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Can preterm deliveries be prevented?
Can preterm deliveries be prevented? Denise M. Main, M.D., Steven G. Gabbe, M.D., Douglas Richardson, M.D., and Sharon Strong, R.N., M.S.N. Philadelphia, Penmylvania Our hospital serves poor, inner-city women who have a 17% preterm delivery rate. Middle-class women in San Francisco at high risk for preterm delivery have benefited from an antepartum program which emphasized patient education and close follow-up. Using a controlled, randomized design, we are investigating the impact of similar interventions. Patients determined to be at high risk before 18 weeks' gestation on the basis of the Creasy system are randomly assigned to the Preterm Labor Prevention Clinic or serve as high-risk controls. Sixty-four women assigned to the Preterm Labor Prevention Clinic and 68 high-risk control women have been delivered of their infants. No significant differences were noted for the percentages of preterm infants, mean gestational age, or birth weight. Preterm rupture of the membranes accounted for 40% of preterm deliveries in all high-risk patients. Thirty percent of preterm births were indicated for maternal or fetal reasons. The remaining 30% represented failure of tocolytic therapy. (AM J OBSTET GYNECOL 1985;151 :892-8.)
Key words: Preterm births, tocolytic therapy, preterm rupture of membranes Indigent women in the United States continue to experience extremely high preterm delivery rates. Perinatal mortality resulting from preterm births in this population is the major contributor to this country's relatively poor performance with respect to international perinatal statistics. 1 To have significant national impact, interventions designed to reduce the incidence of prematurity must benefit poor, inner-city women.'·' The Hospital of the University of Pennsylvania serves such a population. In 1982, 16.5% of pregnant women who registered for prenatal care at the obstetric clinic of the Hospital of the University of Pennsylvania prior to 18 weeks' gestation were delivered of preterm infants. Several investigators have attempted to identify prospectively those women most likely to be delivered before 37 weeks' gestation. Interventions designed to prevent preterm births could then be selectively applied to these high-risk women. Creasy et al.' have modified Papiernik-Berkhauer's risk scoring system and applied it prospectively to women in New Zealand. An initial score of""' l 0 points on this screening survey predicted a 30% chance of preterm delivery. Repeating the risk assessment at 24 to 28 weeks' gestation identified an From the Department of Obstetrics and Gynecology and the Jerrold R. Golding Division of Fetal Medicine, Department of Pediatrics, University of Pennsylvania School of Medicine. Supported by United States Public Health Service Grant MCJ420496-01-0. Presented by invitation at the Third Annual Meeting of the American Gynecologi.cal and Obstetrical Society, Hot Springs, Virginia, September 5-8, 1984. Reprint requests: Steven G. Gabbe, M.D., Department of Obstetrics and Gynpeo/ogy, Hospital of the University of Pennsylvania, 3400
Spruce St., Philadelphia, PA 19104.
892
additional group of women likely to be delivered before 37 weeks' gestation. This scoring system was then used to screen women at the University of California (San Francisco). 5 Those patients receiving ""'10 points were assigned to a special clinic designed to identify preterm labor at an early stage. Interventions in this clinic included weekly or biweekly pelvic examinations to detect asymptomatic cervical changes and education of both staff and patients about the subtle signs of preterm labor. High-risk patients were provided easy access to the medical staff around the clock. With these measures, the overall institutional preterm delivery rate fell from 6. 7% to 2.4%. The control population in this study included retrospective data from the same institution as well as historical and concurrent controls from an affiliated hospital. Material and methods
Using a randomized, controlled study design, we are investigating the impact of similar interventions applied prospectively to a population at great risk for preterm labor. To assess the characteristics of our population, a retrospective chart review was first performed which included all black patients who presented to the obstetric clinic of the Hospital of the University of Pennsylvania at or before 18 weeks' gestation and were delivered at the Hospital of the University of Pennsylvania in 1982. One nurse investigator (S. S.) assigned a risk score using the Creasy method to each of these patients based on the information available at the first clinic visit. This risk assessment system identified 29% of these patients to be at high risk for preterm labor. They accounted for 48% of all preterm births and 62% of all preterm births due to preterm labor or preterm rup-
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Table I. Overall outcome by risk group: Retrospective data High risk
Low
r~~k
Risk score
(~JO)
(
Significance
Gestational age (mean ± SD) (wk) Birth weight (mean ± SD) (gm) Risk score (mean ± SD) Deliveries <37 wk Deliveries <37 wk for PTL or PROM Birth weight <2500 gm Deliveries <37 wk and birth weight <2500 gm
157 37.4 ± 4.6 2729 ± 825 15.5 ± 6.7 42 (26.8%) 37 (23.6%) 48 (30.6%) 35 (22.3%)
377 38.9 ± 2.9 3060 ± 2.9 6.4 ± 2.1 45 (11.9%) 23 (6.1%) 46 (12.2%) 24 (6.4%)
p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001
No.
PTL
= Preterm labor; PROM = preterm rupture of the membranes.
ture of the membranes (Table I). The correlation coefficient between gestational age and risk score was - 0.33 with a total variance explained (r2) of 11 %. Our prospective study was started in April, 1983. All black patients presenting to the obstetric clinic of the Hospital of the University of Pennsylvania at or before 18 weeks' gestation were interviewed by the same nurse specialist and assigned a risk score according to the Creasy system. A cutoff of 18 weeks was selected to allow sufficient time for medical intervention and still include a large number of patients who registered after 12 weeks' gestation. Those women scoring ~10 points were assigned, by means of a random numbers table, either to a group that was offered participation in the Preterm Labor Prevention Clinic or to a group that served as high-risk controls. High-risk control patients were followed up by the obstetric residents in the routine or high-risk clinic at the discretion of the chief residents. Neither the physicians nor the high-risk control patients were informed of their high-risk status. Additionally, those women with scores of .;; 10 were followed up as low-risk controls in the same routine clinics staffed by obstetric residents. Patients agreeing to participate in the Preterm Labor Prevention Clinic were seen on a weekly or biweekly basis by one of two investigators (D. M. M. or S. G. G.) who performed a pelvic examination to assess early changes in cervical dilatation, effacement, consistency, and position. When significant cervical change was detected, uterine activity was monitored with a tocodynamometer. Patient education regarding the subtle signs of preterm labor was taught by the nurse-specialist and these lessons were reinforced by the physicians. Patients were taught to palpate for mild contractions on a daily basis. A 24-hour telephone "hot-line" was provided to assure easy patient access to medical care. Cerclages were performed when the patient's past obstetric history indicated cervical incompetence or when cervical effacement and/or dilatation were documented early in the second trimester and the patient had a history suggestive of cervical incompetence. Prophylactic tocolytic therapy and progestin treatment were not used.
Bed rest and prohibition of intercourse were not routinely recommended. Inpatient management of all women including the Preterm Labor Prevention Clinic group was directed by the residents and staff on service, not by the primary investigators in this study. The best obstetric estimate of gestational age at delivery was determined by analysis of last menstrual period, estimations of early uterine size, gestational age at which fetal heart tones were heard by fetoscope, and ultrasonic dating when done. Pediatric gestational age was based on the modification of Dubowitz testing by Ballard et al." Babies of high-risk controls and Preterm Labor Prevention Clinic patients were examined by one neonatologist (D.R.) who was blinded as to the mother's study group. These examinations were used to correct obstetric dating if results of the two methods differed by more than 3 weeks. Visits to the labor floor, hospital admissions, deliveries, and diagnoses in all study cases were recorded prospectively by the nurse-investigator. Statistical analysis was performed with the Statistical Package for the Social Sciences, and the programs for x2 , t tests, and analysis of variance were used as appropriate. Results
During the first 16 months of the study, 380 patients have been delivered of their infants. Approximately one third of the patients were high risk (I 32 of 380) and were randomly distributed into the Preterm Labor Prevention Clinic and high-risk control populations (Table II). Women in these groups experienced nearly one half of the total preterm deliveries (30 of 62) and almost one half of the preterm deliveries due to preterm labor or preterm rupture of the membranes (22 of 4 7). The ability of a risk score~ 10 to predict preterm delivery was poor with a correlation coefficient between gestational age at delivery and risk score of - 0.14 and a total variance explained (r 2 ) of I.9%. Significantly more women in the Preterm Labor Prevention Clinic visited the labor and delivery suite with complaints suggestive of preterm labor than did gravid women in the high-risk control group (37.5% versus
894 Main et al.
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Am J Obstet Gyneco]
Table II. Overall outcome by risk group Significance
No.
Gestational age (mean :t SD) (wk) Birth weight (mean :t SD) (gm) Deliveries <37 wk Deliveries <37 wk for PTL or PROM Birth weight <2500 gm Birth weight <2500 gm and <37 wk Deliveries <37 wk and <2500 gm for PTL and PROM PLPC
=
Preterm Labor Prevention Clinic; HRC
=
PLPC vs. / (PLPC + HRC) HRC vs. LRC
PLPC
HRC
LRC
64 37 .3 :t 4.3 2830 :t 840 16 (25.0%) II (17.2%) 14 (21.9%) 12 (18.8%) 8 (12.5%)
68 37.3 :t 4.6 2837 :t 813 14 (20.6%) I I (16.2%) 13 (19.1%) II (16.2%) 8 (11.8%)
248 38.4 :t 3.4 3023 :t 748 32 (12.9%) 25 (IO.!%) 37 (14.9%) 24 (9.7%) 14 (5.6%)
high-risk control; LRC
=
NS NS NS NS NS NS NS
p p p
0.05 0.03 0.05 NS NS p = 0.04 p = 0.04 = = =
low-risk control.
Table III. Primary reason for early delivery by risk group
I
Delivery <37 wk PTL, tocolysis failed or contraindicated PTL, mature lecithin/sphingomyelin ratio PROM Hypertension Bleeding Fetal distress Other
HRC
PLPC
16 3 (18.8%) 0
8 (50.0%) 0
2 (12.5%) I (6.2%) 2t (12.5%)
6 I 4 I
14 (42.9%) (7.1%) (28.6%) (7.1%) 0
I (7.1%) It (7.1%)
LRC
Significance*
32 IO (31.3%) 2 (6.3%) IO (31.3%) 3 (9.4%) 3 (9.4%) 2 (6.3%) 2t:j: (6.3%)
NS NS NS NS NS NS NS NS
*Significance of both comparisons: PLPC versus HRC and combined high-risk groups (PLPC + HRC) versus LRC. tlntrauterine fetal death before 24 weeks. :j:Medical complication at 34 weeks. 19.1 %, p = 0.03), indicating that these women had an increased awareness of the symptoms of preterm labor. There was a tendency for more women in the Preterm Labor Prevention Clinic to be diagnosed as having preterm labor, treated with tocolysis, and admitted to the hospital, though these differences did not reach significance. A cerclage was performed in 9.4% of Preterm Labor Prevention Clinic patients and in 2.9% of highrisk control patients. Preterm Labor Prevention Clinic women averaged 13.3 clinic visits as compared to 9.2 visits per high-risk control woman (p = 0.15 ). An average of 14.9 pelvic examinations were performed on each Preterm Labor Prevention Clinic participant before final labor and 4.6 on each high-risk control patient (p = 0.03). Despite the intensive interventions received by women in the Preterm Labor Prevention Clinic, the incidence of preterm delivery was similar in both the Preterm Labor Prevention Clinic and the high-risk control groups. Deliveries prior to 37 weeks occurred in 25.0% of the Preterm Labor Prevention Clinic women as compared to 20.6% of the high-risk control patients. Of the Preterm Labor Prevention Clinic participants, 17 .2% were delivered of preterm infants because of preterm labor or preterm rupture of the membranes, a rate almost identical to the 16.2% experienced by high-risk control women. Low-risk control patients also
experienced a very high preterm delivery rate, 12.9% overall, with 25 of 32 cases related to preterm labor or preterm rupture of the membranes. Preterm rupture of the membranes and/or failed tocolysis were the most common indications for preterm delivery in each group (Table III). There was no unusual skewing of gestational age at delivery among women who were delivered early based on group assignment. Similarly, the distribution of infant weights of those weighing <2500 gm at birth did not differ significantly by group assignment. The two high-risk groups were comparable with respect to age, gravidity, parity, number of early and late abortions, and gestational age at first visit (Table IV). There was no significant difference in the number of women who had a prior premature infant in the past, but the total and mean numbers of prior preterm deliveries in the Preterm Labor Prevention Clinic group were significantly higher than in the high-risk control group. Six patients in the Preterm Labor Prevention Clinic group accounted for 45% of the total prior preterm deliveries for the group. Because it is inappropriate to express means for nonparametric scores, we have presented risk scores in categorical groups of five points each. There was a tendency for more high-risk control women to have scores between IO and 14, although this was not statistically
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Table IV. Comparability of study groups
Age (mean ± SD) (yr) Gravidity (mean ± SD) Parity (mean ± SD) Abortions <14 wk (mean± SD) Abortions> 14 wk (mean ± SD) Prior preterm delivery (mean ± SD) No. of women with prior preterm delivery Gestational age, first visit
PLPC
HRC
23.3 ± 5.1 3.7 ± 1.8 1.3 ± 1.6 1.0 ± 1.5 0.7 ± 1.5 0.7 ± 1.3 29 (45%) 12.7 ± 3.4
22.5 ± 6.1 3.4 ± 1.8 1.3 ± 1.2 0.9 ± 0.8 0.3 ± 0.4 0.4 ± 0.6 22 (32%) 12.8 ± 3.3
LRC
23.5 2.8 1.2 0.6
± ± ± ± 0 0 0 12.I ±
Significance*
5.3 1.8 1.5 0.8
3.3
0.39 0.43 0.99 0.35 0.06 0.03 0.18 0.87
*PLPC versus HRC groups.
Table V. Comparability of risk scores in high risk groups PLPC
p
Table VI. Percentage of preterm deliveries by risk score category
HRC
Preterm deliveries
Risk score
n
%
n
%
Risk score
n
%
10-14 15-19 20-24 25-29 30+
28 II 12 6 7
44 17 19 9 II
42 13 6 4 3
62 19 9 6 4
32/248 13170 4/24
12.9 18.6 16.6 33.3 20.0 50.0
=
0. I 6 by 2 x 5 contingency table.
6118
2/10 5110
Differences among categories >I 0 are not significant. significant (Table V, p = 0.16). Furthermore, there was no difference in preterm delivery rates by risk score category for women with scores between 10 and 30 (Table VI). The subgroup of patients with two or more prior preterm deliveries for any reason constituted a remarkably high-risk population that experienced a preterm delivery rate of 67%. The uneven allocation of these nine patients between the two experimental groups (six to the Preterm Labor Prevention Clinic group, three to the high-risk control group) accounted for much of the difference in risk score between the groups. When these nine patients were removed from the analysis, the results remained unchanged, with 13% of each high-risk group delivered of preterm infants because of preterm rupture of the membranes or preterm labor.
Comment The most striking finding in this investigation was the absence of any demonstrable effect of our rather extensive intervention. For all three measures of outcome (mean gestational age, mean birth weight, and percentage of patients delivered prior to term), the Preterm Labor Prevention Clinic and high-risk control groups were virtually identical. This study remains ongoing. However, the absence of any current evidence of improvement in the intervention group suggests that increases in sample size will be unlikely to dem-
onstrate a significant prolongation in gestation. To exclude the possibility of an improvement of >4 days in gestational age, we calculated that a final sample size of 200 is needed for each high-risk group. Why were our intensive efforts unable to reduce the incidence of pre term deliveries in our population? Certainly patients attending the obstetric clinics at the Hospital of the University of Pennsylvania are at extremely high risk for preterm delivery. Our Preterm Labor Prevention Clinic patients came regularly for their clinic appointments and sought care on the labor and delivery floor when early signs of preterm labor were noted. They developed strong relationships with the special teaching nurse and the physicians staffing the Preterm Labor Prevention Clinic. Perhaps the multitude of factors which contribute to preterm delivery in this population cannot be overcome by more intensive observation and counseling during a single pregnancy. Berkowitz' and other investigators have documented that low socioeconomic status, low pregravid weight, inadequate weight gain during pregnancy, lack of leisure-time physical activities during the pregnancy, and a negative attitudinal expression toward the pregnancy will increase the risk of preterm delivery. 8 Such characteristics are common among black women seeking obstetric care at our hospital. It is entirely possible that conventional medical therapy is not as effective against these factors, even with early detection and timely initiation of treatment.
896 Main et al.
Preterm rupture of the membranes was the greatest single contributor to preterm delivery in the high-risk study groups. Thirty-five percent of all preterm deliveries and 40% of preterm births in the Preterm Labor Prevention Clinic and high-risk control patients were attributed to preterm rupture of the membranes. Other investigators have also found preterm rupture of the membranes to be responsible for approximately one third of all preterm births. 9 Preterm rupture of the membranes is a relative contraindication to inhibition of preterm labor. Thus, the Preterm Labor Prevention Clinic program, with its focus on early detection of preterm labor and rapid access to tocolysis, may have little to offer this group of patients. At least one recent report has suggested that frequent vaginal examinations to assess cervical dilatation and effacement might actually contribute to preterm rupture of the membranes at term. 10 However, in our study preterm rupture of the membranes was not significantly more common in patients who had frequent cervical assessments. An additional 34% of all preterm deliveries were indicated for maternal or fetal reasons. This high rate (5.5%) of intentional preterm deliveries reflects the underlying high-risk population and is nearly as high as the total preterm delivery rate at the University of California (San Francisco). Insofar as the Preterm Labor Prevention Clinic program cannot prevent pregnancyinduced hypertension, abruptio placentae, placenta previa, intrauterine growth retardation, or fetal distress, the only benefit for this group might be easier access to medical care. Finally, 30% of all preterm deliveries represented a failure of tocolysis. Of these patients, 4 7% were identified as high risk and could have received the special intervention. A substantial positive impact in this group would be necessary to produce a significant improvement in the overall performance of the study population. Our retrospective and prospective data demonstrate that there is some predictive value in the risk scoring system (positive predictive value = 23%, negative predictive value = 88%). The outcomes of the high-risk and low-risk groups are different with a high degree of statistical significance. However, the clinical value of this information is questionable. Only 30 of 62 patients who experienced preterm deliveries were correctly classified as high risk, a sensitivity of 48%. This limited sensitivity makes it an inadequate tool for discriminating term from preterm delivery in our population. Creasy et al. 1 assessed risk for preterm birth during the first trimester and repeated the risk assessment at 26 to 28 weeks. In our study, patients were assigned to risk groups only at their first clinic visit. More than one third were found to be at high risk on initial screening. Screening early in pregnancy enabled us to separate
April I, 1985 Am J Obstet Gynecol
the Preterm Labor Prevention Clinic study group from other clinic patients and thereby avoid any spillover for our interventional care to the high-risk control and lowrisk control populations. It was hoped that identification of patients early in pregnancy would provide adequate time for the Preterm Labor Prevention Clinic to improve outcome. With such a large population already at high risk, rescreening was thought to be of little benefit. In addition, rescreening could have overwhelmed the resources of the Preterm Labor Prevention Clinic and mixed the study groups. The question "Can preterm deliveries be prevented?" remains unanswered. The present study suggests that etiologic factors which may play an important role in producing preterm birth in one population and interventions designed to counteract these factors may not be universally applicable. Further research must be directed toward determining the causes of preterm delivery. As Eastman 11 noted almost 40 years ago: "Only when the factors causing prematurity are clearly understood can any intelligent attempt at prevention be made." REFERENCES l. Guyer B, Wallach LA, Rosen SL. Birth-weight-standardized neonatal mortality rates and the prevention of low birth weight: how does Massachusetts compare with Sweden? N Engl J Med I 982;306: I 230. 2. Williams RL, Chen PM. Identifying the sources of the recent decline in perinatal mortality rates in California. N Engl J Med I 982;306:207. 3. Kessel SS, Villar J, Berendes HW, Nugent RP. The changing pattern oflow birth weight in the United States.JAMA 1984;25 I: 1978. 4. Creasy RK, Gummer BA, Liggins GC. System for predicting spontaneous preterm birth. Obstet Gynecol I 980;55:692. 5. Herron MA, Katz M, Creasy RK. Evaluation of a preterm birth prevention program: preliminary report. Obstet Gynecol I 982;59:452. 6. Ballard JL, Novack KK, Driver M. A simplified score for assessment of fetal maturation in newly born infants. J Pediatr I 979;95:769. 7. Berkowitz GS. An epidemiologic study of preterm delivery. AmJ Epidemiol 1981;113:81. 8. Editorial. Precursors of preterm delivery. Lancet I 98 I; 1:1087. 9. Arias F, Tomich P. Etiology and outcome of low birth weight and preterm infants. Obstet Gynecol I 982;60:277. IO. Lenihan JP Jr. Relationship of antepartum pelvic examinations to premature rupture of the membranes. Obstet Gynecol 1984;63:33. I I. Eastman NT. Prematurity from the viewpoint of the obstetrician. Am Pract 1947;1:343.
Editors' note: This manuscript was revised after these
discussions were presented.
Discussion DR. Rov M. PITKIN, Iowa City, Iowa. Preterm birth clearly constitutes the major problem in perinatal medicine. It remains so in spite of the remarkable improvements in outcome provided by modern neonatal
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intensive care techniques and the development and widespread usage of pharmacologic agents for shortterm suppression of labor during the past decade or so. Thus additional means of addressing the problem are required. Dr. Gabbe has reported an extremely important clinical investigation to us today. He has tested the hypothesis that a defined intervention in prenatal care will lower the rate of preterm birth. The population, consisting of indigent urban black women with a prematurity frequency twice or more the national average, is ideal for such study. He used an established scoring system to identify subjects at particular risk and verified the accuracy of this system in his population. Then he applied, randomly and prospectively, an intervention suggested previously to be effective. In other words, keeping in mind the axiom, "A difference, to be a difference, must make a difference," he tested whether antepartum care including frequent visits to a seasoned and interested clinician, an intensive patient educational program, and around-the-dock access to consultation afforded any better outcome than more standard or customary care. It did not, an unfortunate result from the standpoint of our hopes but one which tells us that we had best look elsewhere in our efforts to deal with this most pressing of obstetric problems. Moreover, any disappointment we might feel regarding the negative findings should in no way detract from our admiration for a well-conceived and well-conducted clinical investigation. I have only two questions, both relatively minor: ( 1) Would analysis of nulliparous and parous women separately provide any further insight? This may be important since Creasy et al. (reference 4 of article) have shown that their scoring system is much more applicable to multigravid women than to primigravid women, presumably reflecting the key role of previous obstetric experience. (2) We are told that 9.4% of the Preterm Labor Prevention Clinic patients, who had weekly or biweekly cervical examinations, and 2.9% of the high-risk control patients underwent cerclage operations; what was the rate in the low-risk control group and what was the outcome of the cerclage procedures? DR. RICHARD H. SCHWARZ, Brooklyn, New York. Dr. Gabbe, in the statistics that you presented, although you passed over this point saying it was not significant, I noted that the incidence of premature rupture of the membranes in your study patients was 50%. The incidence in the high-risk control group was just 29%. Was that difference statistically significant, and do you have data on the number of examinations done in the high-risk control women? DR. RICHARD PAUL, Los Angeles, California. I believe Dr. Gabbe stated that there was a problem with frequent failure of tocolysis in these patients. I am curious to know the agent or agents used in these patients. Dr. Gabbe mentioned that premature rupture of the membranes was a relative contraindication to inhibition of preterm labor.
Prevention of preterm deliveries 897
Was tocolysis used in patients with premature rupture of the membranes? DR. ROBERT C. CEFALO, Chapel Hill, North Carolina. The State of North Carolina has a statewide program involving both the public and private sectors evaluating the preterm birth prevention program based on the Creasy/Herron model. Part of the evaluation is to look at the risk scoring tool. Fortunately, we have many physicians who are using the same risk scoring tool. This will give us an evaluation of whether the risk scoring tool for the particular population is appropriate. My question to Dr. Gabbe is, have you looked at the risk scoring tool and weighted the high-risk factors in your high-risk group? You may find out that your tool and the score of 10 are not appropriate for your population. DR. CHARLES FLOWERS, Birmingham, Alabama. We have apparently reached our ability to reduce perinatal mortality among infants weighing about 2500 gm. Our ability to manage major obstetric complications and monitor the condition of the fetus in utero has made congenital anomalies the principal cause of these infant deaths. What are some of the common threads that link these problems? They tend to occur most frequently among lower social groups. Sixty-five percent to 85% of these pregnancies are unplanned and frequently unwanted. There is thus little motivation for self-discipline and prenatal care. These patients are under tremendous stress. They frequently do not know where they will be living during the next 3 months. They live in crowded houses where their families occupy the space appropriate for one. Frequently family and social problems associated with poor housing, poor food, and poor people do not lead to tranquility. These stresses elevate catecholamines, which may reduce uterine blood flow. A reduction in decidual blood flow reduces the nutrition to the membranes. Stress also incites the production of norepinephrine which may stimulate uterine contractions, thus causing premature labor. Uterine contractions alter the lower uterine segment and reduce the integrity of the cervical mucus plug. Bacterial invasions through the cervix and poor nutrition to the membranes make their rupture likely. We are spending millions of dollars on tocolytic agents. We must balance the cost of these agents against the reduction in the incidence of low-birth weight infants. We may be spending money to no avail. Prematurity prevention clinics may be effective if we counsel patients, assist them in reducing the stresses in their life, give them support, and teach them to recognize the earliest signs of labor. The early use of tocolytic agents in combination with an attack on social problems may be effective in reducing these major obstetric problems. The problems of prematurity are social. Let us make our primary attack here. DR. CHARLES MAHAN, Gainesville, Florida. Obviously, if you have seen the poster session, Florida thinks some form of this program is going to work. But
898 Main et al.
it is important to study it and find out what worked in San Francisco that can be applied at other places. I have a couple of questions. One of the elements in our studies and in the San Francisco studies that seemed to pay off the most was having the patient see the same health provider every time she came back for a prenatal visit. It was not mentioned whether that was done in this study. Also, quite a bit of time was spent with those highrisk patients in the San Francisco study, a minimum of 20 minutes at a routine return visit. What were comparable times in the Philadelphia study? And, last, was vaginitis detected and aggressively treated in your study groups? DR. ROBERT K. CREASY, Houston, Texas. First of all, Dr. Gabbe referred to a premature labor prevention clinic. I have never done anything to try to prevent premature labor in the past. We have been trying to prevent premature birth. I was wondering if you could tell us, Dr. Gabbe, what you were doing to prevent the onset of premature labor rather than trying to stop premature labor. Second, could you tell us what number of patients in each group were candidates for the inhibition of premature labor? DR. E. STEWART TAYLOR, Denver, Colorado. I am not surprised by Dr. Gabbe's conclusions: two thirds of prematurity comes from causes we do not understand or have methods to prevent. The incidence of prematurity is two to three times greater among the indigent than among private patients. Better prenatal care will not prevent two thirds of the cases of prematurity, particularly among the indigent population. Through many years of studying this problem, I have concluded that low economic status and its associated problems of a lifetime of poor nutrition, poor hygiene, poor housing, and poor education are probably the causes for our high rate of prematurity in many areas of this country. These problems are social, not obstetric, but when they are solved, the prematurity rate will be reduced by one half to one third its present rate. I do not think that the rate of prematurity can be reduced through better obstetrics. DR. GABBE (Closing). In response to Dr. Pitkin's questions, the distribution of nulliparous and multiparous patients in the two study groups was the same. About a third of patients in the special clinic and in the highrisk control group were nulliparous and two third multiparous. The incidence of preterm delivery was the same in both groups, and, in fact, the scoring system seemed to be most predictive in the high-risk nulliparous patients. Cerclages were performed in six of the Preterm Labor Prevention Clinic patients and in two high-risk control patients. There were no cerclages in the low-risk control group. Of the six cerclages in the Pre term Labor Prevention Clinic patients, two women were delivered of term infants. The others were not, because of abrup-
April I, 1985 Am J Obstet Gynecol
tio placentae and preterm rupture of the membranes. Of the high-risk control patients who had cerclages, one of the two did have a term infant. I hope that answers your questions. We were concerned as well, Dr. Schwarz, about the increased incidence of preterm rupture of the membranes in the Preterm Labor Prevention Clinic patients. It was not significantly higher, but it was a concern, just as we were interested to see that the incidence of preterm delivery for failed tocolysis seemed to be somewhat lower in the special clinic patients. Patients who came to the Preterm Labor Prevention Clinic made, on the average, 14 visits and had 14 pelvic examinations. The high-risk control patients made on the average nine visits and had between four and five pelvic examinations. So that is a concern. As far as the agents used for tocolysis, we use ritodrine as our primary agent and then magnesium sulfate. Tocolytics are almost never given to patients with preterm rupture of the membranes. We have looked, Dr. Cefalo, at the risk scoring system and we are now evaluating what factors might be more predictive. We have also attempted to develop our own tool, looking at some of the factors that Dr. Flowers mentioned. I certainly agree with him. Dr. Hobel has emphasized for some time the concern about stress, so, to try to get a better handle on this, we are looking at factors such as: Do you have a stable home situation? Have you had an argument with your boyfriend? And other general health factors: When was the last time you saw a doctor? When was the last time your children saw a doctor? Dr. Mahan asked about the way the clinic was run. There were two health care providers who saw the patients at every visit, Dr. Denise Main or myself, so they were really only dealing with two staff physicians. We spent quite a bit of time with them and had our special nurse conduct a group therapy session, if you will, so that the patients were counseled and seen for at least 30 minutes on each visit. I agree, Dr. Creasy, that perhaps the clinic should not have been called a Preterm Labor Prevention Clinic, but the Preterm Birth Prevention Clinic. It was more common for patients in the special clinic to be seen on the labor floor, to be diagnosed as being in preterm labor, and to be hospitalized for it, but outside of the number of visits that they made to the labor floor, those treatment differences were not significant. Overall, 24 patients in the Preterm Labor Prevention Clinic groups visited the labor floor for preterm labor, 16 were hospitalized, and six received intravenous tocolytics. Of high-risk control patients, 13 came to the labor floor for preterm labor, seven were hospitalized, and only one received intravenous tocolytics. Finally, I agree with Dr. Taylor who concurs with Dr. Flowers. Dr. Stubblefield said some time back that if we want our rate of preterm birth to be the same as Sweden's, perhaps we will have to have a society that is more like Sweden's.
Key words: Preterm births, tocolytic therapy, preterm rupture of membranes Indigent women in the United States continue to experience extremely high preterm delivery rates. Perinatal mortality resulting from preterm births in this population is the major contributor to this country's relatively poor performance with respect to international perinatal statistics. 1 To have significant national impact, interventions designed to reduce the incidence of prematurity must benefit poor, inner-city women.'·' The Hospital of the University of Pennsylvania serves such a population. In 1982, 16.5% of pregnant women who registered for prenatal care at the obstetric clinic of the Hospital of the University of Pennsylvania prior to 18 weeks' gestation were delivered of preterm infants. Several investigators have attempted to identify prospectively those women most likely to be delivered before 37 weeks' gestation. Interventions designed to prevent preterm births could then be selectively applied to these high-risk women. Creasy et al.' have modified Papiernik-Berkhauer's risk scoring system and applied it prospectively to women in New Zealand. An initial score of""' l 0 points on this screening survey predicted a 30% chance of preterm delivery. Repeating the risk assessment at 24 to 28 weeks' gestation identified an From the Department of Obstetrics and Gynecology and the Jerrold R. Golding Division of Fetal Medicine, Department of Pediatrics, University of Pennsylvania School of Medicine. Supported by United States Public Health Service Grant MCJ420496-01-0. Presented by invitation at the Third Annual Meeting of the American Gynecologi.cal and Obstetrical Society, Hot Springs, Virginia, September 5-8, 1984. Reprint requests: Steven G. Gabbe, M.D., Department of Obstetrics and Gynpeo/ogy, Hospital of the University of Pennsylvania, 3400
Spruce St., Philadelphia, PA 19104.
892
additional group of women likely to be delivered before 37 weeks' gestation. This scoring system was then used to screen women at the University of California (San Francisco). 5 Those patients receiving ""'10 points were assigned to a special clinic designed to identify preterm labor at an early stage. Interventions in this clinic included weekly or biweekly pelvic examinations to detect asymptomatic cervical changes and education of both staff and patients about the subtle signs of preterm labor. High-risk patients were provided easy access to the medical staff around the clock. With these measures, the overall institutional preterm delivery rate fell from 6. 7% to 2.4%. The control population in this study included retrospective data from the same institution as well as historical and concurrent controls from an affiliated hospital. Material and methods
Using a randomized, controlled study design, we are investigating the impact of similar interventions applied prospectively to a population at great risk for preterm labor. To assess the characteristics of our population, a retrospective chart review was first performed which included all black patients who presented to the obstetric clinic of the Hospital of the University of Pennsylvania at or before 18 weeks' gestation and were delivered at the Hospital of the University of Pennsylvania in 1982. One nurse investigator (S. S.) assigned a risk score using the Creasy method to each of these patients based on the information available at the first clinic visit. This risk assessment system identified 29% of these patients to be at high risk for preterm labor. They accounted for 48% of all preterm births and 62% of all preterm births due to preterm labor or preterm rup-
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Table I. Overall outcome by risk group: Retrospective data High risk
Low
r~~k
Risk score
(~JO)
(
Significance
Gestational age (mean ± SD) (wk) Birth weight (mean ± SD) (gm) Risk score (mean ± SD) Deliveries <37 wk Deliveries <37 wk for PTL or PROM Birth weight <2500 gm Deliveries <37 wk and birth weight <2500 gm
157 37.4 ± 4.6 2729 ± 825 15.5 ± 6.7 42 (26.8%) 37 (23.6%) 48 (30.6%) 35 (22.3%)
377 38.9 ± 2.9 3060 ± 2.9 6.4 ± 2.1 45 (11.9%) 23 (6.1%) 46 (12.2%) 24 (6.4%)
p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001
No.
PTL
= Preterm labor; PROM = preterm rupture of the membranes.
ture of the membranes (Table I). The correlation coefficient between gestational age and risk score was - 0.33 with a total variance explained (r2) of 11 %. Our prospective study was started in April, 1983. All black patients presenting to the obstetric clinic of the Hospital of the University of Pennsylvania at or before 18 weeks' gestation were interviewed by the same nurse specialist and assigned a risk score according to the Creasy system. A cutoff of 18 weeks was selected to allow sufficient time for medical intervention and still include a large number of patients who registered after 12 weeks' gestation. Those women scoring ~10 points were assigned, by means of a random numbers table, either to a group that was offered participation in the Preterm Labor Prevention Clinic or to a group that served as high-risk controls. High-risk control patients were followed up by the obstetric residents in the routine or high-risk clinic at the discretion of the chief residents. Neither the physicians nor the high-risk control patients were informed of their high-risk status. Additionally, those women with scores of .;; 10 were followed up as low-risk controls in the same routine clinics staffed by obstetric residents. Patients agreeing to participate in the Preterm Labor Prevention Clinic were seen on a weekly or biweekly basis by one of two investigators (D. M. M. or S. G. G.) who performed a pelvic examination to assess early changes in cervical dilatation, effacement, consistency, and position. When significant cervical change was detected, uterine activity was monitored with a tocodynamometer. Patient education regarding the subtle signs of preterm labor was taught by the nurse-specialist and these lessons were reinforced by the physicians. Patients were taught to palpate for mild contractions on a daily basis. A 24-hour telephone "hot-line" was provided to assure easy patient access to medical care. Cerclages were performed when the patient's past obstetric history indicated cervical incompetence or when cervical effacement and/or dilatation were documented early in the second trimester and the patient had a history suggestive of cervical incompetence. Prophylactic tocolytic therapy and progestin treatment were not used.
Bed rest and prohibition of intercourse were not routinely recommended. Inpatient management of all women including the Preterm Labor Prevention Clinic group was directed by the residents and staff on service, not by the primary investigators in this study. The best obstetric estimate of gestational age at delivery was determined by analysis of last menstrual period, estimations of early uterine size, gestational age at which fetal heart tones were heard by fetoscope, and ultrasonic dating when done. Pediatric gestational age was based on the modification of Dubowitz testing by Ballard et al." Babies of high-risk controls and Preterm Labor Prevention Clinic patients were examined by one neonatologist (D.R.) who was blinded as to the mother's study group. These examinations were used to correct obstetric dating if results of the two methods differed by more than 3 weeks. Visits to the labor floor, hospital admissions, deliveries, and diagnoses in all study cases were recorded prospectively by the nurse-investigator. Statistical analysis was performed with the Statistical Package for the Social Sciences, and the programs for x2 , t tests, and analysis of variance were used as appropriate. Results
During the first 16 months of the study, 380 patients have been delivered of their infants. Approximately one third of the patients were high risk (I 32 of 380) and were randomly distributed into the Preterm Labor Prevention Clinic and high-risk control populations (Table II). Women in these groups experienced nearly one half of the total preterm deliveries (30 of 62) and almost one half of the preterm deliveries due to preterm labor or preterm rupture of the membranes (22 of 4 7). The ability of a risk score~ 10 to predict preterm delivery was poor with a correlation coefficient between gestational age at delivery and risk score of - 0.14 and a total variance explained (r 2 ) of I.9%. Significantly more women in the Preterm Labor Prevention Clinic visited the labor and delivery suite with complaints suggestive of preterm labor than did gravid women in the high-risk control group (37.5% versus
894 Main et al.
April I, 1985
Am J Obstet Gyneco]
Table II. Overall outcome by risk group Significance
No.
Gestational age (mean :t SD) (wk) Birth weight (mean :t SD) (gm) Deliveries <37 wk Deliveries <37 wk for PTL or PROM Birth weight <2500 gm Birth weight <2500 gm and <37 wk Deliveries <37 wk and <2500 gm for PTL and PROM PLPC
=
Preterm Labor Prevention Clinic; HRC
=
PLPC vs. / (PLPC + HRC) HRC vs. LRC
PLPC
HRC
LRC
64 37 .3 :t 4.3 2830 :t 840 16 (25.0%) II (17.2%) 14 (21.9%) 12 (18.8%) 8 (12.5%)
68 37.3 :t 4.6 2837 :t 813 14 (20.6%) I I (16.2%) 13 (19.1%) II (16.2%) 8 (11.8%)
248 38.4 :t 3.4 3023 :t 748 32 (12.9%) 25 (IO.!%) 37 (14.9%) 24 (9.7%) 14 (5.6%)
high-risk control; LRC
=
NS NS NS NS NS NS NS
p p p
0.05 0.03 0.05 NS NS p = 0.04 p = 0.04 = = =
low-risk control.
Table III. Primary reason for early delivery by risk group
I
Delivery <37 wk PTL, tocolysis failed or contraindicated PTL, mature lecithin/sphingomyelin ratio PROM Hypertension Bleeding Fetal distress Other
HRC
PLPC
16 3 (18.8%) 0
8 (50.0%) 0
2 (12.5%) I (6.2%) 2t (12.5%)
6 I 4 I
14 (42.9%) (7.1%) (28.6%) (7.1%) 0
I (7.1%) It (7.1%)
LRC
Significance*
32 IO (31.3%) 2 (6.3%) IO (31.3%) 3 (9.4%) 3 (9.4%) 2 (6.3%) 2t:j: (6.3%)
NS NS NS NS NS NS NS NS
*Significance of both comparisons: PLPC versus HRC and combined high-risk groups (PLPC + HRC) versus LRC. tlntrauterine fetal death before 24 weeks. :j:Medical complication at 34 weeks. 19.1 %, p = 0.03), indicating that these women had an increased awareness of the symptoms of preterm labor. There was a tendency for more women in the Preterm Labor Prevention Clinic to be diagnosed as having preterm labor, treated with tocolysis, and admitted to the hospital, though these differences did not reach significance. A cerclage was performed in 9.4% of Preterm Labor Prevention Clinic patients and in 2.9% of highrisk control patients. Preterm Labor Prevention Clinic women averaged 13.3 clinic visits as compared to 9.2 visits per high-risk control woman (p = 0.15 ). An average of 14.9 pelvic examinations were performed on each Preterm Labor Prevention Clinic participant before final labor and 4.6 on each high-risk control patient (p = 0.03). Despite the intensive interventions received by women in the Preterm Labor Prevention Clinic, the incidence of preterm delivery was similar in both the Preterm Labor Prevention Clinic and the high-risk control groups. Deliveries prior to 37 weeks occurred in 25.0% of the Preterm Labor Prevention Clinic women as compared to 20.6% of the high-risk control patients. Of the Preterm Labor Prevention Clinic participants, 17 .2% were delivered of preterm infants because of preterm labor or preterm rupture of the membranes, a rate almost identical to the 16.2% experienced by high-risk control women. Low-risk control patients also
experienced a very high preterm delivery rate, 12.9% overall, with 25 of 32 cases related to preterm labor or preterm rupture of the membranes. Preterm rupture of the membranes and/or failed tocolysis were the most common indications for preterm delivery in each group (Table III). There was no unusual skewing of gestational age at delivery among women who were delivered early based on group assignment. Similarly, the distribution of infant weights of those weighing <2500 gm at birth did not differ significantly by group assignment. The two high-risk groups were comparable with respect to age, gravidity, parity, number of early and late abortions, and gestational age at first visit (Table IV). There was no significant difference in the number of women who had a prior premature infant in the past, but the total and mean numbers of prior preterm deliveries in the Preterm Labor Prevention Clinic group were significantly higher than in the high-risk control group. Six patients in the Preterm Labor Prevention Clinic group accounted for 45% of the total prior preterm deliveries for the group. Because it is inappropriate to express means for nonparametric scores, we have presented risk scores in categorical groups of five points each. There was a tendency for more high-risk control women to have scores between IO and 14, although this was not statistically
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Table IV. Comparability of study groups
Age (mean ± SD) (yr) Gravidity (mean ± SD) Parity (mean ± SD) Abortions <14 wk (mean± SD) Abortions> 14 wk (mean ± SD) Prior preterm delivery (mean ± SD) No. of women with prior preterm delivery Gestational age, first visit
PLPC
HRC
23.3 ± 5.1 3.7 ± 1.8 1.3 ± 1.6 1.0 ± 1.5 0.7 ± 1.5 0.7 ± 1.3 29 (45%) 12.7 ± 3.4
22.5 ± 6.1 3.4 ± 1.8 1.3 ± 1.2 0.9 ± 0.8 0.3 ± 0.4 0.4 ± 0.6 22 (32%) 12.8 ± 3.3
LRC
23.5 2.8 1.2 0.6
± ± ± ± 0 0 0 12.I ±
Significance*
5.3 1.8 1.5 0.8
3.3
0.39 0.43 0.99 0.35 0.06 0.03 0.18 0.87
*PLPC versus HRC groups.
Table V. Comparability of risk scores in high risk groups PLPC
p
Table VI. Percentage of preterm deliveries by risk score category
HRC
Preterm deliveries
Risk score
n
%
n
%
Risk score
n
%
10-14 15-19 20-24 25-29 30+
28 II 12 6 7
44 17 19 9 II
42 13 6 4 3
62 19 9 6 4
32/248 13170 4/24
12.9 18.6 16.6 33.3 20.0 50.0
=
0. I 6 by 2 x 5 contingency table.
6118
2/10 5110
Differences among categories >I 0 are not significant. significant (Table V, p = 0.16). Furthermore, there was no difference in preterm delivery rates by risk score category for women with scores between 10 and 30 (Table VI). The subgroup of patients with two or more prior preterm deliveries for any reason constituted a remarkably high-risk population that experienced a preterm delivery rate of 67%. The uneven allocation of these nine patients between the two experimental groups (six to the Preterm Labor Prevention Clinic group, three to the high-risk control group) accounted for much of the difference in risk score between the groups. When these nine patients were removed from the analysis, the results remained unchanged, with 13% of each high-risk group delivered of preterm infants because of preterm rupture of the membranes or preterm labor.
Comment The most striking finding in this investigation was the absence of any demonstrable effect of our rather extensive intervention. For all three measures of outcome (mean gestational age, mean birth weight, and percentage of patients delivered prior to term), the Preterm Labor Prevention Clinic and high-risk control groups were virtually identical. This study remains ongoing. However, the absence of any current evidence of improvement in the intervention group suggests that increases in sample size will be unlikely to dem-
onstrate a significant prolongation in gestation. To exclude the possibility of an improvement of >4 days in gestational age, we calculated that a final sample size of 200 is needed for each high-risk group. Why were our intensive efforts unable to reduce the incidence of pre term deliveries in our population? Certainly patients attending the obstetric clinics at the Hospital of the University of Pennsylvania are at extremely high risk for preterm delivery. Our Preterm Labor Prevention Clinic patients came regularly for their clinic appointments and sought care on the labor and delivery floor when early signs of preterm labor were noted. They developed strong relationships with the special teaching nurse and the physicians staffing the Preterm Labor Prevention Clinic. Perhaps the multitude of factors which contribute to preterm delivery in this population cannot be overcome by more intensive observation and counseling during a single pregnancy. Berkowitz' and other investigators have documented that low socioeconomic status, low pregravid weight, inadequate weight gain during pregnancy, lack of leisure-time physical activities during the pregnancy, and a negative attitudinal expression toward the pregnancy will increase the risk of preterm delivery. 8 Such characteristics are common among black women seeking obstetric care at our hospital. It is entirely possible that conventional medical therapy is not as effective against these factors, even with early detection and timely initiation of treatment.
896 Main et al.
Preterm rupture of the membranes was the greatest single contributor to preterm delivery in the high-risk study groups. Thirty-five percent of all preterm deliveries and 40% of preterm births in the Preterm Labor Prevention Clinic and high-risk control patients were attributed to preterm rupture of the membranes. Other investigators have also found preterm rupture of the membranes to be responsible for approximately one third of all preterm births. 9 Preterm rupture of the membranes is a relative contraindication to inhibition of preterm labor. Thus, the Preterm Labor Prevention Clinic program, with its focus on early detection of preterm labor and rapid access to tocolysis, may have little to offer this group of patients. At least one recent report has suggested that frequent vaginal examinations to assess cervical dilatation and effacement might actually contribute to preterm rupture of the membranes at term. 10 However, in our study preterm rupture of the membranes was not significantly more common in patients who had frequent cervical assessments. An additional 34% of all preterm deliveries were indicated for maternal or fetal reasons. This high rate (5.5%) of intentional preterm deliveries reflects the underlying high-risk population and is nearly as high as the total preterm delivery rate at the University of California (San Francisco). Insofar as the Preterm Labor Prevention Clinic program cannot prevent pregnancyinduced hypertension, abruptio placentae, placenta previa, intrauterine growth retardation, or fetal distress, the only benefit for this group might be easier access to medical care. Finally, 30% of all preterm deliveries represented a failure of tocolysis. Of these patients, 4 7% were identified as high risk and could have received the special intervention. A substantial positive impact in this group would be necessary to produce a significant improvement in the overall performance of the study population. Our retrospective and prospective data demonstrate that there is some predictive value in the risk scoring system (positive predictive value = 23%, negative predictive value = 88%). The outcomes of the high-risk and low-risk groups are different with a high degree of statistical significance. However, the clinical value of this information is questionable. Only 30 of 62 patients who experienced preterm deliveries were correctly classified as high risk, a sensitivity of 48%. This limited sensitivity makes it an inadequate tool for discriminating term from preterm delivery in our population. Creasy et al. 1 assessed risk for preterm birth during the first trimester and repeated the risk assessment at 26 to 28 weeks. In our study, patients were assigned to risk groups only at their first clinic visit. More than one third were found to be at high risk on initial screening. Screening early in pregnancy enabled us to separate
April I, 1985 Am J Obstet Gynecol
the Preterm Labor Prevention Clinic study group from other clinic patients and thereby avoid any spillover for our interventional care to the high-risk control and lowrisk control populations. It was hoped that identification of patients early in pregnancy would provide adequate time for the Preterm Labor Prevention Clinic to improve outcome. With such a large population already at high risk, rescreening was thought to be of little benefit. In addition, rescreening could have overwhelmed the resources of the Preterm Labor Prevention Clinic and mixed the study groups. The question "Can preterm deliveries be prevented?" remains unanswered. The present study suggests that etiologic factors which may play an important role in producing preterm birth in one population and interventions designed to counteract these factors may not be universally applicable. Further research must be directed toward determining the causes of preterm delivery. As Eastman 11 noted almost 40 years ago: "Only when the factors causing prematurity are clearly understood can any intelligent attempt at prevention be made." REFERENCES l. Guyer B, Wallach LA, Rosen SL. Birth-weight-standardized neonatal mortality rates and the prevention of low birth weight: how does Massachusetts compare with Sweden? N Engl J Med I 982;306: I 230. 2. Williams RL, Chen PM. Identifying the sources of the recent decline in perinatal mortality rates in California. N Engl J Med I 982;306:207. 3. Kessel SS, Villar J, Berendes HW, Nugent RP. The changing pattern oflow birth weight in the United States.JAMA 1984;25 I: 1978. 4. Creasy RK, Gummer BA, Liggins GC. System for predicting spontaneous preterm birth. Obstet Gynecol I 980;55:692. 5. Herron MA, Katz M, Creasy RK. Evaluation of a preterm birth prevention program: preliminary report. Obstet Gynecol I 982;59:452. 6. Ballard JL, Novack KK, Driver M. A simplified score for assessment of fetal maturation in newly born infants. J Pediatr I 979;95:769. 7. Berkowitz GS. An epidemiologic study of preterm delivery. AmJ Epidemiol 1981;113:81. 8. Editorial. Precursors of preterm delivery. Lancet I 98 I; 1:1087. 9. Arias F, Tomich P. Etiology and outcome of low birth weight and preterm infants. Obstet Gynecol I 982;60:277. IO. Lenihan JP Jr. Relationship of antepartum pelvic examinations to premature rupture of the membranes. Obstet Gynecol 1984;63:33. I I. Eastman NT. Prematurity from the viewpoint of the obstetrician. Am Pract 1947;1:343.
Editors' note: This manuscript was revised after these
discussions were presented.
Discussion DR. Rov M. PITKIN, Iowa City, Iowa. Preterm birth clearly constitutes the major problem in perinatal medicine. It remains so in spite of the remarkable improvements in outcome provided by modern neonatal
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intensive care techniques and the development and widespread usage of pharmacologic agents for shortterm suppression of labor during the past decade or so. Thus additional means of addressing the problem are required. Dr. Gabbe has reported an extremely important clinical investigation to us today. He has tested the hypothesis that a defined intervention in prenatal care will lower the rate of preterm birth. The population, consisting of indigent urban black women with a prematurity frequency twice or more the national average, is ideal for such study. He used an established scoring system to identify subjects at particular risk and verified the accuracy of this system in his population. Then he applied, randomly and prospectively, an intervention suggested previously to be effective. In other words, keeping in mind the axiom, "A difference, to be a difference, must make a difference," he tested whether antepartum care including frequent visits to a seasoned and interested clinician, an intensive patient educational program, and around-the-dock access to consultation afforded any better outcome than more standard or customary care. It did not, an unfortunate result from the standpoint of our hopes but one which tells us that we had best look elsewhere in our efforts to deal with this most pressing of obstetric problems. Moreover, any disappointment we might feel regarding the negative findings should in no way detract from our admiration for a well-conceived and well-conducted clinical investigation. I have only two questions, both relatively minor: ( 1) Would analysis of nulliparous and parous women separately provide any further insight? This may be important since Creasy et al. (reference 4 of article) have shown that their scoring system is much more applicable to multigravid women than to primigravid women, presumably reflecting the key role of previous obstetric experience. (2) We are told that 9.4% of the Preterm Labor Prevention Clinic patients, who had weekly or biweekly cervical examinations, and 2.9% of the high-risk control patients underwent cerclage operations; what was the rate in the low-risk control group and what was the outcome of the cerclage procedures? DR. RICHARD H. SCHWARZ, Brooklyn, New York. Dr. Gabbe, in the statistics that you presented, although you passed over this point saying it was not significant, I noted that the incidence of premature rupture of the membranes in your study patients was 50%. The incidence in the high-risk control group was just 29%. Was that difference statistically significant, and do you have data on the number of examinations done in the high-risk control women? DR. RICHARD PAUL, Los Angeles, California. I believe Dr. Gabbe stated that there was a problem with frequent failure of tocolysis in these patients. I am curious to know the agent or agents used in these patients. Dr. Gabbe mentioned that premature rupture of the membranes was a relative contraindication to inhibition of preterm labor.
Prevention of preterm deliveries 897
Was tocolysis used in patients with premature rupture of the membranes? DR. ROBERT C. CEFALO, Chapel Hill, North Carolina. The State of North Carolina has a statewide program involving both the public and private sectors evaluating the preterm birth prevention program based on the Creasy/Herron model. Part of the evaluation is to look at the risk scoring tool. Fortunately, we have many physicians who are using the same risk scoring tool. This will give us an evaluation of whether the risk scoring tool for the particular population is appropriate. My question to Dr. Gabbe is, have you looked at the risk scoring tool and weighted the high-risk factors in your high-risk group? You may find out that your tool and the score of 10 are not appropriate for your population. DR. CHARLES FLOWERS, Birmingham, Alabama. We have apparently reached our ability to reduce perinatal mortality among infants weighing about 2500 gm. Our ability to manage major obstetric complications and monitor the condition of the fetus in utero has made congenital anomalies the principal cause of these infant deaths. What are some of the common threads that link these problems? They tend to occur most frequently among lower social groups. Sixty-five percent to 85% of these pregnancies are unplanned and frequently unwanted. There is thus little motivation for self-discipline and prenatal care. These patients are under tremendous stress. They frequently do not know where they will be living during the next 3 months. They live in crowded houses where their families occupy the space appropriate for one. Frequently family and social problems associated with poor housing, poor food, and poor people do not lead to tranquility. These stresses elevate catecholamines, which may reduce uterine blood flow. A reduction in decidual blood flow reduces the nutrition to the membranes. Stress also incites the production of norepinephrine which may stimulate uterine contractions, thus causing premature labor. Uterine contractions alter the lower uterine segment and reduce the integrity of the cervical mucus plug. Bacterial invasions through the cervix and poor nutrition to the membranes make their rupture likely. We are spending millions of dollars on tocolytic agents. We must balance the cost of these agents against the reduction in the incidence of low-birth weight infants. We may be spending money to no avail. Prematurity prevention clinics may be effective if we counsel patients, assist them in reducing the stresses in their life, give them support, and teach them to recognize the earliest signs of labor. The early use of tocolytic agents in combination with an attack on social problems may be effective in reducing these major obstetric problems. The problems of prematurity are social. Let us make our primary attack here. DR. CHARLES MAHAN, Gainesville, Florida. Obviously, if you have seen the poster session, Florida thinks some form of this program is going to work. But
898 Main et al.
it is important to study it and find out what worked in San Francisco that can be applied at other places. I have a couple of questions. One of the elements in our studies and in the San Francisco studies that seemed to pay off the most was having the patient see the same health provider every time she came back for a prenatal visit. It was not mentioned whether that was done in this study. Also, quite a bit of time was spent with those highrisk patients in the San Francisco study, a minimum of 20 minutes at a routine return visit. What were comparable times in the Philadelphia study? And, last, was vaginitis detected and aggressively treated in your study groups? DR. ROBERT K. CREASY, Houston, Texas. First of all, Dr. Gabbe referred to a premature labor prevention clinic. I have never done anything to try to prevent premature labor in the past. We have been trying to prevent premature birth. I was wondering if you could tell us, Dr. Gabbe, what you were doing to prevent the onset of premature labor rather than trying to stop premature labor. Second, could you tell us what number of patients in each group were candidates for the inhibition of premature labor? DR. E. STEWART TAYLOR, Denver, Colorado. I am not surprised by Dr. Gabbe's conclusions: two thirds of prematurity comes from causes we do not understand or have methods to prevent. The incidence of prematurity is two to three times greater among the indigent than among private patients. Better prenatal care will not prevent two thirds of the cases of prematurity, particularly among the indigent population. Through many years of studying this problem, I have concluded that low economic status and its associated problems of a lifetime of poor nutrition, poor hygiene, poor housing, and poor education are probably the causes for our high rate of prematurity in many areas of this country. These problems are social, not obstetric, but when they are solved, the prematurity rate will be reduced by one half to one third its present rate. I do not think that the rate of prematurity can be reduced through better obstetrics. DR. GABBE (Closing). In response to Dr. Pitkin's questions, the distribution of nulliparous and multiparous patients in the two study groups was the same. About a third of patients in the special clinic and in the highrisk control group were nulliparous and two third multiparous. The incidence of preterm delivery was the same in both groups, and, in fact, the scoring system seemed to be most predictive in the high-risk nulliparous patients. Cerclages were performed in six of the Preterm Labor Prevention Clinic patients and in two high-risk control patients. There were no cerclages in the low-risk control group. Of the six cerclages in the Pre term Labor Prevention Clinic patients, two women were delivered of term infants. The others were not, because of abrup-
April I, 1985 Am J Obstet Gynecol
tio placentae and preterm rupture of the membranes. Of the high-risk control patients who had cerclages, one of the two did have a term infant. I hope that answers your questions. We were concerned as well, Dr. Schwarz, about the increased incidence of preterm rupture of the membranes in the Preterm Labor Prevention Clinic patients. It was not significantly higher, but it was a concern, just as we were interested to see that the incidence of preterm delivery for failed tocolysis seemed to be somewhat lower in the special clinic patients. Patients who came to the Preterm Labor Prevention Clinic made, on the average, 14 visits and had 14 pelvic examinations. The high-risk control patients made on the average nine visits and had between four and five pelvic examinations. So that is a concern. As far as the agents used for tocolysis, we use ritodrine as our primary agent and then magnesium sulfate. Tocolytics are almost never given to patients with preterm rupture of the membranes. We have looked, Dr. Cefalo, at the risk scoring system and we are now evaluating what factors might be more predictive. We have also attempted to develop our own tool, looking at some of the factors that Dr. Flowers mentioned. I certainly agree with him. Dr. Hobel has emphasized for some time the concern about stress, so, to try to get a better handle on this, we are looking at factors such as: Do you have a stable home situation? Have you had an argument with your boyfriend? And other general health factors: When was the last time you saw a doctor? When was the last time your children saw a doctor? Dr. Mahan asked about the way the clinic was run. There were two health care providers who saw the patients at every visit, Dr. Denise Main or myself, so they were really only dealing with two staff physicians. We spent quite a bit of time with them and had our special nurse conduct a group therapy session, if you will, so that the patients were counseled and seen for at least 30 minutes on each visit. I agree, Dr. Creasy, that perhaps the clinic should not have been called a Preterm Labor Prevention Clinic, but the Preterm Birth Prevention Clinic. It was more common for patients in the special clinic to be seen on the labor floor, to be diagnosed as being in preterm labor, and to be hospitalized for it, but outside of the number of visits that they made to the labor floor, those treatment differences were not significant. Overall, 24 patients in the Preterm Labor Prevention Clinic groups visited the labor floor for preterm labor, 16 were hospitalized, and six received intravenous tocolytics. Of high-risk control patients, 13 came to the labor floor for preterm labor, seven were hospitalized, and only one received intravenous tocolytics. Finally, I agree with Dr. Taylor who concurs with Dr. Flowers. Dr. Stubblefield said some time back that if we want our rate of preterm birth to be the same as Sweden's, perhaps we will have to have a society that is more like Sweden's.