Preterm PROM

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Preterm Premature Rupture ofMembranes: Clinical Outcomes

of Late-Preterm Infants

Julio Mateus, MD,1 Karin Fox, MD,1 Sangeeta Jain, MD,1

Sunil Jain, MD,2 Richard Latta, MD,3 and Jerry Cohen, MPH3

Abstract

Objective:To determine gestational age-specific neonatal outcomes of late preterm infants delivered as a consequenceof premature rupture of membranes (PROM).Methods:Retrospective cohort study of infants born to women deliveredelectively due to preterm PROM between 340/7 and 366/7 weeks of gestation. Neonatal outcomes were compared

between those delivered at 340/7 to 346/7 weeks, at 350/7 to 356/7 weeks, and at 360/7 to 366/7 weeks. Results:192 infantswere identified. The 340/7 to 346/7 week infants had significantly higher neonatal intensive care admission rate (72.5%)compared to those at 350/7 to 356/7 weeks (22.8%) and at 36 to 366/7 weeks (17.8%) (P< .05). Neonatal respiratorydistress syndrome was significantly higher at 340/7 to 346/7 weeks (35.4%) compared with 350/7 to 356/7 week and 360/7 to366/7 week infants (10.5% and 4.1%; P < .05). The longest hospitalization occurred in the 340/7 to 346/7 week infants (248.5 20.0 hours). Conclusion:Substantial short-term morbidity occurred in late preterm infants. The greatest number ofcomplications affected infants born at 340/7 to 346/7 weeks.

Keywords

late-preterm infants, preterm premature rupture of membranes, respiratory distress syndrome, neonatal morbidity

Introduction

Preterm delivery occurred in 12.8% of all births in the

United States in 20061 and is a major factor contributing

to perinatal morbidity and mortality. The rate of preterm

birth has increased by 20% since 1990.1 The majority of

this rise is attributable to births between 340/7 and 366/7

weeks.1,2 Preterm premature rupture of the membranes

(PROM), defined as rupture of membranes before 37

weeks of gestation, is responsible for one third of all pre-

term births and affects approximately 120 000 pregnanciesin the United States each year.3

One of the most debated issues in the management of

preterm PROM is the optimal gestational age of delivery.

Three previous randomized studies compared expectant

management with immediate induction of preterm PROM

at 30 to 34 weeks,4 32 to 36 weeks,5 and 34 to 37 weeks.6

All reached the conclusion that facilitated delivery can

avoid serious perinatal infectious morbidity and mortality

without increasing the risk for neonatal complications

associated with prematurity. However, these data are

limited by the small sample size, the lack of adjunctive

antibiotics to prolong latency, and differences in the inclu-

sion criteria among the trials. Furthermore, the studied

gestational age interval varied in all three, which precludes

us from making a definite conclusion about the optimal

timing to deliver preterm PROM pregnancies.

The American College of Obstetricians and Gyneco-

logists in its latest practice bulletin3 recommends delivery

of preterm PROM at 32 to 33 completed weeks, with

positive fetal lung maturity testing, or at 340/7 weeks.

Similarly, a recent cohort study suggests that prolongation

of preterm PROM beyond 34 weeks has limited benefits.

7

Based on available data, numerous health care centers in

Clinical Pediatrics

49(1) 6065 The Author(s) 2010

Reprints and permission: http://www.sagepub.com/journalsPermissions.nav

DOI: 10.1177/0009922809342460http://clp.sagepub.com

1Department of Obstetrics and Gynecology, University of Texas

Medical Branch, Galveston, TX, USA2Department of Pediatric Neonatology, University of Texas Medical

Branch, Galveston, TX, USA3Department of Obstetrics and Gynecology, Abington Memorial

Hospital , Abington, PA, USA

Corresponding Author:

Julio Mateus, 3.400 John Sealy Annex, 301 University Boulevard,

Galveston, TX 77555-0587, USA

Email: [email protected]


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Mateus et al 61

the United States intentionally deliver preterm PROM at

340/7 weeks. This current obstetrical practice might be a

major contributor to the recent rise in the birth rate of

infants born between 340/7 and 366/7 weeks in this country.

The occupancy of neonatal intensive care units (NICUs)

by this subset of preterm infants has been increasing,

which has given rise to major concerns in the pediatriccommunity responsible for taking care of newborns who

may be seemingly healthy but are at a higher risk than

term infants to develop several neonatal morbidities.8-10

Furthermore, the health costs and the public health impact

associated with this growing phenomenon are currently

unknown but can be enormous nationwide.

The National Institute of Child Health and Human

Development workshop, in 2005, recommended that late-

preterm infants be defined as infants born at 340/7 to 366/7

weeks and identified significant gaps in the knowledge

about this population, including etiological factors, clini-

cal care, and public health impact.2 We, as many otherinstitutions in the United Sates, intentionally delivered

preterm PROM pregnancies at 340/7 weeks. Our study

sought to determine gestational agespecific outcomes of

late-preterm infants electively delivered because of pre-

term PROM in 2 demographically diverse tertiary health

care centers.

Methods

With approval from the Abington Memorial Hospital

(AMH) and the University of Texas Medical Branch at

Galveston (UTMB) Institutional Review Boards, we con-ducted a retrospective cohort study of infants born to

mothers electively delivered secondary to preterm PROM

at 340/7 weeks of gestation in a 3-year period (2005-

2007). Patient identification was performed through

review of an International Classification of Diseases,

ninth revision, codes for preterm PROM. Inclusion crite-

rion was singleton gestation with clinical diagnosis of

preterm PROM at 340/7 weeks. Multifetal gestations,

major fetal anomalies, history of cervical cerclage in

present pregnancy, and outborn infants transferred to our

NICUs after delivery were excluded.

Rupture of membranes was diagnosed by a sterilespeculum exam with positive pooling, ferning, and phen-

aphthazine (nitrazine paper) testing. Cervical cultures

were obtained for Chlamydia trachomatis and Neisseria

gonorrhoeae. Delivery was expeditiously carried out in all

women. Mode of delivery was determined based on

obstetrical indications. Oxytocin was used for labor aug-

mentation in those who were candidates for vaginal

delivery. Women with unknown Group B Streptococcus

status were managed with penicillin G, 5 million units IV

initial dose, then 2.5 million units IV every 4 hours or

ampicillin, 2 g IV initial dose, then 1 g IV every 4 hours until

delivery.11 Women with known Group B Streptococcus

results were managed accordingly.

Major neonatal morbidities relevant to late-preterm

infants were investigated. The selected individual outcomeswere intraventricular hemorrhage (IVH), respiratory dis-

tress syndrome (RDS), necrotizing enterocolitis (NEC),

and neonatal congenital sepsis. RDS was defined as any of

the following: requirement of respiratory support for 24

hours, reticulogranular pattern on chest radiography, and

use of surfactant. Diagnosis of IVH was based on cranial

ultrasound and was classified as follows: grade I, germinal

matrix hemorrhage and/or IVH occupying 50% of the

ventricular area; and grade IV, parenchymal hemorrhage

evident in any location with or without IVH.12 NEC wasdiagnosed by the combination of abdominal distension,

hematochezia, and pneumatosis intestinalis. Congenital

sepsis was diagnosed by the presence of clinical signs

of infection and positive blood or cerebral spinal fluid

cultures during the first 5 days of life. All infants were

followed up till hospital discharge.

Neonatal minor morbidity was defined as the presence

of any of the following: hyperbilirubinemia or metabolic

disturbances (hyperglycemia or hypoglycemia, or hyper-

natremia or hyponatremia). Hyperbilirubinemia was

diagnosed in accordance with the published clinical

practice guidelines,13 and metabolic disturbances weredetermined based on glucose and electrolyte serum levels.

Outcome data were compared between neonates born

at 340/7 to 346/7 weeks, at 350/7 to 356/7 weeks, and at 360/7

to 366/7 weeks. All infants were followed up till hospital

discharge.

Statistical analyses to compare categorical values were

performed by the Pearson chi-square method, and ANOVA

was used to compare means. Continuous data are pre-

sented as mean SEM (standard error of the mean) unless

specified otherwise. A 2-sidedPvalue < .05 was consid-

ered statistically significant.

Figure 1. Population distribution by gestational age andinstitution.

0

510

15

20

25

30

35

40

45

34 0/7-34 6/7

(Weeks)

Frequency

AMH UTMB

36 0/7-36 6/735 0/7-35 6/7


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62 Clinical Pediatrics 49(1)

Results

During the study interval, 192 women with their respec-

tive infants met the eligibility criterion and had complete

maternal and neonatal medical record information required

for the analysis. We collected 107 cases (55.7%) from

AMH and 85 (44.3%) from UTMB. Population distri-

bution by gestational age at delivery and institution is

illustrated in Figure 1. Demographic data, including

maternal age, race distribution, and parity were not sig-

nificantly different between preterm PROM deliveries at340/7 to 346/7 weeks, at 350/7 to 356/7 weeks, and at 360/7 to

366/7 weeks (Table 1). Previous use of antenatal steroids

was not significantly different among the 3 study gesta-

tional ages at delivery (8/62 (8.0%) at 340/7-346/7 weeks,

6/57 (10.5%) at 350/7-356/7 weeks, and 4/73 (5.4%) at

360/7-366/7 weeks;P= NS). Latency was higher at 340/7 to

346/7 weeks than at 350/7 to 356/7 weeks and at 360/7 to 366/7

weeks, but the difference did not reach statistical signifi-

cance (42.8 16.8 hours, 18.4 9.5 hours, 19.0 3.9

hours, respectively). Mode of delivery did not vary among

the 3 gestational ages (Table 1).

Of the 192 infants, 80 were female (41.7%) and 112

were male (58.3%). Gender distribution, birth weight, and

APGAR scores did not vary significantly between the 3

gestational ages (Table 2). Admission rate to the NICU

was significantly higher in infants born at 340/7 to 346/7

weeks (72.5%) as compared with those born at 350/7 to

356/7 weeks and at 360/7 to 366/7 weeks (22.8% and 17.8%;

P< .05%; Table 2). Newborns at 340/7 to 346/7 weeks had

a 3-fold and 4-fold increase in the rate for NICU admis-

sion, as compared with those born at 350/7 to 356/7 weeks

and at 360/7 to 366/7 weeks (Table 3). The rate of admissionto the NICU was not significantly different between

infants born at 350/7 to 356/7 weeks and those born at 360/7

to 366/7 weeks (Table 3). Hospital stay was significantly

longer in those born at 340/7 to 346/7 weeks than in those

born at 350/7 weeks (Table 2; P< .05). Infant hospital

length of stay did not differ significantly between 350/7 to

356/7 and 360/7 to 360/7 weeks.

RDS was the most common major neonatal complica-

tion affecting 31/192 (16.1%) infants. RDS was diagnosed

in 35.4%, 10.5%, and 4.1% of neonates born at 340/7 to

346/7 weeks, at 350/7 to 356/7 weeks, and at 360/7 to 366/7

Table 1. Maternal Characteristics of 192 Preterm PROM Women Delivered Between 340/7 and 366/7 Weeks

Gestational Age at Delivery

340/7-346/7 350/7-356/7 360/7-366/7

Weeks, Weeks, Weeks,N = 62 N = 57 N = 73 PValue

Age range (years) 18-41 17-41 18-41 NSWhite 26 (41.9%) 27 (47.4%) 40 (54.7%) NSHispanic 23 (37.1%) 16 (28.1%) 19 (26.0%) NSBlack 8 (12.9%) 14 (24.5%) 11 (15.1%) NSAsian 1 (1.6%) 0 3 (4.1%) NSNulliparous 26 (41.9%) 34 (59.6%) 40 (64.5%) NSCesarean delivery 18 (29.1%) 12 (21.0%) 14 (20.5%) NS

PROM = premature rupture of the membranes.

Table 2. Characteristics of 192 Infants Born Between 340/7 and 366/7 Weeks

Gestational Age at Delivery

340/7-346/7 350/7-356/7 360/7-366/7

Weeks, Weeks, Weeks,N = 62 N = 57 N = 73 PValue

Females 28 (45.2%) 26 (45.6%) 26 (35.6%) NSMales 34 (54.8%) 31 (54.4%) 47 (64.4%) NSWeight (g), mean SEM 2498 40.1 2741 52.1 2860 54.3 NS5 minute APGAR 7 1 (1.6%) 2 (3.5%) 0 NSNICU admission 45 (72.5%) 13 (22.8%) 13 (17.8%)


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64 Clinical Pediatrics 49(1)

decisions regarding the need to deliver pregnancies at

these gestational ages. Accordingly, both the obstetrician

and the neonatologist should provide comprehensive

counseling to expecting couples explaining these potential

postnatal complications for their unborn child.

Specific neonatal clinical outcomes differed signifi-

cantly at 340/7 to 346/7 weeks as compared to 35 weeks.These differences were also observed in a recent cohort

study where the clinical outcome of infants born at 340/7 to

346/7 weeks resembled more closely the outcome observed

at 320/7 to 336/7 weeks than the outcomes observed in their

late-preterm counterparts.10 Considering that the highest

proportion of morbidity in the late-preterm infant popu-

lation occurs in infants born at 340/7 to 346/7 weeks, the

categorization of these infants as late-preterms originates

relevant scientific questions. In addition, the cutoff of

340/7 weeks to expedite delivery in pregnancies affected

by preterm PROM deserves further investigation.

The neonatal morbidity combined with the prolongedhospital stay in the studied population probably translates

into elevated health costs. Even though we did not perform

a cost analysis, a recent study showed that the hospital costs

related to health care of late-preterm infants compared with

full terms were significantly higher.8 In this study, the

median length of stay was similar for late-preterm and full-

term infants, but there was a relative increase in total cost

of 2.93 (mean) and 1.39 (median) in late-preterm infants

as compared with their full-term counterparts. The cost

difference was $2630 (mean) and $429 (median) per late-

preterm infant. This report is just an example of what could

be the economical repercussions of the recent rise in thelate-preterm birth rate nationwide.

Our study has several strengths. The population studied

was demographically diverse. The 2 participant tertiary

centers serve pregnant women with very different charac-

teristics. Whereas one center serves a large proportion of

the underserved population with a predominance of

Hispanics (66.6%), the other is a community-based hospital

with a predominance of private obstetrical practices and a

larger white population (80%). Including ethnically and

demographically diverse populations increases external

validity. Clinical management protocols were equivalent

between the 2 health care centers; thus, deviation from thestandardized care was minimal.

We recognize several limitations in this study. We

did not include any cases where neonatal or maternal

data were incomplete. Excluded cases might differ some-

what from the population studied. In addition, coding

errors and lack of diagnosis in the reviewed data might

predispose to information bias. We did not include data

from neonatal readmissions, which might underestimate

the reported morbidity. This study only investigated short-

term outcomes, and we did not report other neonatal

complications that could be relevant in this population,

such as feeding difficulties, temperature instability, and

transitory tachypnea.

The clinical management of preterm PROM at 340/7

weeks is still a dilemma worldwide. The rationale to

induce delivery once pregnancy reaches this gestational

age is to avoid a catastrophic event like perinatal death

even though its probability is extremely rare.3,7 In addition,clinical complications in this subset of preterm infants

usually resolve without resulting in long-term disability or

death. Currently, there are 2 ongoing randomized controlled

trials (the PROMT trial and the PPROMEXIL-trial)16,17

that compare expectant management with immediate

delivery in women with preterm PROM between 34 and

37 weeks. We expect that the findings in these studies will

contribute toward determining the optimal obstetrical

management for this common pregnancy complication.

In summary, this cohort study demonstrated the rele-

vant neonatal morbidity in late-preterm infants born after

PROM. We identified significant differences in clinicaloutcomes between infants born at 340/7 to 346/7 weeks and

those born at 35 weeks. We emphasize the importance of

further investigation into new clinical strategies, including

the use of antenatal steroids for pregnancies affected by

preterm PROM at 34 weeks. We also caution against cat-

egorizing this subset of infants as being similar to their

term counterparts.

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