Prospective randomized study of corticosteroids in the management of premature rupture of the membranes and the premature gestation

Prospective randomized study of corticosteroids in the management of premature rupture of the membranes and the premature gestation THOMAS

J.

GARITE, M.D.

ROGER K. FREEMAK, M.D. E. MICHAEL LINZEY, M.D. PATRICIA S. BRALY, M.D. WENDY L. DORCHESTER, B.S. Long Beach, California A prO$p8Ctive randomized study involving patients with premature rupture of the membranes between the twenty-elghthweek and the thirty-fourth week of~ was conducted· conducted. Patients with chprioamnionitis, adv~ ad\t~ labor,· and fetlal distresa, as ·well as ·those with matul:e lecijhin/sphingomyelin ratioS and/or Gramstalns Gram stains podivefqr ~ we... detivered immediately. The remaining patients were randomized. One group received·~. Tocolytic agents were used in this group when necessary. After <48 hours all patIeilts patIet1ts given ~ (CS group) were delivered. The second group w~ rTI8I'lIgtd Il18I'lIgtd expectanU.y(EM ~)and were cielivered __ of 180 patlent8were~. 80 in only when spontaneous labor or infection occurred. A -.of each group. Maternal outcome, inclUding cI'IorioamntonI chorioamnionIU8 and section rates, was not enclometritis rate wassigniflctntt; wassigniflctntly higheI' Inttle CS group (p < 0.0$). different; however, the endometritis Neonatal outcome did not differ in rneanblrthweighla. perinataldNth ptrinataIdNIh rates, neonatatinfectlons, or incidences of respiratory ~. The frequency of .proiongad .hoIpitII atay (>4 week$)was higher in the neonates in the CS group (p < 0.01). The cono/uIiOn conotuaion is 1hat that ~ and active management in patients with preinature. premature rupture of tile· l'MmtIranes membranes and ~ ~ gestations ~ do not decrease the incidence of respiratory clisare8sayndrqme c/i8are8&ayndrqme or perinItaI mortaIily and end may .,.avate aggravate certain infectious complications. (AM. J. OSSTET. OBSTET. GVNECOL. 141:508, 1981.)

ce&ar.an

THE MANAGEMENT OF THE PATIENT with premature rupture of the membranes (PROM) in the preterm gestation is one of the most controversial issues in obstetrics today. In the past, the issue was basically limited to the question of delivery for all patients with PROM to avoid the complications of chorioamnionitis or expectant management of all patients, with delivery performed only when spontaneous labor or chorio-

From the Women's Hospital, Memorial Medical Center of L.ong Beach. Received for publication March 23, 1981. RevisedJune 16,1981. AcceptedJune 19,1981. Reprint requests: Thomas J. Garite, M.D., Women's Hospital, Memorial Medical Center of Long Beach, 2801 Atlantic Ave., Long Beach, California 90801.

508

amniomtls occurred. A more recently introduced treatment modality which further complicates the issue is the use of corticosteroids (CS), as introduced by Liggins and Howie, I to accelerate fetal pulmonary maturity. While many authors have included patients with PROM in their studies on CS,2-6 no author has in a prospectively randomized, controlled fashion· evaluated the use ofCSexdusively inpatients with PROM.It should be realized, of course, that there are several factors which make PROM distinctly different from premature labor alone in considering the use of CSt CS may aggravate infection and/or alter host immune responses in both mother and fetus/neonate. 7 .Furthermore, although controversial, PROM in and of itself may accelerate fetal pulmonary maturity and negate or mask any beneficial effect CS may have.~ Finally, any immediate or long-term adverse effects CS may have on the fetus/neonate 9 • 10 and its subsequent develop0002-93781811210508+08$00.80/0 © 1981 The C. V. :\Iosby Co.

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Corticosteroids in Corticosteroids in management management of of PROM and and premature premature gestation gestation

ment mandate ment mandate documentation documentation of of benefit benefit if if we we are are to to use them. use them.

Material and methods Material A study A study was was designed designed to to compare compare management management apapproaches in proaches in two two groups groups of of patients patients with with PROM PROM bebetween tween 28 28 and and 34 34 weeks weeks of of pregnancy. pregnancy. The The study study group group was managed was managed with with CS CS and and delivery delivery after after 48 48 hours, hours, inincluding tocolysis cluding tocolysis where where necessary. necessary. The The control control group group was managed was managed by by the the usual usual expectant expectant approach, approach, with with delivery performed delivery performed only only when when spontaneous spontaneous labor, labor, chorioamnionitis or chorioamnionitis or fetal fetal distress distress occurred. occurred. for the the study study were were selected selected from from clinic clinic Candidates for Candidates and private and private patients patients admitted admitted to to the the obstetric obstetric services services at at the Cniversity the Cniversity of of California California Irvine Irvine Medical Medical Center Center and and at Women's at Women's Hospital. Hospital. Memorial Memorial Medical Medical Center Center of of Long Beach. Long Beach. Included Included were were patients patients between between the the bebeginning of ginning of the the twenty-eighth twenty-eighth week week and and the the end end of of the the thirty-fourth week thirty-fourth week of of gestation. gestation. Dates Dates were were determined determined by menstrual by menstrual history history and and prenatal prenatal examinations examinations or or in in their absence their absence by by biparietal biparietal diameter diameter (BPD) (BPD) on on ulultrasound, and trasound, and aa best best clinical clinical estimate estimate of of gestational gestational age age was established. was established. Rupture Rupture of of membranes membranes was was docudocumented by mented by sterile sterile speculum speculum examination examination confirming confirming of fluid, fluid, alkaline alkaline pH pH by by l'\itrazine l'\itrazine paper, paper, and and pooling of pooling ferning, determined ferning, determined on on fluid fluid from from the the posterior posterior vagivaginal fornix. nal fornix. 1'\0 1'\0 digital digital examinations examinations were were performed, performed, although some although some patients patients had had been been examined examined digitally digitally prior to prior to maternal maternal transport. transport. Patients Patients with with equivocal equivocal or or undocumented rupture undocumented rupture ofthe ofthe membranes membranes (ROM) (ROM) were were not included not included in in the the study. study. Patients Patients were were evaluated evaluated for for fetal distress fetal distress and and for for chorioamnionitis chorioamnionitis (defined (defined by by fever of fever of 100.4 100.400 F F or or more more in in the the absence absence of of other other exexplanations. such planations. such as as urinary urinary tract tract infection). infection). Patients Patients with with chorioamnionitis chorioamnionitis or or fetal fetal distress distress were were delivered delivered immediately and immediately and were were not not randomized. randomized. Patients Patients in in adadby regular regular contractions contractions and and vanced vanced labor, labor, as as defined defined by clear visibility clear visibility of of the the fetal fetal presenting presenting part part on on initial initial speculum examination. speculum examination. were were allowed allowed to to deliver deliver and and were not were not included. included. Patients Patients were were then then randomized. randomized. PaPatients not given given CS CS and and were were not not tients declining declining study study were were not included in included in the the study. study. Patients Patients in in the the CS CS group group were were given betamethasone, given betamethasone, 12 12 mg mg intramuscularly, intramuscularly, two two doses, 24 doses, 24 hours hours apart. apart. Tocolysis Tocolysis was was used used in in these these papatients whenever tients whenever regular regular contractions contractions occurred. occurred. InitialInitially, intravenous ly, intravenous ethanol ethanol was was used used according according to to the the proprotocol of tocol of Fuchs Fuchs and and associates associates II II but but several several months months into into the study the study this this was was changed changed to to intravenous intravenous magnesium magnesium 12 sulfate by sulfate by aa modified modified protocol protocol of of Steer Steer and and Petrie. Petrie. 12 The modification The modification was was to to maintain maintain the the patient patient continucontinuouslyon aa regimen ouslyon regimen of of 1 1 to to 2 2 gm gm per per hour hour of of magnesium magnesium sulfate until sulfate until the the 4R 4R hours hours of of betamethasone betamethasone was was comcom-

509 509

At the the end end of of the the 48-hour 48-hour period, period, all all patients patients pleted. pleted. At who had who had been been given given betamethasone betamethasone wne wne delivered delivered either by either by discontlOuing discontlOuing the the towlytic towlytic agent, agent, by by inducinducing labor ing labor with with oxytocin, oxytocin, or or by by performing performing cesarean cesarean section. section. Patients randomized to to the the second second group group were were manmanPatients randomized aged expectantly aged expectantly (EM (EM group) group) and and delivered delivered only only when when and/or fetal fetal distress distress occurred. occurred. labor. chorioamnionitis, labor. chorioamnionitis, andlor Prior to Prior to institution institution of of either either management, management, patients patients were placed were placed in in the the Trendelenburg Trendelenburg position position and and monimonian external external Doppler Doppler fetal fetal heart heart rate rate (FHR) (FHR) tored with tored with an monitor for monitor for aa minimum minimum of of 30 30 minutes. minutes. The The patient patient then underwent then underwent immediate immediate ultrasonic ultrasonic examination examination (regardless of (regardless of the the time time of of day) day) where where the the BPD BPD was was dedetermined and termined and aa site site for for amniocentesis amniocentesis was was found. found. If If no no site could site could be be found, found, because because of of either either aa totally totally anterior anterior placenta or placenta or insufficient insufficient fluid, fluid, no no amniocelllesis amniocelllesis was was atattempted. When tempted. When amniocentesis amniocentesis was was successful successful the the fluid fluid was was sent sent to to the the laboratory laboratory for for immediate immediate lecilecithin: sphingomyelin thin: sphingomyelin (L: (L: S) S) ratio, ratio, Gram Gram stain, stain, and and culculture. Management ture. Management was was delayed delayed in in these these patients patients until until S ratio ratio and and Gram Gram stain stain results results were were known known (usu(usuthe L: the L: S ally 33 to ally to 4 4 hours). hours). If If the the L: L: S S ratio ratio was was 1.8: 1.8: 11 or or greater greater the fetus the fetus was was considered considered mature mature and and delivered. delivered. and and the the patient was patient was not not included included il;1 il;1 the the study. study. If If the the Gram Gram stain stain showed bacteria. showed bacteria. the the patient patient was was considered considered to to have have occult or occult or incipient incipient chorioamnionitis chorioamnionitis and and was was delivered delivered immediately. These immediately. These patients patients were were also also excluded excluded from from randomization. The randomization. The validity validity of of this this approach approach was was shown in in aa preliminary preliminary studyYl studyYl shown The route The route of of delivery delivery for for both both groups groups was was deterdetermined by mined by means means 0,:' 0,:' the the same same criteria. criteria. All All breeches breeches were were delivered by delivered by cesarean cesarean section. section. Where Where induction induction of of labor was labor was necessary necessary or or spontaneous spontaneous labor labor occurred, occurred, cecesarean section sarean section was was performed performed for for normal normal obstetric obstetric inindications. dications. The The presence presence of of chorioamnionit.is chorioamnionitis did did not not significantly alter significantly alter indications indications for for cesarean cesarean section section or or the the duration of duration of labor labor allowed. allowed. Prophylactic Prophylactic antibiotics antibiotics (ampicillin, (ampicillin, or or cephalothin cephalothin with with penicillin penicillin allergy) allergy) were were used after used after cord cord clamping clamping in in all all patient.·; patient.·; who who were were delivdelivered by ered by cesarean cesarean section section but but in in no no patient patient who who was was delivered delivered vaginally. vaginally. maternal patient patient data data were were coded coded prospectively. prospectively. All All maternal (l;eonatal data (l;eonatal data were were coded coded after after neonatal neonatal discharge. discharge. The diagnosis The diagnosis of of respiratory respiratory distress distress syndrome syndrome (RDS) (RDS) was made was made only only when when clinical clinical signs signs and and chest chest x-ray x-ray film film and the the newborn newborn infant infant required required at at were confirmatory were confirmatory and least 24 least 24 hours hours of of oxygen oxygen therapy. therapy. While While th(' th(' neonatolneonatologist ogist was was aware aware of of which which form form of of treatment treatment tt he he mother mother received, the received, the radiologist radiologist was was not. not. of data data was was performed performed by by means means of of chichiAnalysis of Analysis square and square and two-tai;ed two-tai;ed tt tests. tests.

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Garite et al.

Kovember 1, 19HI

Am. J. Obstet. Gynewl.

PTS AOMtTTED wmt PROM - 255

t

AMNIONJTIS - 21

ADVANCED LABOR - 9 FETAL DISTRESS - 4

.

+

MAlUIE L:S - 38

POSITIVE GRAM STMf -13 RANDOMIZED

DELNERED

DECI.HED STLOY - 5

CSGROlF - 80

EMGROlP-80

Fig. 1. Management of patients admitted with PROM.

Table I. Comparison of characteristics of patients in EM and CS groups Characteristic Gestational age (wk)* Maternal age (yr) Parity Duration of ROM (hr)*: <12 12-24 24-48 >48 Uterine activity * No contractions Irregular contractions Regular contractions

Table II. Effect of tocolysis: Comparison of all patients admitted with contractions

Significance

Admission to delivery time (hr) <24 24-48 >48

32 ± l.8 23.9 ± 5 l.l ± l.3

3l.7 ± 2.1 24.0 ± 5 0.9 ± l.2

NS NS NS

55 10 3 11

60 8 2 10

NS NS NS NS

33 16

36 20

NS NS

30

22

NS

NS: Not significant. *Determined at the time of admission.

Results The study was carried out between May, 1977, and July, 1980. During that time 255 patients were admitted with PROM between 28 and 34 weeks by best clinical estimate. From this group, a total of 160 patients were randomized, 80 in each group. The remainder of the patients were excluded for various reasons, as previously described and shown in Fig. 1. Two hundred eight patients underwent ultrasonic examination for possible amniocentesis. Ultrasonic examination was not performed in 47 patients because of either clinical chorioamnionitis, fetal distress, or advanced labor. Of the 208 patients, 98 (47%) had successful amniocen-

Tocolysis

(CS group)

34 4 6

11

10 21

p < 0.001 for >24 and >48 hours.

tesis, 12 (6%) had failed amniocentesis, and 97 (47%) did not undergo amniocentesis (no fluid pocket or anterior placenta). Thirteen (13%) of the 98 patients with successful amniocentesis had positive Gram stains for bacteria and were delivered. All 13 subsequently had confirmatory positive cultures. Thirty-eight patients with successful amniocentesis had mature L: S ratios (39%) and were delivered immediately (induction oflaboror cesarean section). In this group there was one case of mild RDS (2.6% RDS). no neonatal mortality. and no neonatal infections. The cesarean section rate in this group was 26%. One hundred sixty patients thus remained and met qualifications for and consented to randomization. Eighty patients were randomized to each group. The two groups appeared to be well matched for gestational age on admission, maternal age and parity, duration of ruptured membranes on admission, and uterine activity on admission (Table I). In the CS group 56 (70%) were delivered between 48 and 72 hours following the first dose of betamethasone (i.e., as per planned protocol), and 67 (84%) were de-

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Corticosteroids in management of PROM and premature gestation

511

?' DC

:i

§

.,D

D

OlD

Fig. %. Duration of ROM at delivery.

Fig. 3. Overall inCldence of postpartum endometritis. EM group = 11 (14%); CS group = 23 (29%).

livered at least 24 hours after the first dose of steroids. In Table II the success of tocolysis, in those patients requiring it, for achieving the 24 to 48 hours necessary for previously rta>Orted beneficial effects of CS is shown. As can be seen, the tocolytic agents (principally magnesium sulfate) were significantly more effective than no tocolytic agent in delaying labor for greater than 24 and greater than 48 hours, respectively. The duration of ROM prior to delivery (latent period) in patients managed expectantly is described in Fig. 2. The percentage of patients admitted without contractions and delivered at various intervals is also shown. As can be seen, in excess of 80% of patients admitted with PROM were delivered within less than 1 week whether or not they were in labor on admission. When the two groups were compared, the total duration of ROM at the time of delivery was not statistically different (EM group, 3.66 ± 7 days ; CS group, 2.73 ± 1.7 days), although tocolysis and active management do suggest a trend toward earlier delivery. The cesarean section rates were not statistically different between the two groups (EM = 25%; CS = 35%). The indications for cesarean section were also similar. The rate of chorioamnionitis occurring after admission was identical in both groups (11 patients, 14%). However, the postpartum endometritis rate was significantly higher in the CS group (p < 0.05). When the endometritis rate after cesarean section is compared to that after vaginal delivery (Fig. 3), it is significantly higher in the group delivered vaginally (p < 0.025). This difference is not accounted for by a difference in the duration of ROM at the time of deli v-

ery in patients with endometritis (EM group, 3.06 ± 2.7 days; CS group, 2.97 ± 1.6 days). Other infectious complications such as wound infection, urinary tract infection, etc., were not different between the two groups. There was no pulmonary edema or other unexpected major maternal complication in either group. Finally, the maternal postpartum hospital stay was similar in both groups, with only three patients in each group requiring hospitalization for more than 7 days following delivery. Seventy-nine live babies were delivered in the EM group, with one fetal death occurring in a patient with a prolapsed umbilical cord . Eighty live births occurred in the CS group. The distribution of the sexes of the neonates born in each group indicates the groups were well matched (CS group, 50 male/30 female; E\1 group, 48 male/32 female). There were, however, a substantially greater number of male infants delivered in the overall study. Gestational ages by neonatal assessment (Dubownz) were similar between the two . groups (33.5 ± 4.4 weeks in the EM group and 33.3 ± 2.4 week sin the CS group) as were birth weights (£<:\1 group, 2,015 ± 531 gm; CS group, I.H64 ::: 491 gm) . There were four neonatal deaths and one fetal death in the EM group and two neonatal deaths in the CS group (difference not significant) . The neonatal deaths included two from multiple congenital anomalies (one from each group), one from necrotizing enterocolitis, and three from RDS (two from the EM group and one from the CS group). These babies ranged from 28 to 34 weeks' gestation. Of particular interest is the neonatal outcome with

512 Garite et a!.

Am.

Table III. Neonatal respiratory distress syndrome SilfTliftcance Overall incidence: Total RDS RDS-on ventilator >24 hr RDS after 48 hr·

17 (21%) 12 (15%)

14 (17%) 12 (15%)

:-.l'S NS

5/36 (14%)

7/56 (12.5%)

NS

6124 (25%) 6/37 (15%)

NS NS NS

RDS and gestational age (wk): 28-30 10/21 (48%) 31-32 2/32 (6%) 33-34 5/26 (19%)

2/19 (11%)

*EM group '= 48 hours of ROM; CS group = 48 hours of betamethasone.

respect to RDS (Table III). The overall incidence of RDS was not different between the two groups. There was no statistically significant difference in the incidence of RDS (12.5%) in CS-treated patients where delivery was delayed by 48 hours or more (56/80 patients) compared to patients who had an equal or greater time of ROM (greater than 48 hours) in the EM group (14%) or compared to the overall EM group (21 % RDS). The number of babies with severe RDS (defined by requiring a ventilator for greater than 24 hours) was identical in the two groups. If patients are grouped by gestational age, there is still no apparent benefit in reducing RDS with CS(Table III). Furthermore, among those patients receiving CS only, there was no difference in the incidence of RDS between babies delivered less than 24 hours later, between 24 and 48 hours later, or after 48 hours. The duration of ruptured membranes did not influence the incidence of RDS in the EM group. There were no differences in the rates of RDS in male versus female babies in either group (EM = nine male and eight female; CS = eight male and six female). Infectious complications of the newborn infant are another important concern. There is no statistical difference between the two groups with respect to septicemia, meningitis, pneumonia, and/or omphalitis. However, it should be noted that all four cases of septicemia were in the CS-treated neonates. There was a significantly larger number of newborn infants who required prolonged hospitalization (greater than 4 weeks) in the CS group (33/80) than in the EM group (16/79) (p < 0.01). Populations at the two institutions are quite different. At LBMWH almost all patients are private. At CCIMC nearly all patients are indigent. However, in spite of these population differences, there was no difference in maternal or neonatal morbidity or mortality between patients from the two institutions.

1I:ovember I, 1981 Obstet. GynecoJ.

J.

Comment The management of the patient who presents with PROM prior to 34 weeks' gestation is one of the most difficult and controversial problems for the obstetrician today. In allowing or facilitating delivery in these patients, one faces the problems of prematurity and, as a consequence, neonatal morbidity and mortality. In delaying delivery, whether passively or actively, one faces the risk of maternal chorioamnionitis and its consequences both to the mother and the fetus/neonate. This dilemma has led to a myriad of management protocols. In 1972, when Liggins and Howie! first described the benefits of CS, which reduced the incidence of neonatal RDS when administered to the mother with threatened premature delivery, a new management alternative was introduced. This study was designed to compare two management alternatives for this problem. The reason that this study was undertaken was that while many studies have been done previously, demonstrating benefit with CS, few of these studies have specifically evaluated the problem of PROM within their study populations. 2- 6 Furthermore, very few studies have looked at the use of CS in patients with PROM specifically,2. 4 and none has been done in a prospectively randomized, controlled fashion. Our study was an effort to evaluate the use of CS in patients with PROM as compared to the more conventional mode of expectant management. Patients between 28 and 34 weeks were selected for study since this is the most difficult group of patients for whom to select the appropriate management. Patients at or beyond the thirty-fifth week of gestation are probably best managed by delivery since infection is probably a greater risk than prematurity; at less than 28 weeks, prematurity is probably more dangerous and expectant management appears best. In order to select patients who presented a real management dilemma, the protocol was designed to eliminate· patients in advanced labor, those with amnionitis, and those with fetal distress. }<"urthermore, amniocentesis was used when possible to eliminate those patients with mature L: S ratios and those with bacterial colonization of the amniotic fluid so that CS or expectant management might be limited when possible to those patients with immature fetuses and without occult or incipient infection. Of the patients who underwent ultrasonic examination for potential amniocentesis, we were successful in obtaining fluid in nearly half. Furthermore, in cases where fluid was obtained, over a third (39%) had mature L: S ratios. In these babies there was no perinatal

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mortality and mortality and very very little little morbidity morbidity (one (one case case of of mild mild RDS). The The patients patients with with positive positive amniotic amniotic fluid fluid Gram Gram RDS). stains all stains all had had subsequent subsequent positive positive bacterial bacterial cultures. cultures. that patients patients with with positive positive We have We have previously previously shown shown that of subsesubseamniotic fluid amniotic fluid cultures cultures have have high high incidences incidences of quent amnionitis quent amnionitis if if not not delivered delivered immediately!3 immediately!3 It It would thus would thus appear appear that that the the utilization utilization of of amniocentesis amniocentesis and bacterial bacterial studies studies might might offer offer aa rational rational way way for L: for L: S S and to select to select patients patients for for immediate immediate delivery delivery or or expectant expectant management. management. This protocol This protocol left left 160 patients patients available available for for randomrandomization during ization during the the period period of of study. study. Taeusch Taeusch and and assoassociates,6 calculating ciates,6 calculating from from previous previous studies studies with with the the use use of CS, of CS, have have said said that that this this sample sample size size should should be be adeadequate to quate to demonstrate demonstrate aa reduction reduction in in the the incidence incidence of of RDS. Furthermore, RDS. Furthermore, other other studies studies have have demonstrated demonstrated aa statistically significant statistically significant effect effect of of CS CS on on the the incidence incidence of of RDS with RDS with less less patients patients than than in in this this study. study.2,2, 3.3. 3, 6 The analysis The analysis of of gestational gestational age age on on admission, admission, matermaternal age nal age and and parity, parity, duration duration of of ruptured ruptured membranes, membranes, and uterine and uterine activity activity on on admission admission as as well well as as the the number number of female of female and and male male infants infants ultimately ultimately born born in in each each group suggested group suggested that that the the two two groups groups were were well well matched matched and, therefore, and, therefore, probably probably well well randomized. randomized. Since previous reports reports have have suggested suggested that that CS CS must must Since previous be be administered administered to to the the mother mother at at least least 24 hours hours and and preferably 48 preferably 48 hours hours prior prior to to delivery,1 delivery,1 it it is is important important to to demonstrate that demonstrate that we we were were able able to to obtain obtain that that much much time time in aa substantial in substantial number number of of patients patients prior prior to to delivery delivery in in patients patients given given CS. CS. Indeed, Indeed, 56 56 of of the the 80 80 babies babies were were hours after after the the first first dose dose of of betabetadelivered 48 delivered 48 hours methasone and methasone and another another 11 were were delivered delivered at at least least 24 hours after hours after the the first first dose. dose. Therefore, Therefore, the the sample sample size size of of patients treated patients treated with with an an adequate adequate duration duration of of CS CS is is 12 demonstrated probably reasonable. probably reasonable. Steer Steer and and Petrie Petrie 12 demonstrated that magnesium that magnesium sulfate sulfate can can be be an an effective effective tocolytic tocolytic premature labor. labor. This This study study agent in agent in patients patients with with premature and premature premature shows that shows that in in patients patients with with PROM PROM and labor, magnesium labor, magnesium sulfate sulfate as as aa tocolytic tocolytic agent agent can can be be the 24 to to 48 48 hours hours significantly successful significantly successful in in achieving achieving the needed to needed to obtain obtain the the intended intended benefit benefit from from betabetaof magnemagnemethasone. No methasone. No appreciable appreciable adverse adverse effect effect of sium sulfate sium sulfate was was seen seen in in this this study. study. reported by by others,14 others,14 the the As has As has been been previously previously reported onset of onset of labor labor and and subsequent subsequent delivery delivery usually usually occur occur within aa short within short time time following following PROM, PROM, even even in in the the prepremature gestation. mature gestation. As As can can be be seen seen in in Fig. Fig. 2, 2, nearly nearly 90% 90% of patients of patients in in this this population population managed managed expectantly expectantly were delivered were delivered less less than than 11 week week following following PROM. PROM. It It has has been pointed been pointed out out many many times, times, and and we we agree, agree, that that it it is is not reasonable not reasonable to to expect expect aa significant significant amount amount of of time time for fetal for fetal growth growth and and maturity maturity in in utero utero in in the the vast vast

513 513

of patit!nts patit!nts with with PROM. PROM. This This study study demondemonmajority of majority that even even in in patients patients presenting presenting with with PROM PROM and and strates that strates no uterine no uterine activity activity (labor), (labor), over over 80% 80% are are delivered delivered within aa week within week because because of of spontaneous spontaneous labor labor or or inducinduction of tion of labor labor because because of of infection. infection. Maternal complications Maternal complications were were not not significantly significantly differdifferent in ent in the the two two groups groups except except for for the the incidence incidence of of postpartum endometritis postpartum endometritis following following vaginal vaginal delivery. delivery. that we we could could not not withhold withhold prophylactic prophylactic ananWe felt We felt that tibiotics from tibiotics from patients patients delivered delivered by by cesarean cesarean section section since this since this treatment treatment has has been been shown shown to to be be beneficial. beneficial. However, in in the However, the patients patients delivered delivered vaginally. vaginally. prophyprophynot used used and and the the incidence incidence of of lactic antibiotics lactic antibiotics were were not postpartum endometritis postpartum endometritis was was considerably considerably higher higher in in patients treated patients treated with with CS. CS. This This did did not not seem seem to to be be due due to to aa difference difference in in duration duration of of ROM ROM between between the the two two and associates associates 66 are are the the only only other other auaugroups. Teusch groups. Teusch and reported an an increased increased incidence incidence of of any any thors who thors who have have reported infectious and this this infectious complications complications in in patients patients given given CS, CS. and greater increased incidence increased incidence was was in in patients patients delivered delivered greater than 48 than 48 hours hours after after initiation initiation of of CS CS therapy, therapy . as as were were the the of our our patients. patients. All All other other authors authors have have reremajority majority of ported no no increase increase in in infectious infectious complications complications with with CS, ported CS. but again but again most most were were not not studying studying patients patients with with PROM PROM alone. alone. It was It was surprising surprising to to note note that that there there were were substantially substantially more boys more boys than than girls girls delivered delivered in in both both groups. groups. This This is is important to important to evaluate evaluate because because of of previously previously reported reported differences in. differences in. the the incidence incidence and and severity severity in in RDS RDS bebetween tween male male and and female female newborn newborn infants. infants. The The explanaexplanathe disparity disparity in in boy boy versus versus girl girl deliveries deliveries in in this this tion for tion for the study study is is not not dear. dear. In In the the group group of of patients patients with with labor labor prior to to randomization. randomization, there there were were equal equal delivered prior delivered numbers of numbers of male male and and female female infants. infants. and and thIS thIS does does not not account for account for the the difference. difference. The birth The birth weigh!s weigh!s and and gestational gestational ages ages were were compacompaThere was was no no statistical statistical differdifferrable rable in in both both groups. groups. There ence in ence in perinatal perinatal deaths deaths between between the the two two groups. groups. The The one fetal one fetal death death o<:curred o<:curred some some time time after after discharge discharge the hospital hospital in in aa case case managed managed expectantly, expectantly, folfolfrom from the lowing the lowing the occurrence occurrence of of aa prolapsed prolapsed cord. cord. This This points points out the out the necessity necessity for for speculum speculum examination examination and and proproFHR monitoring monitoring following following admission admission to to rule rule longed FHR longed out cord out cord compression, compression, which which should should minimize minimize the the conconsequences of sequences of this this problem. problem. Two Two of of the the neonates, neonates, one one in in group, died died as as aa result result of of multiple multiple congenital congenital each group, each anomalies incompatible with life. life. One One baby baby in in the the EM EM anomalies incompatible with group died group died of of necrotizing necrotizing enterocolitis. enterocolitis. Therefore, Therefore, only three only three babies babies died died as as aa consequence consequence of of RDS, RDS, two two in in the EM the EM group group and and one one in in the the CS CS group; group; certainly certainly there there was no was no appreciable appreciable difference difference between between the the two two groups. groups. is important important to to note note that that the the low low overall overall However. However, it it is

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perinatal mortality rate of 44/1,000 in the randomized patients or, :when corrected for congenital anomalies, 31/1,000 is excellent for babies of these gestational ages regardless of management. Therefore, such good neonatal management may have masked any perinatal mortality differences which might have been achieved with either of the two management protocols. Looking specifically at RDS, we can see no difference between the two groups regardless of how this is analyzed. The reasons for the failure to demonstrate a reduction in the incidence of RDS with CS and the disparity between these results and those of the vast majority of the other studies are somewhat difficult to explain. However, there are a number of possible explanations. This study was limited to patients with PROM and was indeed prospective and randomized and in these respects was somewhat different from other studies. As pointed out by Quirk and associates!5 and since the overall incidence of RDS is fairly low compared to that of other studies, perhaps this is a consequence of good aggressive obstetric management, avoidance of intrapartum hypoxia and stress, and atraumatic delivery. Another factor which might account for the lack of any difference in the incidence of RDS between the CS and EM groups is the effect of duration of ROM alone in the EM group in decreasing RDS. While this study docs not demonstrate a clear statistical difference, there is somewhat of a trend toward a lower incidence of RDS after 48 hours. Finally, there is a tendency in this study toward more babies in the 32- to 34-week group where less benefit with CS has been previously demonstrated. "Ve were, however, unable to demonstrate benefit even in the earlier gestational age groups, as pointed out in Table III. Infectious complications in the newborn infant are also of concern. While we were unable to show distinct differences in neonatal infectious complications, all four cases of blood culture-proved septicemia were in the CS-treated neonates. The incidence of this entity is too small to draw firm statistical conclusions from a study of this size; however, the fact that all four cases

REFERENCES I. Liggins, G. C., and Howie, R. N.: A controlled trial of

antepartum glucocorticoid treatment for the prevention of the respiratory distress syndrome in premature infants, Pediatrics 50:515, 1972. 2. Mead, P. B., and Clapp,]. F.: The use of betamethasone and timed delivery in management of premature rupture of the membranes in the preterm pregnancy, j. Reprod. Med. 19:3, 1977. 3. Block, M. F., Kling, O. R., and Crosby, W. M.: Antenatal glucocorticoid therapy for the prevention of respiratory distress syndrome in the premature infant, Obstet. Gynecol. 50: 186, 1977.

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GVIlecol.

occurred in the CS group is a trend which suggests concern and possibly further investigation. Finally. with respect to neonatal outcome, the incidence of prolonged neonatal hospitalization (greater than 't weeks) in the CS group is difficult to explain, since there was no apparent difference in gestational ages and significant morbidities between the two groups which might prolong hospitalization. This prospectively randomized, controlled study failed to demonstrate any improvement in neonatal morbidity or mortality with a protocol of betamethasone administration and delivery after 48 hours over conventional expectant management. There was an increased incidence of maternal endometritis following vaginal delivery in patients treated with CS. There was also a suggestion of a possible relationship between neonatal septicemia and corticosteroids. We suggest that the overall approach of a sterile speculum examination to document amniorrhexis, prolonged FHR monitoring to rule out fetal distress from umbilical cord compression, amniocentesis with delivery of mature babies and those colonized with bacteria, and an aggressive obstetric and neonatal approach in a tertiary center leads to an overall excellent outcome. It is, therefore, our conclusion that the important elements in the management of patients with PROM in premature gestations include the foregoing factors and that CS are not beneficial when used in the patient with PROM and combined with an active approach and delivery after 48 hours. Furthermore, certain infectious complications may be increased when CS are used. Therefore, we would recommend against the use of CS in patients with PROM. We wish to express our appreciation to the attending staff, fellows, residents, and nurses involved in conducting this study without whose help it would not have been possible. Specifically we wish to thank Ms .. Cathy Rommal, Dr. Yorom Sorokin, and Dr. Gary Edwards for their contributions in accumulating data. We would also like to thank Dr. Edward J. Quilligan for his review and constructive comments on the manuscript.

4. Eggers. T. R., Doyle, L. W., and Pepperell, R.].: Premature rupture of membranes, Med. ]. Aust. 1:209, 1979. 5. Papageorgiou, A. K., Desgranges, M., Masson, M., et al.: A controlled double blind study of antenatal betamethasone, Pediatr. Res. 12:53, 1978. 6. Taeusch, H. W., Frigoletto, F., Kitzmiller,j., et al.:Riskof respiratory distress syndrome after prenatal dexamethasone therapy, Pediatrics 63:63, 1979. 7. Beck,]. C., and johnson,]. W. C.: Maternal administration of glucocorticoids, Clin. Obstet. Gynec61. 23:93, 1980. 8. Mead, P. B.: Management of the patient with premature rupture of the membranes, Clin. Perinatol. 7:243, 1980.

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9. Taeusch. Taeusch, H. W.: Glucocorticoid prophylaxis for respiratory of potential potential toxicity. toxicity. J. J. tory distress distress syndrome: syndrome: A A review review of Pediatr. 87:617,1975. Pediatr. 87:617,1975. 10. Johnson, 10. johnson, J. J. W. W. C., C., Mitzner, Mitzner, W., W., London, London, W. W. T., T., et et al.: al.: and the the rhesus rhesus fetus: fetus: Multisystemic Multisystemic efefBetamethasone and Betamethasone fects, A:\f. fects, A:\f. J. J. OBSTET. OBSTET. GYNECOL. GYNECOL. 133:677, 133:677, 1979. 1979. 11. Fuchs, 11. Fuchs, F., F., Fuchs, Fuchs, A. A. R., R., Poblette, Poblette, U. U. F.,jr, F.,Jr, et et al.: al.: Effect Effect of of alcohol on alcohol on threatened threatened premature premature labor, labor, AM AM .. .J. .J. OBSTET. OBSTET. GYNECOL. 99:627, GYNECOL. 99:627, 1967. 1967. 12. Steer, 12. Steer, C. C. ~., and and Petrie, Petrie, R. R. H.: H.: A A comparison comparison of of alcohol alcohol and magnesium and magnesium sulfate sulfate in in the the prevention prevention of of premature premature labor, AM labor, AM .. .J. .J. OBSTET. OBSTET. GYNECOL. GYNECOL. 129:1, 129:1, 1977. 1977.

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13. Garite, 13. Garite, T.j., T.j., Freeman, Freeman, R. R. K., K., Linzey, Linzey, E. E. M., M., et et al.: al.: The The use use of amniocentesis of amniocentesis in in patients patients with with premature premature rupture rupture of of membranes, Obstet. membranes, Obstet. Gynecol. Gynecol. 54:226,1979. 54:226,1979. 14. Gunn, 14. Gunn, G., G., MisheIl, MisheIl, D., D., and and Morton, Morton, D.: D.: Premature Premature ruprupture of ture of the the fetal fetal membranes, membranes, A:\f. A:\f. J. J. OBSTET. OBSTET. GYNECOI. GYNECOI. 106:469, 1970 106:469, 1970 15. Quirk, Quirk. J. j. G., G., Raker, Raker, R. R. K., K., Petrie, Petrie, R. R. H., H., et ct al.: al.: The The use use of of 15. glucocorticoids and glucocorticoids and unstressed unstressed labor labor with with atraumatic atraumatic dedeof respiratory respiratory distress distress synsynliveries in liveries in the the prevention prevention of AM .. .J. .J. OBSTET. OBSTET. GYNECOL. GYNECOL. 134:76H, 134:76H. 1979. 1979. drome, AM drome,