Practice Essentials

Preterm labor is defined as the presence of uterine contractions of sufficient frequency and
intensity to effect progressive effacement and dilation of the cervix prior to term gestation.
Occurring at 20-37 ee!s" gestation# preterm labor precedes almost half of preterm births and is
the leading cause of neonatal mortality in the $nited %tates.
Essential update: FDA warns against extended magnesium sulfate injections in
pregnancy
&he $% 'ood and (rug )dministration *'()+ has issued a safety alert advising against the off-
label administration of magnesium sulfate in,ections to pregnant omen for more than --7 days
as a means of stopping preterm labor# as this agent can lead to lo calcium levels and bone
abnormalities in the fetus.
./# 2# 30
&he arning as based in part on /1 case reports of s!eletal abnormalities in infants hose
mothers had received magnesium sulfate in,ections to stop preterm labor. 2n these cases# fetuses
ere exposed to the drug for nearly /0 ee!s# on average# ith neonates developing transient
osteopenia and fractured bones. 3pidemiologic evidence also indicates a connection beteen
maternal administration of magnesium sulfate for more than --7 days and hypocalcemia and
s!eletal abnormalities in neonates.
./# 2# 30
Risk of preterm labor
&he exact mechanisms of preterm labor are largely un!non but are believed to include the
folloing4
(ecidual hemorrhage such as abruption and mechanical factors such as uterine
overdistention from multiple gestation or polyhydramnios
5ervical incompetence *eg# trauma# cone biopsy+
$terine distortion *eg# m6llerian duct abnormalities# fibroid uterus+
5ervical inflammation as a result of# for example# bacterial vaginosis *78+ or
trichomonas
9aternal inflammation:fever *eg# urinary tract infection+
;ormonal changes *eg# mediated by maternal or fetal stress+
$teroplacental insufficiency *eg# hypertension# insulin-dependent diabetes# drug abuse#
smo!ing# alcohol consumption+
Risk assessment during pregnancy
Physical assessment
&he integrity of the cervix and the extent of any prior in,ury to the cervix may be assessed by
speculum and digital examination. &he presence of asymptomatic bacteriuria# sexually
transmitted disease *%&(+# and symptomatic 78 may be investigated
History
) history of prior preterm deliveries places the patient in the high-ris! category. Of the predictors
of preterm birth# past obstetric history may be one of the strongest predictors of recurrent preterm
birth.
Cervical length
) short cervical length in the early or late second trimester has been associated ith a mar!edly
increased ris! of preterm labor and delivery. 2n a study# a cervical length of 2- mm or less at 21
ee!s had a <=> sensitivity for prediction of preterm delivery at less than 3- ee!s.
.<0
Laboratory tests
2n patients ith a history of midtrimester loss# laboratory tests for ris! assessment include the
folloing4
?apid plasma reagent test
@onorrheal and chlamydial screening
8aginal p;:et smear:hiff test
)nticardiolipin antibody
Aupus anticoagulant antibody
)ctivated partial thromboplastin time
One-hour glucose challenge test
2n addition# one should consider &O?5; *toxoplasmosis# other infections# rubella#
cytomegalovirus infection# herpes simplex+# immunoglobulin @# and immunoglobulin 9
screening henever the historical or clinical suspicion is present.
Diagnosis
5ontractions of sufficient frequency and intensity to effect progressive effacement and dilation of
the cervix at 2<-37 ee!s" gestation are indicative of active preterm labor. 2f the diagnosis of
preterm labor is suspected# but not confirmed# it may be prudent to first obtain a vaginal fetal
fibronectin *''B+ sample before pelvic cervical examination. 2f the diagnosis remains in doubt
after the exam# the ''B specimen can be sent to the lab for analysis.
Management
Progesterone
%tudies support the use of progesterone supplementation to reduce preterm birth in patients at
high ris! for recurrent preterm delivery.
Tocolytic agents
5riteria that indicate consideration of tocolytic therapy include more than C contractions per hour
resulting in a demonstrated cervical change or presumed prior cervical change *transvaginal
cervical length D 2- mm# E-0> cervical effacement# or cervical dilation F20 mm+. 2f
contractions are present ithout cervical change# management options include continued
observation or therapeutic sleep for the patient *eg# morphine sulphate /0-/- mg subcutaneous+.
&he most common tocolytic agents used to treat preterm labor include the folloing4
9agnesium sulfate *9g%O<+4 Gidely used as the primary tocolytic agent because it has
similar efficacy to terbutaline *one of the previous agents of choice+# ith far better
tolerance
2ndomethacin4 )n appropriate first-line tocolytic for early preterm labor *D 30 !+ or
preterm labor associated ith polyhydramnios
Bifedipine4 (espite its unlabeled status# several randomiHed studies have found
nifedipine to be associated ith a more frequent successful prolongation of pregnancy
than other tocolytics
!er!iew
Preterm labor is defined as the presence of uterine contractions of sufficient frequency and
intensity to effect progressive effacement and dilation of the cervix prior to term gestation
*beteen 20 and 37 !+. Preterm labor precedes almost half of preterm births and preterm birth
occurs in approximately /2> of pregnancies and is the leading cause of neonatal mortality in the
$nited %tates.
.-# C0
2n addition# preterm birth accounts for 70> of neonatal morbidity# mortality#
and health care dollars spent on the neonate# largely due to the 2> of )merican omen
delivering very premature infants *D 32 !+.
.-# C0
(espite the current use of material# effort# and money in perinatal medical technology# neonatal
mortality rates for neborns born in the $nited %tates *- per /#000 babies+ may ran! as lo as
32
nd
among the 33 industrialiHed nations# superior only to Aatvia.
.70
%uccessful reduction of perinatal morbidity and mortality associated ith prematurity may
require the implementation of effective ris! identification and behavioral modification programs
for the prevention of preterm laborI these in turn require both an improved understanding of the
psychosocial ris! factors# etiology# and mechanisms of preterm labor and programs for accurate
identification of pregnant omen at ris! for premature labor and delivery. 2n fact# recent
evidence suggests that early identification of at-ris! gravidas ith timely referral for
subspecialiHed obstetrical care may help identify omen at ris! for preterm labor and delivery
and decrease the extreme prematurity *D 32 !+ rate# thereby reducing the morbidity# mortality#
and expense associated ith prematurity.
.10
"oals of management
&he focus of this article is the prevention# diagnosis# and treatment of preterm labor ith intact
membranes. &he management of preterm labor associated ith ruptured membranes is revieed
in Premature ?upture of 9embranesI hoever# the overall goals of both management schemes
are similar.
@oals of obstetric patient management of preterm labor should include */+ early identification of
ris! factors associated ith preterm birth# *2+ timely diagnosis of preterm labor# *3+ identifying
the etiology of preterm labor# *<+ evaluating fetal ell-being# *-+ providing prophylactic
pharmacologic therapy to prolong gestation and reduce the incidence of respiratory distress
syndrome *?(%+ and intra-amniotic infection *2)2+# *C+ initiating tocolytic therapy hen
indicated# and *7+ establishing a plan of maternal and fetal surveillance ith patient:provider
education to improve neonatal outcome.
Risk of Preterm #abor
&he exact mechanism*s+ of preterm labor is largely un!non but is believed to include decidual
hemorrhage# *eg# abruption# mechanical factors such as uterine overdistension from multiple
gestation or polyhydramnios+# cervical incompetence *eg# trauma# cone biopsy+# uterine
distortion *eg# m6llerian duct abnormalities# fibroid uterus+# cervical inflammation *eg# resulting
from bacterial vaginosis .780# trichomonas+# maternal inflammation:fever *eg# urinary tract
infection+# hormonal changes *eg# mediated by maternal or fetal stress+# and uteroplacental
insufficiency *eg# hypertension# insulin-dependent diabetes# drug abuse# smo!ing# alcohol
consumption+.
.-# C0
)lthough prediction of preterm delivery remains inexact# a variety of maternal and obstetric
characteristics are !non to increase the ris!# presumably via one of these mechanisms. 'inally#
the fetus plays a role in the initiation of labor. 2n a simplistic sense# the fetus recogniHes a hostile
intrauterine environment and precipitates labor by premature activation of a fetal-placental
parturition pathay.
?is! factors for preterm birth include demographic characteristics# behavioral factors# and
aspects of obstetric history such as previous preterm birth. (emographic factors for preterm
labor include nonhite race# extremes of maternal age *D /7 y or E3- y+# lo socioeconomic
status# and lo prepregnancy eight. Preterm labor and birth can be associated ith stressful life
situations *eg# domestic violenceI close family deathI insecurity over food# home# or partnerI
or! and home environment+ either indirectly by associated ris! behaviors or directly by
mechanisms not completely understood. 9any ris! factors may manifest in the same gravida.
9ethods used for predicting preterm birth include home uterine activity monitoring *;$)9+#
assessments of salivary estriol# fetal fibronectin *''B+# the presence of 78# and cervical length
assessment.
Ghile hospital tocodynamometry has been effective for monitoring uterine contractions
to evaluate preterm labor# ;$)9 has not been proven valuable in detecting or
preventing preterm birth and is not currently recommended for use.
&he proposed use of salivary estriol measurements in detecting preterm labor as based
on the belief that the adrenal gland production of dehydroepiandrosterone increases
before the onset of labor# hich results in an increase of maternal estriol. $nfortunately#
maternal estriol levels sho diurnal variation# pea!ing at night# and are suppressed by
betamethasone administration# thereby decreasing the predictive value of salivary estriol
in the detection of preterm delivery ris!.
''B is a basement membrane protein that helps bind placental membranes to the decidua.
Ghile a negative ''B is helpful in predicting omen ho are not destined to deliver
preterm# a positive ''B has limited value in predicting omen ho ill deliver preterm.
Bevertheless# ''B has a predictive value in identifying patients ho ill or ill not
deliver ithin the subsequent /-2 ee!s.
Ghile the presence of 78 has been associated ith the ris! of preterm delivery#
prospective treatment trials eradicating asymptomatic 78 failed to reduce the ris! of
preterm delivery.
Aonger term prediction of the ris! of preterm delivery is achieved by cervical length
measurements. ) short cervical length in the early or late second trimester has been
associated ith a mar!edly increased ris! of preterm labor and delivery *see discussion
on cervical length+. &he prediction of preterm delivery may potentially be improved by
combining ''B testing ith measurements of cervical length.
Preconceptual e!aluation
Ghile the ris! for preterm birth in nulliparous patients is hard to determine# past obstetric
experience and personal behavior may provide significant insight into future pregnancy outcome
in multiparous omen. 2dentifying at-ris! patients preconceptually may allo additional
treatment options. Gomen ho see! birth control have a 30> chance of becoming pregnant in
the next 2 years# suggesting that these omen represent one potential opportunity for
intervention. &he presence of the folloing ris! factors should be addressed prior to pregnancy.
$er!ical trauma
&he most common etiologies for cervical in,ury are elective abortion# surgeries to treat cervical
dysplasia# and in,ury occurring at delivery. ) single uncomplicated elective abortion at less than
/0 ee!s" gestation does not increase the ris! of midtrimester loss or preterm birth unless the
cervix has been forcibly dilated to more than /0 mm at the time of the abortion. ;oever#
patients ith a history of multiple first-trimester elective terminations or one or more second-
trimester elective abortions may be at increased ris! for preterm delivery. 5ervical dilatation ith
laminaria or cervical ripening agents# such as misoprostol# appears to be less traumatiHing to the
cervix than mechanical dilation.
5ervical dysplasia should be treated appropriately henever diagnosed. ;oever the incidence
of preterm birth and cervical incompetence may be increased 200-300> after preconceptual
surgical treatment *eg# cold !nife cone# cryoconiHation# laser cone# A33P+ of cervical
intraepithelial neoplasia *52B+. &he ris! of subsequent preterm delivery may be proportional to
the amount of cervical tissue removed during surgery. %urprisingly# the ease of performing A33P
for relatively minor abnormalities may have paradoxically led to more cervical in,ury than as
observed ith the relatively more invasive cone biopsy.
Obstetric trauma may be underestimated as a ris! for midtrimester loss or preterm birth. Ghile
omen may relate a history of cervical laceration# often they are unaare of the in,ury and the
obstetric records of the previous delivery may be misleading as to the extent of the cervical
in,ury. &herefore# visual inspection of the cervix is important to assess the degree of in,ury and
ris!. (efects that involve more than -0> of the cervical length may indicate a higher ris! for
midtrimester loss. &he accuracy of transvaginal ultrasonic measurements to determine ris! of
cervical incompetence# specifically in the presence of a history of cervical trauma# has yet to be
determined.
"enital tract infection
&he young gynecology patient diagnosed ith gonorrhea# chlamydia# or trichomoniasis has an
approximate 2-> ris! of reinfection during the subsequent /2 months# but a clear association
beteen these organisms and preterm delivery has not been established. 78 is a vaginal
syndrome associated ith an alteration of the normal vaginal flora rather than an infection
specific to any one organism and a lac! of vaginal inflammation is evident hen compared ith
vaginitis. &he diagnosis of 78 should be suspected ith a positive @ram stain result or the
presence of 3 of < traditional diagnostic signs *homogenous gray-hite discharge# E20> clue
cells on saline et smear# positive hiff test# and a vaginal p; E<.-0+ Patients should be treated
per the $% 5enters for (isease 5ontrol and Prevention guidelines# ith test-of-cure sampling
and subsequent treatment if necessary.
Preterm labor%birt& &istory
) history of prior preterm deliveries places the patient in the high-ris! category. Of the predictors
of preterm birth# past obstetric history may be one of the strongest predictors of recurrent preterm
birth. @iven a baseline ris! of /0-/2># the ris! of recurrent preterm birth after /# 2# and 3
consecutive preterm births may be increased to approximately /-># 30># and <-># respectively.
Preconceptual counseling should help encourage patients to ma!e informed decisions concerning
future pregnancy in light of prematurity ris! in the presence of previous preterm delivery. Often
the best time to counsel the patient is at her <- to C-ee! postpartum chec! after a preterm
delivery.
Ay!!e et al found that spontaneous preterm delivery# preeclampsia# or fetal groth deviation in a
first singleton pregnancy predisposes omen to those complications in their second pregnancy#
especially if the complications ere severe. 2n a registry-based cohort study of -3C#</= (anish
omen# delivery beteen 32 and 3C ee!s of gestation increased the ris! of preterm delivery in
the second pregnancy from 2.7> to /<.7> *odds ratio .O?0 C./2I =-> confidence interval .520#
-.1<-C.<2+ and increased the ris! of preeclampsia from /./> to /.1> *O? /.C0I =-> 52# /.</-
/.1/+. ) first delivery before 21 ee!s increased the ris! of a second preterm delivery to 2C.0>
*O? /3./I =-> 52# /0.1-/-.=+ and increased the ris! of preeclampsia to 3.2> *O? 2.=CI =-> 52#
/.10-<.11+.
&he optimal method of preterm birth in multiple gestations has yet to be proven. 5ervical
cerclage# prophylactic bed rest# and empiric use of tocolytics have not been successful. 9ost
recently# a randomiHed controlled trial by Aim et al suggests that the use of /7J-
hydroxyprogesterone caproate does not prevent neonatal morbidity or preterm birth in multiple
pregnancies.
.=0
Preeclampsia in a first pregnancy ith delivery beteen 32 and 3C ee!s increased the ris! of
preeclampsia in a second pregnancy from /<./> to 2-.3> *O? 2.01I =-> 52# /.17-2.3/+ and
increased the ris! for a small for gestational age infant from 3./> to =.C> *O? 2.12I =-> 52#
2.31-3.3-+. 'etal groth 2 to 3 standard deviations belo the mean in a first pregnancy increased
the ris! of preeclampsia from /./> to /.1> *O? /.C2I =-> 52# /.3<-/.=C+ in the second
pregnancy.
./00
%ee the @estational )ge from 3stimated (ate of (elivery calculator.
Midtrimester loss
9idtrimester loss has many etiologies# including infection *eg# syphilis+# antiphospholipid
syndrome# diabetes# substance abuse# genetic disorders# congenital m6llerian abnormalities#
cervical trauma# and cervical incompetence. $nfortunately# many midtrimester losses remain
unexplained. ) complete or!up *see ;istory of midtrimester loss+ may be of value in selected
patients folloing a midtrimester loss.
Assessment of Risk During Pregnancy
P&ysical Assessment "uidelines to Establis& Risk
)ssessment during the first prenatal exam should include the patientKs obstetric history# infection
ris!# and the presence of cervical or uterine abnormalities. 2f an evaluation for antiphospholipid
syndrome is included# it should include anticardiolipin and lupus anticoagulant antibodies.
Previous preterm deliveries# including autopsy reports and medical records# if appropriate and
available# should be revieed. %ocial stressors *including housing and food availability+# social
support in the family# financial stability# domestic violence# drug abuse involving the patient or
her family# and death or serious illness in a close family member should be assessed.
&he integrity of the cervix and the extent of any prior in,ury to the cervix may be assessed by
speculum and digital examination. &he presence of asymptomatic bacteriuria# %&(# and
symptomatic 78 may be investigated.
2n some patients# formal cervical length assessment may be of use in ris! assessment.
5ervical length during prenatal care# particularly at 2<-21 ee!s" gestation# has been
demonstrated to be the most sensitive prenatal predictor of preterm birth beteen both high- and
lo-ris! omen. 2n a mixed high- and lo-ris! population of singleton pregnancies# transvaginal
ultrasound-measured cervical length at 2< ee!s as highly correlated ith the ris! of
spontaneous preterm delivery before 3- ee!s.
.<0
&he relative ris! of preterm delivery among
omen ith a cervix 2- mm or shorter at 2< ee!s as C.2. 'urthermore# at 21 ee!s# a short
cervix *L2- mm+ as associated ith a =.C relative ris! of preterm delivery. 5ervical length 2-
mm or shorter at 21 ee!s had a <=> sensitivity for prediction of preterm delivery at less than
3- ee!s# a value mar!edly greater than that of cervical funneling.
)mong high-ris! omen ith a history of one or more spontaneous preterm births *excluding
those ith multiple gestation# uterine anomalies# and prior cervical surgeries+# 20> of patients
demonstrated a cervical length shorter than 2- mm by transvaginal ultrasonography at 22-2-
ee!s.
.//0
)mong these patients ith a short cervix and one previous preterm birth# 37.->
delivered at less than 3- ee!s. 2n contrast# patients ith a cervical length longer than 2- mm
had a preterm rate *D 3- !+ of only /0.C>. 5ervical length has similarly been demonstrated as
the optimal predictor of preterm delivery in lo-ris! omen. 2n an assessment of lo-ris!
omen# short cervical length at 2<-21 ee!s as detected in 1.-> of omen.
./20
&hese patients
demonstrated a relative ris! of C.= for preterm delivery at less than 3- ee!s. )s compared ith
fetal fibronectin or 7ishop score# cervical length demonstrated the greatest sensitivity *3=>+#
ith a specificity of =2.-> and a negative predictive value of =1>.
Ghereas cervical length assessment by digital exam is a semisub,ective measurement# a recent
study has demonstrated the value of an ob,ective cervico-portio length measurement using
5erivlenH# an intravaginal measuring device.
./30
&hese manually obtained cervical length
measurements appear to be reproducible# accurate# and predictive of a short cervical length by
transvaginal ultrasonography. &herefore# 5erivlenH may represent a lo-cost# ob,ective screening
tool to identify at-ris! patients for preterm delivery.
2n addition to the 2<-21 ee! assessment# evidence shos the value of early midtrimester
cervical length measurement. %tudies of Oen et al from the 9aternal 'etal 9edicine $nits
Betor!
./<0
demonstrate the value of cervical length measurements beteen /C ee!s and 23
ee!s and C days. %erial transvaginal ultrasonographic cervical length measurements in a high-
ris! population demonstrated that a cervix shorter than 2- mm resulted in a relative ris! of <.-
for spontaneous preterm birth at less than 3- ee!s# ith a C=> sensitivity# 10> specificity# -->
positive predictive value# and 11> negative predictive value. )s the B2; 9aternal 'etal
9edicine $nits Betor! is initiating a study of progesterone treatment for patients ith a short
cervix in the early midtrimester# a program of routine cervical length screening may soon be
,ustified.
)mong patients ith a short cervix# education should be provided concerning the signs and
symptoms of preterm labor# especially as the pregnancy approaches potential viability. Prenatal
visits:contacts may be scheduled at more frequent intervals to increase patient interaction ith
the care provider# especially beteen 20 and 3< ee!s" gestation# hich may decrease the rate of
extreme preterm birth.
.10
Management of 'pecific Problems
?andomiHed clinical trials of cerclage for sonographically suspected cervical incompetence
*shortened cervical length and:or funneling+ have been inconclusive ith respect to prevention of
preterm delivery.
.-0
;oever# a history of midtrimester losses ith loss of cervical integrity# often
results in recommendation for cerclage placement beteen /3 and /7 ee!s" gestation. Ghen the
patient has a history of midtrimester loss after cone or A33P biopsy therapy# prophylactic
cerclage may be considered# but consulting ith a maternal fetal medicine specialist may be
beneficial due to the potential ris!s and the controversial proven benefit.
) meta-analysis of randomiHed trials in omen ith cervical length less than 2- mm on
transvaginal ultrasonography found that cerclage significantly prevents preterm birth and
composite perinatal mortality and morbidity in omen ith previous spontaneous preterm birth
and singleton gestation.
./-0
%imcox et al conducted a randomiHed controlled trial in 2<7 patients to determine if history or
ultrasonography provided a better basis for hether omen at ris! of preterm birth should
undergo cervical cerclage. Gomen treated on the basis of ultrasound criteria *cervical length D 20
mm+ ere significantly more li!ely to undergo cerclage *32> vs /=>I relative ris! .??0 /.CC+
and to receive progesterone *3=> vs 2->I ??# /.--+ than ere those treated on the basis of
clinician preference. ;oever# the rate of preterm delivery beteen 2< and 33 ee!s as /-> in
both groups. &he results of this study shoed that ultrasonographic screening of high-ris!
omen to determine the need of cerclage resulted in more intervention but similar outcome
compared ith those determined to need cerclage based on history.
./C0
(istory of midtrimester loss
) history of prior midtrimester losses is carefully revieed at the initial visit to distinguish
incompetent cervix from other causes *eg# abruption# infection# intrauterine death# ruptured
membranes+ ith revie of the pathology or autopsy reports if available. Parental !aryotypes are
generally not helpful unless more than one midtrimester loss has occurred or a midtrimester loss
has occurred in hich the fetus as structurally or genetically abnormal.
%pecific laboratory tests# including a rapid plasma reagent test# gonorrheal and chlamydial
screening# vaginal p;:et smear:hiff test# anticardiolipin antibody# lupus anticoagulant
antibody# activated partial thromboplastin time# and a /-hour glucose challenge test are helpful in
the evaluation. 2n addition# one should consider &O?5; *toxoplasmosis# other infections#
rubella# cytomegalovirus infection# herpes simplex+# immunoglobulin @# and immunoglobulin 9
screening henever the historical or clinical suspicion is present. ;oever# a random drug
screen is not alays recommended unless other supporting high-ris! behavior exists.
) preconceptual hysterosalpingogram may be of benefit in patients ith a history of 2 or more
midtrimester losses. One can also attempt to pass a Bo. 1 ;egar dilator into the nonpregnant
cervixI easy passage may be a sign of cervical incompetence. (uring pregnancy# henever the
suspicion of incompetent cervix exists# one should consider performing baseline transvaginal
ultrasonography to assess cervical length# especially at /3-/7 ee!s" gestationI abnormal
findings include a length less than 2.- cm# funneling greater than - mm# or dynamic changes.
) cerclage may be indicated after 2 or more midtrimester losses consistent ith incompetent
cervix or in hich the etiology is un!non and the transvaginal ultrasonography of the cervix is
abnormal. ) cerclage is usually performed electively at /3-/7 ee!s" gestation.
) genetic amniocentesis may be performed prior to the placement of cerclage in patients at high
ris! for genetic disease. Prior to an elective cerclage# sampling the patientKs vagina and cervix for
78# gonorrheal# chlamydial# or trichomonal infection is also recommended# ith appropriate
treatment instituted. &he efficacy of prophylactic antibiotics for cerclage is yet to be
demonstrated.
)&e use of progesterone t&erapy to reduce preterm birt&
?ecent studies support the use of progesterone supplementation to reduce preterm birth in
patients at high ris! for recurrent preterm delivery *ie# prior preterm birth D 37 ee!sK gestation#
short cervical length+. Gee!ly in,ections of /7 alpha-hydroxyprogesterone caproate resulted in a
substantial reduction in the rate of recurrent preterm delivery among omen ho ere at high
ris! for preterm delivery and reduced the li!elihood of several complications in their infants.
./70
2n
addition# prophylactic vaginal progesterone reduced the frequency of uterine contractions and the
rate of preterm delivery in omen at high ris! for prematurity.
./10
2n October 2001# the )merican 5ollege of Obstetricians and @ynecologists issued a 5ommittee
Opinion stating that progesterone supplementation for the prevention of recurrent preterm birth
should be offered to omen ith a singleton pregnancy and a prior spontaneous preterm birth
due to spontaneous preterm labor or premature rupture of membranes. Progesterone
supplementation for asymptomatic omen ith an incidentally identified very short cervical
length *D /- mm+ may be considered.
./=0
On 'ebruary <# 20//# the $% 'ood and (rug )dministration *'()+ approved /7-
hydroxyprogesterone *9a!ena+ to reduce ris! of preterm delivery before 37 ee!s" gestation in
omen ith singleton pregnancy and a history of at least one spontaneous preterm birth. /7-
;ydroxyprogesterone is not intended for use in omen ith multiple gestations or other ris!
factors *eg# short cervical length+ for preterm birth.
&he dose is 2-0 mg */ mA+ intramuscularly in the hip every ee! until 37 ee!s" gestation or
delivery# hichever occurs first. 2nitiate beteen /C ee!s" gestation and before 2/ ee!s"
gestation *ie# 20 ! and C d+.
&he '() revieed data from a multicenter# randomiHed# double-blind clinical trial. &he study
included <C3 omen ho ere pregnant ith a single fetus and had a history for preterm
delivery. ?ates of delivery before 37 ee!sK gestation ere 37> in omen randomiHed to /7-
hydroxyprogesterone and --> in controls.
) separate study evaluated children born to mothers enrolled in the controlled trial. 2n this study#
children aged 2.--- years reached similar developmental targets# regardless of the mother"s
treatment. &he confirmatory study that is ongoing ill be folloed by a similar infant follo-up
study to be completed about 20/1.
) multicenter# randomiHed placebo-controlled study demonstrated that intravaginal progesterone
gel effectively prevented preterm delivery in patients ith a short cervix */0-20 mm+. 8aginal
progesterone as associated ith a significant reduction in rate of preterm birth before 21# 33#
and 3- ee!s" gestationI infant respiratory distress syndromeI and neonatal morbidity and
mortality. 5urrently# applications for '() approval are in process. Of note# the predicted clinical
impact of treatment of all patients ith short cervix is greater than among patients ith prior
spontaneous preterm birth.
.200
Management of Preterm #abor
Preterm labor may be difficult to diagnose and a potential exists for overtreatment of uterine
irritability. &ocolytic agents# hile generally safe in appropriate dosages ith proper clinical
monitoring# have potential morbidity and should only be used after consideration of the ris!s and
benefits of such use. Beonatal morbidity and mortality are greatly affected by gestational age#
especially hen the pregnancy is less than 21 ee!s" gestation. &ocolysis should be used ith
caution hen the fetus is previable because the expected prolongation of the pregnancy is
limited# and the neonate has a minimal chance of survival at less than 23 ee!s. &he li!elihood
of survival is further reduced in the presence of significant medical complications# such as intra-
amniotic infection *2)2+ at these ages.
On the other hand# the ris! of neonatal mortality and morbidity is lo after 3< completed ee!s
of gestationI although a trial of acute tocolysis may be initiated# aggressive tocolytic therapy is
generally not recommended beyond 3< ee!s# due to potential maternal complications. 7eteen
2< and 33 ee!s" gestation# benefits of tocolytic therapy are generally accepted to outeigh the
ris! of maternal and:or fetal complications and these agents should be initiated provided no
contraindications exist. )lthough aggressive tocolysis is not typically used beyond 3< ee!s"
gestation# clinicians are advised not to deliver patients at this gestation ithout indication
because of a higher ris! of neonatal morbidity in infants born at 3<-3C ee!s" gestation
compared ith deliveries at 37-<0 ee!s" gestation.
.2/0
&he folloing table depicts survival# ma,or short-term morbidity# and intact long-term survival
by gestational age.
&able. Beonatal 9orbidity and 9ortality by @estational )ge *Open &able in a ne indo+
"estational
Age* wk
'ur!i!al Respiratory
Distress
'yndrome
+ntra!entricular
(emorr&age
'epsis ,ecroti-ing
Enterocolitis
+ntact
2< <0> 70> 2-> 2-> 1> ->
2- 70> =0> 30> 2=> /7> -0>
2C 7-> =3> 30> 30> //> C0>
27 10> 1<> /C> 3C> /0> 70>
21 =0> C-> <> 2-> 2-> 10>
2= =2> -3> 3> 2-> /<> 1->
30 =3> --> 2> //> /-> =0>
3/ =<> 37> 2> /<> 1> =3>
32 =-> 21> /> 3> C> =->
33 =C> 3<> 0> -> 2> =C>
3< =7> /<> 0> <> 3> =7>
&ocolytic agents have not proven to be efficacious in preventing preterm birth or reducing
neonatal mortality or morbidity. &he primary purpose of tocolytic therapy today is to delay
delivery for <1 hours to allo the maximum benefit of glucocorticoids to decrease the incidence
of ?(%. Ghile tocolytics can be successful for <1 hours hen membranes are intact# some
clinical studies suggest that the effectiveness of tocolytics is only slightly better than bedrest and
hydration# both of hich have feer adverse effects than tocolytic therapy.
Diagnosis
5ontractions of sufficient frequency and intensity to effect progressive effacement and dilation of
the cervix at 2<-37 ee!s" gestation are indicative of active preterm labor. 2f the diagnosis of
preterm labor is suspected# but not confirmed# it may be prudent to first obtain a vaginal fetal
fibronectin *''B+ sample before pelvic cervical examination. 2f the diagnosis of preterm labor
becomes obvious after the pelvic examination# the ''B specimen can be subsequently discarded.
;oever# if the diagnosis remains in doubt# the ''B specimen can be sent to the lab for analysis.
5riteria that indicate consideration of tocolytic therapy include more than C contractions per hour
resulting in a demonstrated cervical change or presumed prior cervical change *transvaginal
cervical length D 2.- cm# E-0> cervical effacement# or cervical dilation F2 cm+. 2f contractions
are present ithout cervical change# management options include continued observation or
therapeutic sleep *eg# morphine sulphate /0-/- mg subcutaneous+.
Ghen using strict criteria in omen at 2< 0:7 to 33 C:7 ee!s" gestation for Mfalse preterm laborN
*one contraction or less in /0 min# cervical dilation D 2 cm# and no evidence of cervical change
over 2 h of observation+# 5hao et al demonstrated that these patients had a greater incidence of
late preterm *3<-3C ee!s" gestation+ but not early preterm delivery *D 3< ee!s" gestation+#
compared ith a control obstetric population.
.220
;oever# those patients ith cervical dilation of
/ cm ere more li!ely to delivery prior to 3< ee!s" gestation. )lthough this study provides
some guidance as to management# a negative ''B result and:or evidence of abated contractions
may be of additional value in discharging patients ith false preterm labor. 2n addition# measures
of absolute or change in cervical length *effacement+# in addition to dilation# may be of value in
discriminating true versus false preterm labor.
Assessment prior to tocolytic t&erapy
One should alays attempt to determine gestational age by first identifying the first day of the
last menstrual period *A9P+ and confirming it by one or more of the folloing4
Positive pregnancy test *home or clinic+ prior to the expected date of the second missed
period
$terine siHe determined by bimanual examination prior to /2 ee!sK gestation
(oppler fetal heart tones noted prior to /2 ee!sK gestation
$ltrasonographic estimation of gestational age *ie# first trimester ithin / !# second
trimester ithin 2 !# and third trimester ithin 3 !+
Ghen the A9P is not reliable# the gestational age is determined by the first ultrasonography.
'olloing gestational age determination# assessment of fetal ell-being# fetal groth# and
evaluation of congenital anomaly should be conducted. %ubspecialist consultation *9'9+ is
recommended in the presence of suspected fetal anomalies because tocolytics are generally
contraindicated for any congenital anomaly incompatible ith life. &ocolytics are not indicated
in patients ith either suspected or confirmed 2)2. $se of tocolytics is relatively contraindicated
hen evidence of a hostile intrauterine environment exists# such as the folloing4
Oligohydramnios
Bonreactive nonstress test results
Positive contraction stress test results
)bsent or reversed diastolic flo upon (oppler examination of umbilical blood flo
?epetitive severe variable decelerations
%ignificant vaginal bleeding consistent ith abruption# unless patient is stable and fetal
ell being established
E!aluate for t&e presence of genital tract infection
&ocolytics are contraindicated in the presence of symptomatic 2)2. &he definition of 2)2
infection *ie# chorioamnionitis+ includes a temperature greater than 31.0O5 */00.0O'+ and 2 of the
- folloing signs4
G75 count greater than /-#000 cells:mm
3
9aternal tachycardia greater than /00 beats per minute *bpm+
'etal tachycardia greater than /C0 bpm
&ender uterus
'oul-smelling discharge
2n situations in hich the diagnosis remains unclear# an amniocentesis for fluid culture
*aerobic:anaerobic bacteria+# @ram stain *bacteria present if @ram stain is positive or if G75
count is E-0 cells:mm
3
+# glucose level *positive if D /- mg:dA+# or leu!ocyte esterase evaluation
may be considered. ;oever# amniocentesis may result in a false-positive ''B test result if the
''B is performed after amniocentesis.
.-0
Patients ith preterm labor may be assessed for the presence or absence of loer genital tract
infection.
%terile speculum examination for ruptured membranes
3ndocervical sampling for gonorrhea and chlamydia
8aginal fluid p;
Get smear for 78 and trichomonal infection if indicated
@7% culture
$rinalysis and culture *if indicated+
Positive results are treated ith appropriate antibiotics.
Assess for medical contraindications to tocolysis
&ocolytics should be used ith considerable caution in pregnant patients ith cardiac disease#
especially those ho require medication or have a history of congestive heart failure# cardiac
surgery# significant pulmonary disease# renal failure# or maternal infection *ie# pneumonia#
appendicitis# pyelonephritis+. 2n these cases# it may be prudent to consult ith an 9'9
specialist.
%pecific tocolytic agents should not be used henever !non allergies exist. 2ndomethacin is
contraindicated in the presence of aspirin-induced asthma# coagulopathy# or significant liver
disease. 9agnesium sulfate should not be used in con,unction ith select medications# such as
calcium channel bloc!ers# or hen myasthenia gravis or neuromuscular disorders exist. 7eta-
mimetics *eg# terbutaline+ may be contraindicated in the presence of cardiac arrhythmia# valvular
disease# and ischemic heart disease and may alter glucose homeostasis in patients ith diabetes.
Fetal t&erapy
&he administration of glucocorticoids is recommended in the absence of clinical infection
henever the gestational age is beteen 2< and 3< ee!s. )n attempt should be made to delay
delivery for a minimum of /2 hours to obtain the maximum benefits of antenatal steroids.
;oever# a randomiHed clinical trial by Porto et al shoed that treatment ith corticosteroids at
3<-3C ee!s of pregnancy does not reduce the incidence of respiratory disorders in neborn
infants.
.230
&he recommended dosage of 7etamethasone consists of to /2 mg doses 2< hours apart hile
four doses of C mg of dexamethasone should be administered at C-hour intervals. Ghenever the
folloing clinical conditions exist# the glucocorticoid regimen may require modification4
2n the presence of insulin-dependent or gestational diabetes# the provider should be
prepared for control of blood sugars.
2n the event of an acutely distressed fetus# indicative of fetal hypoxia# the use of
prophylactic steroids should not delay the delivery of an acutely distressed fetus.
)lthough the use of repeated doses of glucocorticoids remains controversial# a meta-analysis
concluded that repeated doses of prenatal corticosteroids in omen ho remained at ris! for
preterm birth 7 or more days after an initial course reduced the ris! of their infants developing
respiratory distress syndrome and reduced serious infant outcomes *relative ris! 0.13 and 0.1<#
respectively+. &reatment ith repeat doses as associated ith a reduction in mean birtheight
of approximately 7C gI hoever# no differences in groth assessments or disabilities at early
childhood ere noted in follo-up.
.2<0
2n vie of these conclusions# the authors suggest that the
clinician consider use of a single repeated dose of glucocorticoids if the patient remains at
significant ris! for preterm delivery ithin the next 7 days# at a gestational age less 3< ee!s.
"roup . streptococci prop&ylaxis
)ll patients in preterm labor should be considered at high ris! for neonatal @7% sepsis. Patients
in preterm labor ith the potential to deliver should receive prophylactic antibiotics against @7%#
unless @7% culture is negative. Prophylactic antibiotics should be administered hen the
diagnosis of preterm labor is made and should be continued until delivery or for a minimum of
72 hours. Patients should be re-treated if preterm labor recurs or hen the patient enters labor at
term depending upon culture results.
)ocolytic Agents
&he most common tocolytic agents used for the treatment of preterm labor are magnesium
sulfate *9g%O<+# indomethacin# and nifedipine. 2n the past# beta-mimetic agents# such as
terbutaline or ritodrine# ere the agents of choice# but in recent years their use has been
significantly curtailed due to maternal and fetal side effects# such as maternal tachycardia#
hyperglycemia# and palpitations &he use of these agents can lead to pulmonary edema#
myocardial ischemia# and cardiac arrhythmia.
2n 'ebruary 20//# the $% 'ood and (rug )dministration *'()+ required the addition of a ne
7lac! 7ox Garning and contraindication to the terbutaline prescribing information to arn about
the ris! of use for preterm labor. &he decision as based on reports of death and serious adverse
reactions# including tachycardia# transient hyperglycemia# hypo!alemia# arrhythmias# pulmonary
edema# and myocardial ischemia folloing prolonged the administration of oral or in,ectable
terbutaline to pregnant omen. &he '() concluded that the ris! of serious adverse events
outeighs any potential benefit to pregnant omen receiving prolonged treatment ith
terbutaline in,ection *E<1-72 h+ or acute or prolonged treatment ith oral terbutaline.
&he tocolytic agents currently used to treat preterm labor appear to be equally efficacious in
delaying delivery for at least <1 hours. Ghile 9g%O< is associated ith more maternal toxicity#
indomethacin is associated ith more fetal and neonatal toxicity.
;aas et al analyHed randomiHed controlled trials of tocolysis to determine the optimal first-line
tocolytic agent for treatment of premature labor. 'ifty-eight studies satisfied the inclusion
criteria. ) random-effects meta-analysis shoed that all tocolytic agents ere superior to placebo
or control groups at delaying delivery both for at least <1 hours *-3> for placebo compared ith
7--=3> for tocolytics+ and 7 days *3=> for placebo compared ith C/-71> for tocolytics+. Bo
statistically significant differences ere found for the other outcomes# including the neonatal
outcomes of respiratory distress and neonatal survival. &he decision model demonstrated that
prostaglandin inhibitors provided the best combination of tolerance and delayed delivery.
.2-0
Magnesium sulfate
9agnesium sulfate is idely used as the primary tocolytic agent because it has similar efficacy
to terbutaline ith far better tolerance. 5ommon maternal side effects include flushing# nausea#
headache# drosiness# and blurred vision. &he mother should be monitored for toxic effects# such
as respiratory depression or even cardiac arrest# that can occur at supratherapeutic levels. 2n
addition# magnesium sulfate readily crosses the placenta and may lead to respiratory and motor
depression of the neonate.
)lthough magnesium sulfate is approved to prevent seiHures in preeclampsia and for control of
seiHures in eclampsia# its use for preterm labor is off-label. &he '() issued a safety alert
arning not to exceed --7 days of continuous 28 magnesium sulfate hen the agent is used for
preterm labor. Aonger treatment duration may lead to hypocalcemia in the developing fetus and
result in neonates ith s!eletal abnormalities related to osteopenia. ;ypermagnesemia causes
hypocalcemia as a result of a decrease in the secretion of parathyroid hormone.
.30
%everal observational studies have reported an association of antenatal treatment ith
magnesium sulfate for preterm labor or preeclampsia ith a decreased ris! of cerebral palsy in
lo birth eight or preterm infants.
.2C# 27# 210
Ghile the use of magnesium sulfate for the prevention
of cerebral palsy in preterm infants has been recently suggested# it has yet to receive universal
acceptance.
)ntenatal magnesium sulfate should be considered for use in omen at high ris! of delivery
before 3< ee!sK gestation# mainly in those ith premature rupture of membranes# active labor#
and planned delivery ithin 2< hours. Aoading and maintenance doses# and the duration of the
treatment specifically for neuroprotection should not normally exceed C g# /-2 g:h# and 2< hours#
respectively.
&he use of magnesium sulfate usually requires baseline maternal laboratory evaluation# including
575 count and serum creatinine level# urine output greater than 30 mA:h# normal vital signs# and
appropriate maternal mentation. &he initial recommended loading dose is <-C g 28 over 20
minutes# folloed by a maintenance dose of /-< g:h depending on urine output and persistence of
uterine contractions.
9aintenance of magnesium sulfate therapy requires careful assessment of maternal mentation#
visual symptoms# (&?s# and cardiac rate ith discontinuation henever evidence of toxicity
exists. $rine output should be carefully monitored and ideally maintained at greater than -0
mA:h. Aimiting intravenous inta!e to prevent pulmonary edema may be prudent. Oral inta!e can
be maintained at the discretion of the provider. %erum magnesium levels may be obtained / hour
after the loading dose and then every C hours and the maintenance dosage should be titrated to
maintain a serum level of <-1 mg:dA.
%ince the primary therapeutic goal of tocolysis is to delay preterm delivery ithin <1 hours from
the initiation of steroid prophylaxis# little evidence suggests that extended 9g%O< therapy is
beneficial. &he authors recommend discontinuing magnesium sulfate therapy after <1 hours in
most patients unless the gestational age is less than 21 ee!s hen a gain of an additional 3-<
days may significantly reduce neonatal morbidity and mortality. (ue to the ris! of toxicity#
consulting an 9'9 specialist may be beneficial if magnesium sulfate is to be continued for more
than 72 hours. %ince no clinical evidence suggests that oral beta-mimetics# subcutaneous
terbutaline pump# or oral magnesium compounds are effective in delaying preterm birth#
alternative tocolysis is not currently recommended after the discontinuation of 28 9g%O<
therapy.
Ghen acute mild toxicity exists in the presence of normal urine output# magnesium sulfate
should be temporarily discontinued until the serum magnesium level and (&?s return to normal.
2f the toxicity symptoms are life threatening# administering / g of calcium gluconate by slo
intravenous push and strongly considering not reinstituting magnesium sulfate despite the return
to normal levels is recommended.
+ndomet&acin
2ndomethacin is an appropriate first-line tocolytic for the pregnant patient in early preterm labor
*D 30 !+ or preterm labor associated ith polyhydramnios. ) more significant inflammatory
response in the membranes and decidua is observed at gestational ages less than 30 ee!s
compared ith 30-3C ee!s. 2ndomethacin reduces prostaglandin synthesis from decidual
macrophages. &he fetal renal effects of indomethacin may be beneficial to reduce
polyhydramnios.
Prostaglandin synthetase inhibitors# such as indomethacin# have been shon to have efficacy
similar to that of terbutaline but are associated ith infrequent maternal side effects. ;oever#
these agents readily cross the placenta and can cause oligohydramnios due to a decrease in fetal
renal blood flo if used for more than <1 hours. &he administration of indomethacin is often
limited to <1 hours# and baseline labs# including 575 count and liver function tests *A'&s+#
should be ordered prior to initiation of therapy.
(uring treatment# urine output# maternal temperature# and amniotic fluid index *)'2+ should be
evaluated periodically. &he initial recommended dose is /00 mg P? folloed by -0 mg PO every
C hours for 1 doses. 2f oligohydramnios occurs# the amniotic fluid usually reaccumulates hen
the indomethacin is stopped# but persistent fetal anuria# renal microcystic lesions# and neonatal
death have been reported. 2ndomethacin can also cause premature closure or constriction of the
ductus arteriosus. %ince this effect is more common after 32 ee!sK gestation# indomethacin
therapy is not usually recommended after 32 ee!s.
,ifedipine
Bifedipine# a calcium channel bloc!er# is commonly used to treat high blood pressure and heart
disease because of its ability to inhibit contractility in smooth muscle cells by reducing calcium
influx into cells. 5onsequently# nifedipine has emerged as an effective and safe alternative
tocolytic agent for the management of preterm labor. (espite its unlabeled status# several
randomiHed studies have shon that the use of nifedipine in comparison ith other tocolytics is
associated ith a more frequent successful prolongation of pregnancy# resulting in significantly
feer admissions of neborns to the neonatal intensive care unit# and may be associated ith a
loer incidence of ?(%# necrotiHing enterocolitis# and intraventricular hemorrhage.
) systemic revie by 5onde-)qudelo found that nifedipine as associated ith significantly
feer maternal adverse events than P2 -adrenergic-receptor agonists and magnesium sulfate for
tocolysis in omen ith preterm labor.
.2=0
) recommended initial dosage of nifedipine is 20 mg orally# folloed by 20 mg orally after 30
minutes. 2f contractions persist# therapy can be continued ith 20 mg orally every 3-1 hours for
<1-72 hours ith a maximum dose of /C0 mg:d. )fter 72 hours# if maintenance is still required#
long-acting nifedipine 30-C0 mg daily can be used.
5ontraindications of nifedipine therapy include allergy to nifedipine# hypotension# hepatic
dysfunction# concurrent use of beta-mimetics or 9g%O<# transdermal nitrates# or other
antihypertensive medication. Other commonly reported side effects of nifedipine are maternal
tachycardia# palpitations# flushing# headaches# diHHiness# and nausea. 5ontinuous monitoring of
the fetal heart rate is recommended as long as the patient has contractionsI the patientKs pulse and
blood pressure should be carefully monitored. Pregnant omen ith liver disease should not be
prescribed nifedipine.
Follow/up $are
) true episode of preterm labor becomes a poerful ris! factor for recurrent preterm birth# in
addition to other ris! factors present prior to the current episode. &he prior ris! factor may have
been modifiedI for example# infection may have been identified and treated or behavioral ris!
factors may have been modified. Aittle evidence indicates that prophylactic oral beta-mimetic#
subcutaneous beta-mimetics# or oral magnesium gluconate reduce the incidence of recurrent
preterm birth and therefore should not be prescribed.
'requent contact# face-to-face or by telephone# ith a !noledgeable provider appears to be as
effective as home uterine activity monitoring *;$)9+ or continued pharmacological therapy.
(irect contact ith the patient is supplemented by education and phone access to a
!noledgeable# consistent provider. %ome unique situations exist in hich ;$)9 is still felt to
be beneficial# including patients ho are paraplegic and unable to appreciate any muscular
contractions.
&he goal of follo-up therapy is to maximally reduce recurrence ris! and to speed the access to
subspecialty care if preterm labor should recur.
+npatient
Once the episode of preterm labor has been arrested# a gradual return to limited activity should
be encouraged prior to hospital discharge. &he folloing factors may influence the decision to
discharge the patient4
5ervical dilation
'etal presentation
Bumber of fetuses
@estational age
)ccess to the hospital
%ocial support at home *transportation at all times# telephone+
&he ability to maintain limited activity and pelvic rest
@ood patient compliance
2f the patient as referred to a subspecialty care facility# the local obstetrical and pediatric
providers should be comfortable ith home management. 2f labor should recur# they may have to
manage the rapid delivery of premature infant.
&he patient should be informed regarding the signs and symptoms of recurrent preterm labor.
&he critical signs of recurrent preterm labor include contractions greater than < per hour#
rhythmic bac! or thigh pain# increasing pelvic pressure# unusual discharge# vaginal
spotting:bleeding# or rupture of membranes.
utpatient
&he provider should have increased contact ith the patient# and the patient should be directed to
a specific individual to report symptoms of preterm labor or complications. &he contact may be
via a combination of telephone contacts and office visits. Ghen genital tract infection may have
played a role in the preterm laborI a repeat culture may be recommended 2-< ee!s after
discharge.
2f inpatient tocolysis as unsuccessful and the patient delivered preterm# the patient and family
should receive education concerning the etiology and ris! of recurrence in subsequent
pregnancies. 'e etiologies exist for hich prediction of subsequent preterm delivery in future
pregnancies is /00> accurate. &ime should be spent at the postpartum visit revieing the
patientKs clinical history# laboratory data# and pathology reports. Preconceptual counseling may
also be critical in the decision of the patient to again become pregnant and in managing her
pregnancy
Preterm Labor
Author: Michael G Ross, MD, MPH; Chief Editor: Carl V Smith
http://emedicie!medscape!com/article/"#$%%&'o(er(ie)*sho)all