag-
nesium sulfate when used for tocolysis (RR 4.56, 95% CI 1.00–20.9),5 other societies
(Society of Obstetricians and Gynecologists of Canada [SOCG] and National Health
and Medical Research Council of Australia [NHMRC])49,53 suggest adopting the min-
imum dosage used in the published trials and when delivery seems imminent at less
than 30 weeks.53 Although the maternal serum concentration of magnesium is
affected by maternal weight and the presence of multiple gestations and cord blood
levels are inversely related to birth weight centile, it is unclear whether a correlation
exists between the maternal serum level and a neuroprotective effect. Because it is
unclear whether the duration of infusion and neonatal serum magnesium levels are
associated with the risk of death,54,55 it may be equally prudent to administer magne-
sium sulfate for the shortest duration.

MODE OF DELIVERY

When assessing the evidence from the literature for the optimal mode of delivery in
prematurity, in terms of reduction of neonatal mortality and severe morbidity, several
variables need to be taken into account, such as fetal presentation, indication for pre-
term birth (eg, PTL, severe fetal growth restriction, or preeclampsia), the initially
intended route of delivery, and the fetal status on admission.
12 Locatelli et al

Box 1
Protocol for magnesium sulfate in neuroprophylaxis used in the RCT of Rouse and colleagues

Inclusion criteria
 Gestational age 24.0 to 31.6 weeks
 High risk for PTD within 2 hours caused by any indication (eg, PTL 4 cm dilation)
Exclusion criteria
 Active labor at greater than 8 cm dilation
 Major fetal anomalies
 Maternal contraindications to magnesium sulfate (pulmonary hypertension, myasthenia
gravis, class II–IV cardiac disease, severe acute pulmonary disease, and renal insufficiency)
Management
 Discontinue any tocolysis.
 Use magnesium 6-g load over 20 to 30 minutes, followed by 2 g/h.
 Maximum duration of treatment is 12 hours.
 Discontinue magnesium if delivery is no longer considered imminent.
 Restart magnesium if delivery is deemed imminent again (reload if magnesium is
discontinued >6 hours prior).
 Serum magnesium levels are not required.

Data from Rouse DJ, Hirtz DG, Thom E, et al. A randomized controlled trial of magnesium sul-
fate for the prevention of cerebral palsy. N Engl J Med 2008;359:895–905.

Fetal Growth Restriction

The issue has not been adequately studied, and the results are often contradictory. In
a population of small-for-gestational-age (SGA) neonates born at 26 to 31 weeks,
those delivered by cesarean section had increased survival rates; the benefit disap-
peared for SGA neonates born at greater than 33 weeks.56 The survival advantage
for SGA neonates at gestational ages of 26 to 31 weeks persisted after adjustment
for sociodemographic and medical factors.
More recently, in 2885 cephalic SGA live-born neonates delivered between 25 and
34 weeks of gestation, cesarean delivery was not associated with improved neonatal
outcomes in terms of intraventricular hemorrhage, subdural hemorrhage, seizures, or
sepsis and was associated with an increased risk of respiratory distress syndrome af-
ter adjusting for confounders.57
It should be noted that studies originating from the pediatric literature use SGA as
surrogate for fetal growth restriction. The features of fetal heart rate monitoring differ
in the preterm fetus from the term fetus, making interpretation difficult during labor.
Physiologic reserves available to combat hypoxia are less in a preterm fetus than
those available to a term fetus, and even more so for a growth restricted fetus, so
that a preterm fetus may suffer a hypoxic insult sooner.
It is commonly accepted that cesarean section offers survival advantage to a fetus
so severely growth restricted as to require elective preterm delivery (particularly at
<34 weeks) regardless of fetal presentation.58 Vaginal delivery should be considered
for the growth-restricted fetus when the woman is in labor. Induction of labor may also
be possible under continuous fetal heart rate monitoring, in favorable obstetric situa-
tions and in the absence of severe fetal hemodynamic disturbances.59
 Obstetric Interventions in Preterm Labor 13

Breech Presentation
From randomized studies there is insufficient evidence to recommend one mode of de-
livery over the other; however, the small number of women recruited limits the statistical
power even of meta-analysis. A Cochrane systematic review of 4 RCTs (involving 116
women) in singleton pregnancies and refractory PTL at less than 37 weeks compared
immediate caesarean versus planned vaginal birth. All trials were stopped early
because of difficulties with recruitment. Women with breech presentation were more
likely to experience major postpartum complications in the planned cesarean delivery
group (RR 7.21, 95% CI 1.37–38.08). There was a trend for lower perinatal mortality
with cesarean delivery (RR 0.29, 95% CI 0.07–1.14) across all gestational ages (be-
tween 26 and 32 weeks: RR 0.50 [0.02, 10.34], 28–36 weeks: RR 0.22 [0.03, 1.73]).60
Evidence from cohort studies consistently suggests that cesarean delivery offers a
survival advantage in the presence of nonvertex presentation. A recent systematic re-
view and meta-analysis of nonrandomized studies assessed the association between
mode of delivery and neonatal mortality in women with preterm breech presentation
between 25 and 36 weeks and included 7 studies and 3557 women. The weighted
risk of neonatal mortality was 3.8% in the cesarean delivery group and 11.5% in the
vaginal delivery group (pooled RR 0.63, 95% CI 0.48–0.81), suggesting that cesarean
delivery significantly reduces neonatal mortality as compared with vaginal delivery.61
The largest and most recent data are derived from the National Institute of Child
Health and Human Development (NICHD)-sponsored Consortium on Safe Labor, in
which 2906 singleton pregnancies eligible for a vaginal delivery between 24 and
32 weeks were analyzed. Neonatal mortality in attempted vaginal delivery was
compared with planned cesarean delivery stratified by presentation. For breech pre-
sentation, neonatal mortality was increased at 24 0/7 to 27 6/7 weeks’ gestation
(25.2% vs 13.2%, P<.003) and at 28 0/7 to 31 6/7 weeks (6.0% vs 1.5%, P 5 .016).
Even at the lowest gestational ages (24.0–24.6 weeks), among breech presentations,
planned cesarean delivery was associated with a lower incidence of neonatal death
and asphyxia after controlling for other factors.62
At periviable gestational ages (<24 weeks), neonatal survival and neurodevelopmen-
tal disabilities among survivors vary greatly according to local protocols of perinatal
care in terms of tocolysis, antenatal steroids, neonatal resuscitation, and intensive
care support, among others.62 The individual effect of mode of delivery in such cases
is difficult to assess, and management should incorporate input from the family.63

Cephalic Presentation
In the largest cohort study to date (the NICHD-sponsored Consortium on Safe Labor)
on 20,231 singleton, live-born, cephalic neonates delivered between 24 and 34 weeks
of gestation (excluding congenital anomalies, operative vaginal deliveries, birth weight
<500 g, and fetal growth restriction), associations between method of delivery and
neonatal morbidities were estimated using logistic regression. After controlling for
maternal age, ethnicity, education, primary payer, prepregnancy weight, gestational
age, diabetes, and hypertension, cesarean delivery compared with vaginal delivery
was associated with increased odds of respiratory distress (aOR 1.74, 95% CI
1.61–1.89) and 5-minute Apgar score less than 7 (aOR 2.04, 95% CI 1.77–2.35).64
In the NICHD-sponsored Consortium on Safe Labor mentioned earlier for vertex
presentation, 79% attempted vaginal delivery and 84% were successful.62 There
was no difference in neonatal mortality, suggesting that attempted vaginal delivery
for vertex presentation has a high success rate and there is no difference in neonatal
mortality (unlike breech presentation).
14 Locatelli et al

Operative Vaginal Delivery

It is relatively contraindicated in preterm fetuses at less than 34 weeks. Data on vac-
uum extraction from Swedish national registers revealed that vacuum was used in
5.7% of the preterm deliveries and that intracranial hemorrhage (1.51%), extracranial
hemorrhage (0.64%), and brachial plexus injury (0.13%) were higher compared with
other modes of delivery.65

DELAYED CLAMPING OF UMBILICAL CORD

Timing of Cord Clamping
It is estimated that 25% to 60% of the total blood volume of the fetal-placental circu-
lation is stored in the placenta. Early clamping of the cord (within the first 5–10 seconds
of birth) results in a decrease to the neonate of 15 to 40 mL/kg of bodyweight.66 Three
quarters of the transfusion occurs in the first minute after birth.
Early cord clamping (clamping within the first 60 seconds from birth) was originally
thought to be important in the active management of the third stage of labor; but
because of the lack of evidence for it, the recommendation has been withdrawn in
some guidelines.67 Indeed, because delaying the clamping until the umbilical circula-
tion has ceased approximates the natural physiology, early cord clamping should be
considered the intervention and need for it should be demonstrated.
Delayed cord clamping leads to an expansion in intravascular volume that facilitates
the cardiopulmonary transition, and it reduces iron and hematopoietic stem cells loss.
Delayed cord clamping may not be desired in neonates at risk for polycythemia and
neonatal jaundice, such as severe preterm fetal growth restriction, maternal alloimmu-
nization, and macrosomia caused by maternal diabetes.
RCTs in both term and preterm infants have consistently demonstrated that delayed
clamping is associated with significant benefits (Table 6).68–70 In preterm infants,
delayed cord clamping reduces the need for inotropic medications and increases sys-
temic blood pressure. Delayed cord clamping also seems to be protective of motor
disability in male very-low-birth-weight infants.71 The optimal interval between cord
clamping and whether such an interval is gestational age related are unknown. Addi-
tional data will probably come from the ongoing Australian Placental Transfusion
Study, evaluating delayed cord clamping in neonates less than 30 weeks.

Table 6
Effects of delayed umbilical cord clamping from meta-analysis of RCTs

RR (95% CI)
Preterm
Need for blood transfusion 0.61 (0.46–0.81)
IVH (all grades) 0.59 (0.41–0.85)
NEC 0.62 (0.43–0.90)
Mortality (<32 wk) 0.42 (0.19–0.95)
Term
Jaundice requiring 1.59 (1.03–2.46)
phototherapy
Iron deficiency at 3–6 mo 0.56 (0.40–0.79)
Anemia 0.53 (0.40–0.70)

Abbreviations: IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis.

Data from Refs.68–70
 Obstetric Interventions in Preterm Labor 15

Currently the World Health Organization (WHO) recommends delaying cord clamp-
ing for 1 to 3 minutes after birth with the infant held at or below the level of the
placenta.72 The American College of Obstetricians and Gynecologists’ recommenda-
tions support delaying clamping in preterm neonates for 30 to 60 seconds after deliv-
ery.73 Contraindications to delayed cord clamping are infants requiring immediate
evaluation and resuscitation for nonreassuring status, in the presence of placental ab-
normalities (such as at cesarean sections done for placenta previa, vasa previa, or
placental abruption), thick meconium-stained amniotic fluid, the presence of severe
congenital anomalies, multiple pregnancy, severe fetal growth restriction with absent
or reversed-end-diastolic flow in the umbilical artery at prenatal Doppler ultrasound,
alloimmunization, and unstable maternal status.

Concerns
Implementation of delayed cord clamping has been sporadic, with most UK obstetri-
cians clamping the cord within 20 seconds of birth both at term and preterm.
Several concerns have been raised, including
 Risk for hypothermia: Such risk can be avoided by putting the neonate immedi-
ately skin to skin on the maternal abdomen during delayed cord clamping and
covering him with a warm blanket. Raising the neonate above the vaginal level
is, however, contrary to the WHO’s recommendations, as it could lead to
baby-to-placenta transfusion. A recent trial has provided some reassurance,
showing that in term neonates after vaginal delivery, gravity does not have an
effect on the volume of placental transfusion.66 Whether this also applies to pre-
term infants or those delivered by cesarean section is unknown.
 Delayed neonatal resuscitation: It is commonly perceived that early cord clamp-
ing is needed in infants who require immediate neonatal resuscitation, particu-
larly those born extremely preterm or by cesarean section. A new strategy
proposed is to milk the umbilical cord (3 times over a duration of <30 seconds);
such a strategy achieves significant improvement in hemodynamic stability
through 24 hours of age, higher hematocrit, lower need for transfusion, and over-
all improved outcome compared with a historic untreated cohort.74 Alternatively,
resuscitation of the compromised newborn can be initiated at the side of the
mother with the umbilical cord intact.
 Cord blood gas analysis: The timing of cord clamping could affect the interpre-
tation of cord blood gases; only a few small studies have addressed the issue,
and the results are partly contradictory. Recently Di Tommaso and colleagues75
reported that, in term neonates, blood gas analysis may be performed in the un-
clamped cord after birth without reducing the accuracy of the analysis.
 Uterotonic administration: There are no studies evaluating the transfusion of
oxytocic drugs through the placenta and no reported evidence of any harmful ef-
fects on the baby.76 Uterotonic agents following birth and before cord clamping
increase the rate of placental transfusion and enhance the effect of delayed
clamping.
In summary, the practice of delayed cord clamping can be easily adopted for most
preterm and term vaginal deliveries.

SUMMARY

The aforementioned obstetric practices in women with PTL have the potential to
contribute substantially to decreasing neonatal morbidities. The evidence in support
16 Locatelli et al

of most practices is quite strong. Each institution should prepare specific protocols of
care and conduct periodic audits to verify their consistent implementation.

REFERENCES

1. Iams JD, Berghella V. Care for women with prior preterm birth. Am J Obstet Gy-
necol 2010;203:89–100.
2. Neilson JP, West HM, Dowswell T. Betamimetics for inhibiting preterm labour. Co-
chrane Database Syst Rev 2014;(2):CD004352.
3. Flenady V, Wojcieszek AM, Papatsonis DN, et al. Calcium channel blockers for inhib-
iting preterm labour and birth. Cochrane Database Syst Rev 2014;(6):CD002255.
4. King JF, Flenady V, Cole S, et al. Cyclo-oxygenase (COX) inhibitors for treating
preterm labour. Cochrane Database Syst Rev 2005;(2):CD001992.
5. Crowther CA, Brown J, McKinlay CJ, et al. Magnesium sulphate for preventing
preterm birth in threatened preterm labour. Cochrane Database Syst Rev
2014;(8):CD001060.
6. Flenady V, Reinebrant HE, Liley HG, et al. Oxytocin receptor antagonists for inhib-
iting preterm labour. Cochrane Database Syst Rev 2014;(6):CD004452.
7. Duckitt K, Thornton S, O’Donovan OP, et al. Nitric oxide donors for treating pre-
term labour. Cochrane Database Syst Rev 2014;(5):CD002860.
8. American College of Obstetricians and Gynecologists. Magnesium sulfate use in
obstetrics. Committee opinion No. 573. Obstet Gynecol 2013;122:727–8.
9. Haas DM, Caldwell DM, Kirkpatrick P, et al. Tocolytic therapy for preterm delivery:
systematic review and network meta-analysis. BMJ 2012;345:e6226.
10. Nassar AH, Abu-Musa AA, Awwad J, et al. Two dose regimens of nifedipine for
management of preterm labor: a randomized controlled trial. Am J Perinatol
2009;26:575–81.
11. Flenady V, Hawley G, Stock OM, et al. Prophylactic antibiotics for inhibiting pre-
term labour with intact membranes. Cochrane Database Syst Rev 2013;(12):
CD000246.
12. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of an-
tibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of
the ORACLE II trial. Lancet 2008;372:1319–27.
13. Crowley P. Prophylactic corticosteroids for preterm birth. Cochrane Database
Syst Rev 2000;(2):CD000065.
14. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung matura-
tion for women at risk of preterm birth. Cochrane Database Syst Rev 2006;(3):
CD004454.
15. Been J, Degraeuwe P, Kramer B, et al. Antenatal steroids and neonatal outcome
after chorioamnionitis: a meta-analysis. BJOG 2011;118:113–22.
16. Hayes EJ, Paul DA, Stahl GE, et al. Effect of antenatal corticosteroids on survival
for neonates born at 23 weeks of gestation. Obstet Gynecol 2008;111:921–6.
17. RCOG. Antenatal corticosteroids to reduce neonatal morbidity (Green-top 7).
2010; Available at: https://www.rcog.org.uk/globalassets/documents/guidelines/
gtg_7.pdf. Accessed February 10, 2015.
18. Garite TJ, Kurtzman J, Maurel K, et al. Impact of a ‘rescue course’ of antenatal
corticosteroids: a multicenter randomized, placebo-controlled trial. Am J Obstet
Gynecol 2009;200:248.e1–9.
19. McKinlay CJ, Crowther CA, Middleton P, et al. Repeat antenatal glucocorticoids
for women at risk of preterm birth: a Cochrane Systematic Review. Am J Obstet
Gynecol 2012;206:187–94.
 Obstetric Interventions in Preterm Labor 17

20. Zephyrin LC, Hong KN, Wapner RJ, et al. Gestational age-specific risks vs ben-
efits of multicourse antenatal corticosteroids for preterm labor. Am J Obstet Gy-
necol 2013;209:330.e1–7.
21. Miller J, Pupkin M, Hill G. Bacterial colonization of amniotic fluid from intact fetal
membranes. Am J Obstet Gynecol 1980;136:796–804.
22. Gomez R, Romero R, Mazor M, et al. The role of infection in preterm labor and
delivery. In: Elder MG, Lamont RF, Romero R, editors. Preterm labor. New York:
Churchill Livinstone; 1997. p. 85–125.
23. Cobo T, Palacio M, Navarro-Sastre A, et al. Predictive value of combined amniotic
fluid proteomic biomarkers and interleukin6 in preterm labor with intact mem-
branes. Am J Obstet Gynecol 2009;200:499.e1–6.
24. Buhimschi CS, Buhimschi IA, Abdel-Razeq S, et al. Proteomic profiling of intra-
amniotic inflammation: relationship with funisitis and early-onset sepsis in the pre-
mature neonate. Pediatr Res 2007;61:318–24.
25. Kacerovsky M, Lenco J, Musilova I, et al. Proteomic biomarkers for spontaneous
preterm birth: a systematic review of the literature. Reprod Sci 2014;21:283–95.
26. Romero R, Miranda J, Chaiworapongsa T, et al. Sterile intra-amniotic inflammation
in asymptomatic patients with a sonographic short cervix: prevalence and clinical
significance. J Matern Fetal Neonatal Med 2014. [Epub ahead of print].
27. Lee SE, Romero R, Jung H, et al. The intensity of the fetal inflammatory response
in intra-amniotic inflammation with and without microbial invasion of the amniotic
cavity. Am J Obstet Gynecol 2007;197:294.e1–6.
28. Lee J, Oh KJ, Yang HJ, et al. The importance of intra-amniotic inflammation in the
subsequent development of atypical chronic lung disease. J Matern Fetal
Neonatal Med 2009;22:917–23.
29. Pereira L, Reddy AP, Alexander AL, et al. Insights into the multifactorial nature of
preterm birth: proteomic profiling of the maternal serum glycoproteome and
maternal serum peptidome among women in preterm labor. Am J Obstet Gynecol
2010;202:555.e1–10.
30. Romero R, Mazaki-Tovi S, Vaisbuch E, et al. Metabolomics in premature labor: a
novel approach to identify patients at risk for preterm delivery. J Matern Fetal
Neonatal Med 2010;23:1344–59.
31. Varner MW, Marshall NE, Rouse DJ, et al. The association of cord serum cyto-
kines with neurodevelopmental outcomes. Am J Perinatol 2015;30:115–22.
32. Sorokin Y, Romero R, Mele L, et al. Umbilical cord serum interleukin-6, C-reactive
protein, and myeloperoxidase concentrations at birth and association with
neonatal morbidities and long-term neurodevelopmental outcomes. Am J Perina-
tol 2014;31:717–26.
33. Lee SK, McMillan DD, Ohlsson A, et al. The benefit of preterm birth at tertiary care
centers is related to gestational age. Am J Obstet Gynecol 2003;188:617–22.
34. Shlossman PA, Manley JS, Sciscione AC, et al. An analysis of neonatal morbidity
and mortality in maternal (in utero) and neonatal transports at 24–34 weeks’
gestation. Am J Perinatol 1997;14:449–56.
35. Chung JH, Phibbs CS, Boscardin WJ, et al. Examining the effect of hospital-level
factors on mortality of very low birth weight infants using multilevel modeling.
J Perinatol 2011;31:770–5.
36. Doyle LW, Bowman E, Callanan C, et al. Changing outcome for infants of birth-
weight 500–999 g born outside level 3 centres in Victoria. Aust N Z J Obstet Gy-
naecol 1997;37:253–7.
37. Chien LY, Whyte R, Aziz K, et al. Improved outcome of preterm infants when deliv-
ered in tertiary care centers. Obstet Gynecol 2001;98:247–52.
18 Locatelli et al

38. Towers CV, Bonebrake R, Padilla G, et al. The effect of transport on the rate of
severe intraventricular hemorrhage in very low birth weight infants. Obstet Gyne-
col 2000;95:291–5.
39. Lorch SA, Baiocchi M, Ahlberg CE, et al. The differential impact of delivery hos-
pital on the outcomes of premature infants. Pediatrics 2012;130:270–8.
40. Health Canada. Family-centred maternity and newborn care: national guidelines.
Ottawa (Canada): Minister of Public Works and Government Services; 2000.
41. Cantwell R, Clutton-Brock T, Cooper G, et al. Saving Mothers’ Lives: reviewing
maternal deaths to make motherhood safer: 2006-2008. The Eighth Report of
the Confidential Enquiries into Maternal Deaths in the United Kingdom. BJOG
2011;118(Suppl 1):1–203.
42. Drummond PM, Colver AF. Analysis by gestational age of cerebral palsy in
singleton births in north-east England 1970-94. Paediatr Perinat Epidemiol
2002;16:172–80.
43. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy
in very low birthweight infants? Pediatrics 1995;95:263–9.
44. Doyle LW, Crowther CA, Middleton P, et al. Antenatal magnesium sulfate and
neurologic outcome in preterm infants: a systematic review. Obstet Gynecol
2009;113:1327–33.
45. Mittendorf R, Dambrosia J, Pryde PG, et al. Association between the use of ante-
natal magnesium sulfate in preterm labor and adverse health outcomes in infants.
Am J Obstet Gynecol 2002;186:1111–8.
46. Crowther CA, Hiller JE, Doyle LW, et al. Effect of magnesium sulfate given for neu-
roprotection before preterm birth: a randomized controlled trial. JAMA 2003;290:
2669–76.
47. Marret S, Marpeau L, Zupan-Simunek V, et al. Magnesium sulfate given before
very-preterm birth to protect infant brain: the randomized controlled PREMAG
trial. BJOG 2007;114:310–8.
48. Rouse DJ, Hirtz DG, Thom E, et al. A randomized controlled trial of magnesium
sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359:895–905.
49. Magee L, Sawchuck D, Synnes A, et al. SOGC clinical practice guideline. Magne-
sium sulphate for fetal neuroprotection. J Obstet Gynaecol Can 2011;33:516–29.
50. Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of
cerebral palsy in preterm infants less than 34 weeks’ gestation: a systematic re-
view and meta-analysis. Am J Obstet Gynecol 2009;200:595–609.
51. Costantine MM, Weiner SJ, Eunice Kennedy Shriver National Institute of Child
Health and Human Development Maternal-Fetal Medicine Units Network. Effects
of antenatal exposure to magnesium sulfate on neuroprotection and mortality in
preterm infants: a meta-analysis. Obstet Gynecol 2009;114:354–64.
52. Gibbins KJ, Browning KR, Lopes W, et al. Evaluation of the clinical use of mag-
nesium sulfate for cerebral palsy prevention. Obstet Gynecol 2013;121:235–40.
53. Australian Government National Health and Medical Research Council. Antenatal
magnesium sulphate prior to preterm birth for neuroprotection of the fetus, infant
and child. National clinical practice guidelines. Available at: http://www.nhmrc.
gov.au/_files_nhmrc/publications/attachments/cp128_mag_sulphate_child.pdf.
54. McPherson JA, Rouse DJ, Grobman WA, et al. Association of duration of neuro-
protective magnesium sulfate infusion with neonatal and maternal outcomes. Ob-
stet Gynecol 2014;124:749–55.
55. Basu SK, Chickajajur V, Lopez V, et al. Immediate clinical outcomes in preterm
neonates receiving antenatal magnesium for neuroprotection. J Perinat Med
2011;40:185–9.
 Obstetric Interventions in Preterm Labor 19

56. Lee HC, Gould JB. Survival rates and mode of delivery for vertex preterm neo-
nates according to small- or appropriate- for-gestational-age status. Pediatrics
2006;118:e1836–44.
57. Werner EF, Savitz DA, Janevic TM, et al. Mode of delivery and neonatal out-
comes in preterm, small for gestational age newborns. Obstet Gynecol 2012;
120:560–4.
58. Mercer BM. Mode of delivery for periviable birth. Semin Perinatol 2013;37:
417–21.
59. Perrotin F, Simon EG, Potin J, et al. Delivery of the IUGR fetus. J Gynecol Obstet
Biol Reprod (Paris) 2013;42:975–84.
60. Alfirevic Z, Milan SJ, Livio S. Caesarean section versus vaginal delivery for pre-
term birth in singletons. Cochrane Database Syst Rev 2013;(9):CD000078.
61. Bergenhenegouwen LA, Meertens LJ, Schaaf J, et al. Vaginal delivery versus
caesarean section in preterm breech delivery: a systematic review. Eur J Obstet
Gynecol Reprod Biol 2014;172:1–6.
62. Reddy UM, Zhang J, Sun L, et al. Neonatal mortality by attempted route of deliv-
ery in early preterm birth. Am J Obstet Gynecol 2012;207:117.e1–8.
63. Raju TN, Mercer BM, Burchfield DJ, et al. Periviable birth: executive summary of a
joint workshop by the Eunice Kennedy Shriver National Institute of Child Health
and Human Development, Society for Maternal-Fetal Medicine, American Acad-
emy of Pediatrics, and American College of Obstetricians and Gynecologists.
Obstet Gynecol 2014;123:1083–96.
64. Werner EF, Han CS, Savitz DA, et al. Health outcomes for vaginal compared with
cesarean delivery of appropriately grown preterm neonates. Obstet Gynecol
2013;121:1195–2000.
65. Aberg K, Norman M, Ekeus C. Preterm birth by vacuum extraction and neonatal
outcome: a population-based cohort study. BMC Pregnancy Childbirth 2014;
22(14):42.
66. Vain NE, Satragno DS, Gorenstein AN, et al. Effect of gravity on volume of
placental transfusion: a multicentre, randomized, non-inferiority trial. Lancet
2014;384:235–40.
67. Ceriani Cernadas JM, Carroli G, Pellegrini L, et al. The effect of timing of cord
clamping on neonatal venous hematocrit values and clinical outcome at term: a
randomized, controlled trial. Pediatrics 2006;117(4):e779–86.
68. Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term
neonates: systematic review and meta-analysis of controlled trials. JAMA 2007;
21(297):1241–52.
69. Rabe H, Diaz-Rossello JL, Duley L, et al. Effect of timing of umbilical cord clamp-
ing and other strategies to influence placental transfusion at preterm birth on
maternal and infant outcomes. Cochrane Database Syst Rev 2012;(8):CD003248.
70. Backes CH, Rivera BK, Haque U, et al. Placental transfusion strategies in very
preterm neonates: a systematic review and meta-analysis. Obstet Gynecol
2014;124:47–56.
71. Mercer JS, Vohr BR, Erickson-Owens DA, et al. Seven-month developmental out-
comes of very low birth weight infants enrolled in a randomized controlled trial of
delayed versus immediate cord clamping. J Perinatol 2010;30:11–6.
72. World Health Organization. Guidelines on basic newborn resuscitation. Geneva
(Switzerland): World Health Organization; 2012.
73. American College of Obstetricians and Gynecologists. Timing of umbilical cord
clamping after birth. Committee opinion no. 543. Obstet Gynecol 2012;120:
1522–6.
20 Locatelli et al

74. Patel S, Clark EA, Rodriguez CE, et al. Effect of umbilical cord milking on
morbidity and survival in extremely low gestational age neonates. Am J Obstet
Gynecol 2014;211:519.e1–7.
75. Di Tommaso M, Seravalli V, Martini I, et al. Blood gas values in clamped and un-
clamped umbilical cord at birth. Early Hum Dev 2014;90:523–5.
76. Soltani H, Hutchon DR, Poulose TA. Timing of prophylactic uterotonics for the
third stage of labour after vaginal birth. Cochrane Database Syst Rev
2010;(8):CD006173.