The mammary stimulation test—A predictor of preterm delivery?

The mammary stimulation test- A predictor of preterm delivery? Robert D. Eden, MD, Robert J. Sokol, MD, Yoram Sorokin, MD, Helen J. Cook, RNC, MSN, Gail Sheeran, RNC, and Lawrence Chik, PhD Detroit, Michigan Clinical risk identification for preterm delivery, the major cause of perinatal morbidity and mortality, remains problematic. To test the hypothesis that a provocative test for uterine contractility at the beginning of the third trimester would reliably identify patients destined to be delivered before and at term, we designed the mammary stimulation test. Uterine contractions In response to nipple stimulation at a mean of 28.6 weeks' gestation, were evaluated in 94 gravid patients at risk for preterm delivery. The mammary stimulation test, the results of which were not used for clinical management, was positive in 50% of patients tested and had a sensitivity of 84% and a positive predictive value of 34% (x 2 = 11.15, P < 0.01). Ninety-four percent of patients predicted to be delivered at term actually were delivered at term (negative predictive value). Furthermore, no patients with a negative mammary stimulation test were delivered within 1 month of testing or were delivered of infants weighing <2000 gm. Discriminant analysis indicated that the mammary stimulation test provided information beyond that available from clinical risk factors alone. A cost analysis suggested that the use of the mammary stimulation test could reduce the cost of ambulatory uterine activity monitoring by nearly 50%. If these findings can be validated in additional samples, the mammary stimulation test may be useful in prematurity prevention programs. (AM J OSSTET GVNECOL 1991 ;164: 1409-19.)

Key words: Mammary stimulation test, prematurity, nipple stimulation

Preterm birth remains the major cause of perinatal morbidity and mortality and results in significant expenditures of health care resources. 1 2 Preventing prematurity is highly desirable but is hampered by the limitations of clinical risk assessment. Current programs, including clinical risk assessment, patient behavioral modification, ambulatory uterine activity monitoring, and tocolysis, have not produced a decrease in the incidence of prematurity. 1 " 1 Clinical risk assessment and scoring for preterm delivery are based primarily on epidemiologic and medical factors, including selected social and demographic factors, obstetric and medical histories, and current pregnancy complications.'" Although risk scoring systems are helpful in identifying women destined to be delivered prematurely, they have low sensitivities and From the Department of Obstetrics and G.~necology, Wayle State UnlVerslt~.

Supported In part b.~ a grant from Healthdyne Pennatal Senllces. Annual PrIZe Award, presented at the Fifty-eighth Annual Meetlllg of the Central AssoczatlOn of ObstetriCians and G~necologlstS. LOlllSVille, Kentuck~. October 11-13,1990. Reprllit reque.~ts. Robert D Eden, MD, Department ofObstetll[j and G_~necology. Hutzel Hospital, 4707 St. Antome Blvd.. Detroit. M1 48201 6/6/28940

positive predictive values." The addition of ambulatory uterine activity monitoring may contribute to improved identification of the at-risk patient,H.II but its costeffectiveness is questionable. I 12·1" Our hypothesis, which is based on a theoretical consideration of the endocrine control of parturition, states that a provocative test of uterine contractility at the beginning of the third trimester could identify patients destined to be delivered prematurely. We designed the. mammary stimulation test for this purpose. This study prospectively evaluates the ability of the mammary stimulation test to predict preterm delivery in a sample of at-risk patients.

Methods During a 6-month period, 94 gravid patients who were between 24 and 32 weeks' gestation and were attending a core-city antenatal clinic for the medically indigent were enrolled in a research protocol approved by the Human Investigation Committee of Wayne State University. Demographic factors, gestational duration, and clinical risk factors were recorded. After written informed consent was obtained, the patient was placed in semi-fowler's position. Doppler fetal heart rate was obtained, and a tokotransducer was applied (Hewlett-

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June 1991 Am J Obstet Gynecol

Table I. Clinical characteristics, antenatal risk factors, and mammary stimulation test results for preterm and term delivery groups No. of patients Maternal characteristics Maternal age (yr) Gravidity Parity Gestational duration at testing (wk) Antenatal risk factors Major factors Previous preterm delivery* Multiple gestation* Cervical incompetence* > 1 previous* Cone biopsy Minor factors 1 Previous elective abortion Late prenatal care* Maternal stress Pregnancy < 12 mo Fibroid uterus Chronic urinary tract infection Maternal age < 16 yr Bleeding after 18 wk Positive mammary stimulation test

Preterm

Term

Total

19 (20%)

75 (80%)

94 (100%)

23.7 3.5 1.3 28.9

± ± ± ±

6.5 2.1 l.l 2.2

23.1 3.2 1.2 28.5

± ± ± ±

5.3 2.1 1.4 2.2

23.2 3.2 1.2 28.6

± ± ± ±

5.5 2.1 1.3 2.2

13 (68%) 9 (47%) 3 (16%) 2 (ll%) 5 (26%) 0(0%)

24 12 2 3 9 3

(32%) (16%) (3%) (4%) (12%) (4%)

37 21 5 5 14 3

3 (16%) 4 (21%) 2 (11 %) 3 (16%) 2 (11 %) 0(0%) 1(5%) 0(0%) 16 (84%)

18 4 6 3 3 4 2 2 31

(24%) (5%) (8%) (4%) (4%) (5%) (3%) (3%) (41%)

21 (22%) 8 (9%Jt 8 (9%) 6 (6%) 5 (5%) 4(4%) 3 (3%) 2 (2%) 47 (50%)t

(39%)t (22%)t (5%)t (5%) (15%) (3%)

*Risk factors used in discriminant analysis (Table V). tp < 0.05.

Packard 8040A). According to a standard protocol of nipple stimulation contraction stress testing,17 baseline uterine activity was evaluated for at least 10 minutes, after which the patient lightly stimulated one breast (nipple) through her clothing for 2 minutes. Stimulation was discontinued if contractions occurred. If contractions did not occur, the same protocol was repeated after a 2-minute rest period for up to three cycles. If there was still no uterine activity, the patient first performed unilateral stimulation for 10 minutes, followed, if necessary, by bilateral stimulation for another 10 minutes. When uterine activity subsided, we discontinued monitoring. All patients had management by resident and staff physicians who did not know the mammary stimulation test results. The primary outcome measure, which was chosen a priori, was preterm delivery, which we defined as delivery before 37 completed weeks' gestation by best obstetric estimate. Secondary outcome measures included preterm labor, the need for tocolysis, and testto-delivery interval. Contingency tables were constructed to evaluate the relationship of mammary stimulation test results to outcome measures. In exploratory analyses, differences in continuous variables were evaluated by the Student t test, and categoric variables were evaluated by X2 • We used discriminant analyses, which included the inde-

pendent variables of candidate clinical risks and mammary stimulation test results and the dependent variables of preterm delivery and preterm labor, to determine whether mammary stimulation test results provided information beyond that available from clinical risks. A p value of <0.05 was considered significant. Results

Of the 94 patients in the study sample, 19 (20%) had preterm delivery. Clinical characteristics, antepartum risks, and mammary stimulation test results (independent variables) are shown in Table I. As we anticipated, preterm delivery was preceded by an excess of recognized antepartum medical and obstetric risk factors. The preterm and term delivery groups did not differ in the gestational duration (approximately 28.5 weeks) at which the mammary stimulation test was performed. However, the mammary stimulation test was positive about twice as frequently among the patients who had preterm delivery than among those who were delivered at term (84% vs 41 %, respectively). Table II documents pregnancy outcomes, including the primary and secondary outcome measures (dependent variables). Among the 19 patients who were delivered before term, only one infant died in the neonatal period. There were no complications attributable to mammary stimulation test testing.

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Table II. Outcome measures for preterm and term delivery groups

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ I-----.:.p---=.re-te-r-m~--r----T-e-rm-----,----T-ot-a-l--No. of patients Preterm labor Tocolysis Mammary stimulation test-Delivery interval (wk) Gestational duration (wk) Birth weight (gm) Cesarean section Required NICU stay Maternal postpartum stay (days)

19 (20%) 6 (32%) 4 (21%) 4.3 ± 2.3 33.5 ± 2.2 1987 ± 431 6 (31%) 10 (53%) 3.0 ± 1.5

94 (100%) 16 (17%) 12 (13%) 9.1 ± 3.8* 38.2 ± 3.0* 2961 ± 784 13 (14%)* 13 (14%)* 2.8 ± 1.5

75 (80%) 10 (13%) 8 (11%) 10.7 ± 2.8 39.7 ± 1.1 3291 ± 573 7 (9%) 3 (4%) 2.7 ± 1.5

NICU, Neonatal intensive care unit. *p < 0.05.

Table IlIA. Relationship of mammary stimulation test results to preterm delivery

Mammary stimulatIOn test Positive Negative TOTAL

X'

P Value

Odds ratio Relative risk Sensitivity Specificity Positive predictive value Negative predictive value At risk Explained variance

Table IIIB. Relationship mammary stimulation test results to preterm labor

Preterm deltvery Yes

I

16 3 19

No

Total

31 44 75

47 47 94

11.15 <0.01 7.6 ± 5.1 2.0 84% 59% 34% 94% 50% 12%

Relationships of mammary stimulation test results to the primary and secondary outcome measures are shown in the contingency tables (Tables lilA, IIIB, and IIIC). The odds that a patient with a positive mammary stimulation test would be delivered before term were increased 7.6-fold. A positive mammary stimulation test correctly identified 16 of the 19 patients who were delivered before term (sensitivity = 84%). In addition, a negative test preceded term delivery in 44 of 4 7 patients (negative predictive value = 94%). Among the three patients with negative mammary stimulation tests who were delivered before term, delivery occurred after 34 weeks' gestation, none had a test-to-delivery interval of <5 weeks. Furthermore, all babies born to mothers with negative mammary stimulation tests weighed >2000 gm. Mammary stimulation test results were related to the occurrence of preterm labor with a strength similar to that for preterm delivery (explained variance = 12%).

Mammary stimulatIOn test Positive Negative TOTAL

X'

P value

Odds ratio Relative risk Sensitivity Specificity Positive predictive value Negative predictive value At risk Explained variance

Preterm labor Yes

1

23 8 31

No

Total

24 39 63

47 47 94

10.83 < 0.01 4.7 ± 2.3 1.9 74% 62% 50% 83% 50% 12%

No patient with a negative mammary stimulation test was delivered during the month after the test (positive predictive value = 100%), and all patients who were delivered during the succeeding month had a positive mammary stimulation test (specificity = 100%). To evaluate the potential role of the mammary stimulation test in clinical care, test results were related to preterm delivery in patients with the major risk factors shown in Table I. The results of this analysis are shown in Table IV. Limiting use of the mammary stimulation test to high-risk patients doubles the explained variance (24%) of the classification. However, comparing Tables lilA, IIIB, IIIC, and IV reveals that six patients who were delivered before term did not have major highrisk factors and that five of these had positive mammary stimulation tests. Finally, to better understand the relationship of mammary stimulation test results and clinical factors as potential predictors of preterm outcomes, we per-

1412 Eden et al.

June 1991 Am J Obstet Gynecol

Table IIIC. Mammary stimulation test-to-delivery interval Mammary stImulatIOn test-to-delivery interval Mammary stimulatIOn test

~5

TOTAL

Relative risk Sensitivity Specificity Positive predictive value Negative predictive value At risk Explained variance

Table IV. Relationship of mammary stimulation test results to preterm delivery in high-risk patients Preterm delivery

TOTAL

X'

P Value

Odds ratio Relative risk Sensitivity Specificity Positive predictive value Negative predictive value At risk Explained variance

Yes

<5 wk

Total

0 12 12

47 47 94

13.76 <0.01 2.3 57% 100% 100% 26% 50.0% 15%

X'

P Value

Positive Negative

I

47 35 82

Negative Positive

Mammary stimulation IRst

wk

I

II 2 13

No

Total

8 16 24

19 18 37

8.88 <0.01 11.0 ± 9.7 2.5 85% 67% 58% 89% 51% 24%

formed two discriminant analyses, that allowed the clinical factors to be entered before the mammary stimulation test results. In addition to demographic data, clinical factors included the risk factors indicated by asterisks in Table I. Two antenatal risk factors, previous preterm delivery and late prenatal care, contributed significantly to the classification of preterm delivery [F (2,91) = 8.9, R' = 16.4%]. The mammary stimulation test significantly improved the classification by adding an additional 7.7% of explained variance [F (3,90) = 9.5, R' = 24.1 %]. Four clinical factors contributed significantly to the classification of preterm labor [F (4,89) = 12.4, R' = 35.8%]. The mammary

stimulation test significantly improved this classification, as well, by adding an additional 5.2% of explained variance [F (5,88) = 12.3, R 2 = 35.8%]. The resulting jackknifed classifications are shown in Tables VA and VB. Comparison of Table VA with Table IlIA reveals that, although including clinical risks doubles the explained variance and improves the specificity from 59% to 91 %, six cases of preterm birth, which are correctly classified by the mammary stimulation test alone, are misclassified when clinical risks are taken into account, thereby decreasing the sensitivity from 84% to 53%. Comparing Table 1I1B with Table VB reveals that considering clinical risks improves the positive predictive value from 49% to 73% and the specificity from 62% to 87% without substantially diluting the sensitivity. Comment

The key finding in this study is that a new provocative test, the mammary stimulation test, predicts preterm delivery and can be used to predict both preterm labor and not being delivered within 1 month of testing. In addition, the mammary stimulation test provides more extensive information than do the usual clinical risk factors considered useful for identifying patients destined to deliver before term. The seed that led to our development of the mammary stimulation test derived from exposure of one of the authors (R.J.S.) to a technique used by Drs. Arpad Csapo and Jacques Sauvage at Washington University in 51. Louis more than two decades ago. Uterine response to oxytocin challenge was used as a marker of the evolution of uterine contractility l8 to predict whether induction of labor would be successful and to

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Volume 164 Number 6. Part 1

Table VA. Jackknifed classifications from discriminant analysis for preterm delivery

Mammary stimulation test

I

No

Total

17 77

Positive risk Negative risk

10

7

9

TOTAL

19

68 75

Odds ratio Relative risk Sensitivity Specificity Positive predictive value Negative predictive value At risk Explained variance

Table VB. Jackknifed classifications from discriminant analysis for preterm labor

Proelem delivery Yes

1413

94

10.8 ± 6.6

5.0 53% 91% 59%

88% 18%

24%

Risk factors: MST results. previous preterm delivery, late prenatal care.

answer the question, "Is the myometrium in a state that is ready for labor?" During the past two decades, substantial research has been used to explain the basis for the evolving uterine response to oxytocin challenge. 19 It appears that uterine sensitivity to oxytocin increases with advancing gestational age as a result of an increase in the number and effectiveness of myometrial oxytocin receptors!O-n Because oxytocin sensitivity increases before the onset of labor, several investigators have correlated uterine activity, oxytocin sensitivity, and perterm labor and delivery.19 Uterine activity and oxytocin sensitivity are increased in patients who are delivered before term. 2 '.26 Finally, a separate line of research indicates that nipple stimulation results in oxytocin release and elevation of plasma levels of oxytocin. 27·29 As a result of these studies, we speculate that in patients destined to be delivered before term, the mammary stimulation test reveals the state of the myometrium as marked by increased sensitivity to oxytocin endogenously released by nipple stimulation. The results presented here should be interpreted cautiously. This initial series of patients is small. Validation in larger samples with different demographic characteristics will be necessary. In particular, the utility of the mammary stimulation test must be tested in samples with lower prevalences of preterm labor and delivery. An additional caveat is that the initial criterion for mammary stimulation test positivity was simply stated in the study protocol as "the presence of uterine contractility." More specific criteria were derived heuristically by one of the investigators (R.D.E.) in con-

Mammary sllmulalwn 'lest

Positive risk Negative risk TOTAL

Odds ratio Relative risk Sensitivity Specificity Positive predictive value Negative predictive value At risk Explained variance

Preleml labor

I

Yes

22 9 31

No

8

55

63

Total

30 64 94

16.8 ± 8.2 5.2 71% 87% 73% 86% 32% 12%

Risk factors include: mammary stimulation test results, gravidity, abortions, multiple gestation, and previous preterm delivery.

Table VI. Mammary stimulation test criteria I. Positive test a. Any spontaneous uterine contraction(s»40 seconds before initiation of nipple stimulation b. Any uterine contraction(s) of >40 seconds by completion of two stimulation cycles (8 minutes from the onset of stimulation) 2. Negative test Absence of uterine activity [contraction(s) that last for >40 seconds before or during stimulation.

junction with interpreting the tracings. The resulting criteria are shown in Table VI. To be classified as a positive mammary stimulation test, uterine activity (contractions >40 seconds in duration) should be noted before the onset of stimulation (Fig. I) or in response to nipple stimulation before the end of the second 2minute rest period (Fig. 2). To be classified as a negative mammary stimulation test (Fig. 3), uterine activity should not be observed before the 'end of the second rest period (8 minutes after the onset of unilateral breast stimulation). In this series all mammary stimulation tests that became positive did so before 8 minutes after the onset of unilateral stimulation. Although interpretation of the tracings was entirely blinded as to clinical outcome, these recommended criteria also require validation. Despite the caveats noted in the previous paragraph, the mammary stimulation test appears to have considerable promise for clinical application. It appears to be more sensitive in detecting risk for prematurity than

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Am.J Obstet

G~necol

••••• •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••

.................

"

"

.

.................................................................................................... Fig. 1. Spontaneous positive mammary stimulation test. Spontaneous uterine contraction(s) are noted before initiation of nipple stimulation.

.... ..

.

.

....................................................................................................

................................................................................................... . Fig. 2. Positive mammary stimulation test. Uterine contractions are noted by completion of two stimulation cycles.

Mammary stimulation test to predict preterm delivery

Volume 164 l'\umber n. Pall I

.11

1

'1

11

,

'11

,

11

'11

111

11

'111

,.,

11 . . 11

11

I

,

tll

1415

..

II

.

•

Fig. 3. Negative mammary stimulation test. Absence of uterine activity before or during stimulation.

200 High-risk patients

I

I

Protocol B

Protocol A

I

200 patients MST screening at 28 weeks (cost per test $75) $30.000

I

200 Patients

J.

Home uterine monitoring ($90/day) Weekly prenatal care

I

I

PositIve MST

Negative MST

100 Patients

100 Patients

I

I

I . Home utenne

Weekly prenatal care

monitoring ($90/day) Weekly prenatal care 4 weeks

I

MST re~creening (32 weeks) (cost per test $75) $15,000 8 weeks

.l-

I

4 weeks

8 weeks I

+

Total costs

Total costs

$1,008,000

$534.000

$5,040 per patient

$2,670 per patient

I

Fig. 4. Potential cost savings of home uterine aCtIvity monitormg when preceded by mammary stimulation test (MST) screening.

are clinical factors. The nipple stimulation and monitoring methods" are well validated and safe and currently are widely used in clinical practice to perform contraction stress tests. Performing the mammary stimulation test usually requires aboUl 20 minutes, which is a duration between that needed for fetal nonstress testing and that for contraction stress testing. In addition, the mammary stimulation test appears to reliably identify patients who will nol be delivered prematurely.

Thus it appears that mammary stimulation test testing could be a highly cost-effective component of prematurity prevention. Currently, formal prematurity prevention programs consist of clinical t-isk assessment, patient behavioral modification, and ambulatory uterine activity monitoring. The most controversial and the most expensive of these techniques is ambulatory uterine activity monitoring, and its contribution to prematurity prevention

1416 Eden et al.

is controversial. With a method such as the mammary stimulation test, which is more accurate than clinical risk assessment in predicting preterm delivery, the numbers of patients requiring daily uterine activity monitoring might be reduced, and cost-effectiveness might be improved. Fig. 4 depicts a cost analysis of an ambulatory uterine activity monitoring program both with and without mammary stimulation test screening, it uses assumptions that are based on observed rates in the current series. Monitoring is routinely begun at 28 weeks' gestation and continues for 8 weeks in a hypothetical sample of 200 patients at risk for preterm delivery. Under protocol A, all patients are monitored at home at a cost of $90 per day, which results in a total cost in excess of $1 million. However, if mammary stimulation test screening is used at 28 weeks at a cost of $75 per test to determine risk status, 100 patients (those with negative mammary stimulation tests) do not require home uterine activity monitoring (protocol B). Because the predictive value of a negative mammary stimulation test persists for at least 5 weeks, patients are retested in 1 month (32 weeks) to reevaluate risk status. The net savings of the mammary stimulation test screening program are nearly half the cost of an ambulatory uterine activity monitoring program. In conclusion, the mammary stimulation test appears to have the theoretical rationale, predictive utility, simplicity, safety, and low cost that recommend additional study to determine whether it should playa major role in the care of pregnant women. REFERENCES 1. Health United States 1987. Rockville, Maryland: US Department of Health and Human Services, 1988:48. 2. Vital statistics of the United States: natality. Rockville, Maryland: US Department of Health and Human Services, 1987;1:255. 3. US Center for Health Statistics. Characteristics of births, United States, in 1973-1975. Washington DC: US Government Printing Office, 1978. 4. Cole HM. Home monitoring of uterine activity. ]AMA 1989;261 :3027. 5. Creasy RK, Gummer BA, Liggins GC. A system for predicting spontaneous preterm birth. Obstet Gynecol 1980;55:692-5. 6. Main DM, Gabbe SG. Risk scoring for preterm labor: where do we go from here? AM ] OBSTET GYNECOL 1987;157:178-93. 7. Poland ML, Ager ]W, Olson KL, Sokol R]. Quality of prenatal care: selected social, behavioral and biomedical factors and birth weight. Obstet GynecoI1990;75:607-11. 8. Katz M, Newman R, Gill P]. Assessment of uterine activity in ambulatory patients at high risk of preterm labor and delivery. AM] OBSTET GYNECOL 1986;154:44-7. 9. Katz M, Gill P], Newman RB. Detection of preterm labor by ambulatory monitoring of uterine activity. Obstet Gynecol 1986;68:773-8. 10. Morrison]C, Martin]N, Martin RW, Goohin KS, Wiser WL. Prevention of preterm birth by ambulatory assessment of uterine activity: a randomized study. AM] OBSTET GYNECOL 1987;156:536-43.

June 1991 Am J Obstet Gynecol

II. Morrison]C. Home monitoring: is tocodynamometry useful? Yes. Contemp Ob Gyn 1990;35:96-113. 12. lams ]D, Johnson FF, O'Shaughnessy RW, West LC. A prospective random trial of home uterine activity monitoring in pregnancies at increased risk of preterm labor. AM] OBSTET GYNECOL 1987;157:638-43. 13. lams ]D, Johnson FF, O'Shaughnessy RW. A prospective random trial of home uterine activity monitoring in pregnancies at increased risk of preterm labor. Part II. AM] OBSTET GYNECOL 1988;159:595-603. 14. Porto M, Nageotte MP, Hill 0, Keegan KA, Freeman RK. The role of home uterine activity monitoring in the prevention of preterm birth [Abstract 7]. In: Proceedings of the seventh annual meeting of the Society of Perinatal Obstetricians, February 5-7,1987, Lake Buena Vista, Florida. Lake Buena Vista, Florida: Society of Perinatal Obstetricians, 1987. 15. Dyson DC, Wellman E, Dyson], Armstrong MA. The role of home uterine monitoring in the prevention of preterm birth in high risk patients [Abstract 69]. In: Proceedings of the eighth annual meeting of the Society of Perinatal Obstetricians, February 3-6, 1988, Las Vegas, Nevada. Las Vegas: Society of Perinatal Obstetricians, 1988. 16. Porto M. Home monitoring: essential tool or expensive accessory? Contemp Ob Gyn 1990;35: 114-24. 17. Freeman RK, Lagrew DC. The contraction stress test. In: Eden RD, Boehm FH, eds. Assessment and care of the fetus: physiological, clinical and medicolegal principles. Norwalk, Connecticut: Appleton & Lange, 1990:351-64. 18. Csapo A, Sauvage]. The evolution of uterine activity during pregnancy. Acta Obstet Gynecol Scand 1968;47:181212. 19. Soloff MS. Endocrine control of parturition. In: Wynn RM, Jollie WP, eds. Biology of the uterus. New York: Plennum Medical, 1989:559-607. 20. Fuchs AR, Poblete VR. Oxytocin and uterine function in pregnant and parturient rats. Bioi Reprod 1970;2:387400. 21. Alexandrova M, Soloff MS. Oxytocin receptors and parturition. III. Increases in estrogen receptor and oxytocin receptor concentrations in the rat myometrium during PGF-2 alpha-induced abortion. Endocrinology 1980; 106:739-43. 22. Fuchs AR, Periyasamy S, Alexandrova M, Soloff MS. Correlation between oxytocin receptor concentration and responsiveness to oxytocin in pregnant rat myometrium. Endocrinology 1983;1l3:742-9. 23. Turnbull AC, Anderson ABM. Uterine contractility and oxytocin sensitivity during human pregnancy in relation to the onset oflabour. Br] Obstet GynaecoI1968;75:278. 24. Aubry RH, Pennington ]C. Identification and evaluation of high risk pregnancy: the perinatal concept. Clin Obstet Gynecol 1973; 16:3. 25. Vanden Driessche R, Reygaerts]. Controle de la menace d'accouchement premature par Ie test de sensibilite a' 1'0cytocine. In: Berge R, Noordhoff BS, eds. Symposium on prenatal care. Groningen: Noordhoff, 1960:446. 26. Takahashi K, Diamond F, Bieniarz ], Yen H, Burd L. Uterine contractility and oxytocin sensitivity in preterm, term, and postterm pregnancy. AM ] OBSTET GYNECOL 1980; 136:774-9. 27. Amico ]A, Finley BE. Breast stimulation in cycling women, pregnant women and a woman with induced lactation: pattern of release of oxytocin, prolactin and luteinizing hormone. Clin Endocrinol (Oxf) 1986;25:97106. 28. Finley BE, Amico], Castillo M, Seitchik]. Oxytocin and prolactin responses associated with nipple stimulation contraction stress tests. Obstet Gynecol 1986;67:836-9. 29. Hatjis CG, Morris M, Rose ]C, Kofinas AD, Penry M, Swain M. Oxytocin, vasopressin and prolactin responses associated with nipple stimulation. South Med] 1989; 82: 193-6.

Volume 164 Number 6. Part I

Editors' notp: This manuscript was revised after these discussions were presented.

Discussion DR. WASHINGTON C. HILL, Nashville, Tennessee. Predicting which patients will develop preterm labor or will be delivered before term is, at this time, fair at best. Eden and co-workers have joined the ranks of many of us in trying to devise a method to predict which myometrium is susceptible to going into labor before term. They do this by designing a new test with new initials, the MST, thereby adding another eponym of obstetrics (EOO) to an already crowded perinatal alphabet soup (FCI, LIS, AST, CST, OCT, BSST, D/A, PTL, NST, AFV, FAD, PUBS, FSI, A/B, SID, FBP, etc.). This test utilizes the breast stimulation stress test in attempting to predict which patients may develop preterm labor or have preterm delivery. It will be difficult at best for anyone test, clinical evaluation, or system to predict preterm labor or preterm delivery. The individual methods alone are simply not sensitive enough or do not have a high enough positive predictive value. A combination of these methods in forming a preterm labor screening index will probably be more successful. I would like to critique this article by looking at the five characteristics, mentioned by the authors, that make [this topic] worthy of further study: theoretical rationale, predictive utility, simplicity, safety, and low cost. The theoretical rationale of the mammary stimulation test is based on a difference in the myometrium that will go into labor early versus the myometrium that will progress into labor at term. It is theorized that there are more numerous or more sensitive oxytocin receptors in the former. Data suggest that this may indeed be the case. There is, however, a difference between (a) using known amounts of exogenous oxytocin to see if the uterus is ready for labor and (b) using unknown amounts of endogenous oxytocin produced by nipple stimulation to see if preterm labor will develop or preterm delivery will occur. Point a is not equal to point b. Eenie, meenie, mini, mo: What do the data really show about predictive utility? The reader is bombarded with many statistics: positive predictive value, sensitivity, specificity, negative predictive value, percent at risk, X2 , explained variance, relative risk, odds ratio, p value, jackknifed classifications, discriminant analysis, and contingency table. The "bottom line" appears to be that with a small number of patients the sensitivity, specificity, positive predictive value, and negative predictive value of the mammary stimulation test are in the same range as those of other reported methods devised for predicting preterm labor or preterm delivery. In fact, in assessing the predictability of the mammary stimulation test, risk scoring is also used. The ability to predict preterm delivery or term delivery is also affected and confused by introducing and confounding variable

Mammary stimulation test to predict preterm delivery

1417

of tocolytic therapy. Some patients who had a positive mammary stimulation test and subsequently were delivered before term or at term had tocolytic therapy. The same is true for some who had preterm labor. The predictive value of a negative mammary stimulation test for preterm delivery was very high in this small number of patients, but it certainly was not reliable enough in this preliminary report to eliminate home uterine activity monitoring from a prematurity prevention program because three patients were delivered preterm. The real negative predictive value has yet to be determined. The mammary stimulation test is simple and easy to perform. As with the breast stimulation stress test, there will be patients who prefer not to stimulate themselves. Although the test is simple, will it be useful or predictive? I don't know if the mammary stimulation test is safe; it may be, but there are no data on the interval from the administration of the mammary stimulation test to the onset of preterm labor. Could the mammary stimulation test (performed correctly or incorrectly) cause preterm labor, preterm delivery, or both in higher-risk patients? Which came first, the chicken or the egg? Could performing the mammary stimulation test cause hyperstimulation? As the authors mentioned, it is necessary to study more patients with variable risks to answer these and other important questions. The test is inexpensive, but this is only one variable in determining its real value. An inexpensive useless test is still a useless, cheap test. I agree with the authors that the final verdict on the mammary stimulation test is not in yet and that we should be cautious in interpreting this limited experience. I have the following questions for them, whom I commend for winning the Annual Prize Award and for making an excellent attempt in tackling a very difficult problem that is elusive to many investigators. 1. The authors note that no patients with a negative mammary stimulation test were delivered before 34 weeks or had a baby weighing <2000 gm. What was the similar breakdown for patients with a positive mammary stimulation test? 2. What was the interval from the mammary stimulation test to the onset of preterm labor? 3. What was the regimen of tocolysis, and how do the authors deal with this confounding variable when interpreting their data? 4. How was preterm labor defined? 5. All studies reporting on the breast stimulation stress test have involved hyperstimulation. What was the incidence in this study? 6. How early could this test be used? DR. RANDALL T. KELLY, Dearborn, Michigan. I do not feel that this article will cause a revolution in perinatal medicine, but I do feel that the practice of obstetrics will change in the future as a result of the authors' pioneering work on uterine contraction activity testing. The article deserves little criticism, but there are a few things that I would like to discuss.

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Eden et al.

If a test in medicine is to be universally performed, as I feel that this one (or something similar to it) will be on all pregnant patients, then nomenclature that is more easily accepted and understood by physician and layman alike will help us to maintain that test in the public domain. In addition, pregnant patients will be more willing to accept it as a routine test of pregnancy. Perhaps a better name for the test would be the breast stimulation test for preteI'm labor or the nipple stimulation test for preteI'm labor. In any case, removal of the word mammary would be helpful, because many of our patients do not know what that word means. I think that there should be something about preteI'm labor in the name of the test. In the first paragraph of the article, Dr. Eden states that with all of our current programs, there has been no decrease in the incidence of prematurity. This is true. The problem is, though, that many patients have no access to any program, no discussions about preteI'm labor and its symptoms are provided during prenatal care. In the Methods section, a reference is listed for the standard protocol of nipple stimulation contraction stress testing. This reference, which is from Dr. Eden and Dr. Boehm's textbook, does not have a protocol for the nipple stimulation contraction stress test in that chapter as listed in the reference. There is a big range of gestational ages in this study (24 to 32 weeks). One could say that sensitivity to oxytocin or other hormones could differ significantly at 24 weeks when compared with 32 weeks, and so using fetuses of one gestational age would make a "cleaner" study. Exactly how the nipple is stimulated is not discussed, nor is whether the stimulation is continuous for the 2minute period. Stimulation was discontinued if contractions occurred. Later, it appeared that even one contraction was sufficient for discontinuation. There should be a discussion of criteria regarding these contractions, and what is considered a positive or a negative mammary stimulation test should be established. I also have a few questions. In Table I, did the patients with cervical incompetence have a cerclage? This should be delineated. In Table II only 6 of the 19 patients who were delivered before term had preteI'm labor. Were some patients delivered early because of a medical problem, such as severe preeclampsia, which might make the uterus more sensitive to oxytocin at that stage of pregnancy? This should be discussed. There is a statement that nipple stimulation results in oxytocin release and in an increase of plasma levels of oxytocin. This is still a slightly controversial point that could have been examined with plasma oxytocin levels in this study. Perhaps a plasma oxytocin level, prostaglandin level, or prostaglandin metabolite level at a certain stage in pregnancy will be our future test with better sensitivity. The overall series is small. The authors realize this. The participants in the study were not randomly selected; this limits the ability to generalize the findings.

June 1991 Am J Obstet Gynecol

The study considers a group of patients who are at an extremely high risk for preteI'm labor. Another study on groups with a much lower risk for preteI'm labor (and thus perhaps with fewer confounding variables, such as poor socioeconomic status, previous preteI'm delivery, and late prenatal care) would make a much "cleaner" study. Again, the criteria for positive and negative tests are not dealt with until the Comment section and Table VI. Even though the criteria for contractions and positive and negative testing were originated heuristically, I feel that they should have been discussed in the Methods section so that the reader would understand the remainder of the article without having to read it many times. The statistical analyses are complete and appropriate for the type of data collected and for the nature of the research project, but the authors often did not explain or discuss the statistics or the analyses sufficiently. More description and interpretation of the tables would have been useful and would have made the data more understandable to the reader. Very specific data are provided with minimal comments in the tables. The authors do state that the results of the study should be interpreted cautiously. I agree with this. However, I do feel that this is a good solid pilot study. In the future a test similar to the mammary stimulation test, as described here, or some other test along the same lines will be routine for all obstetric patients. DR. ROBERT J. CARPENTER, Houston, Texas. One thing I didn't see was a breakdown of singleton versus twin gestations and their data base. I would like to have some information on that and on how the removal of twins may change the data. DR. WILLIAMJ. Orr, St. Louis, Missouri. I would like to congratulate the authors on their excellent pilot .study and in trying to predict those patients at risk with premature labor. I have one question, however, about the statistical analysis of their data. The positive and negative predictive values of any test are significantly influenced by the incidence of the disease process in question. I want to know whether Bayesian analysis was used to correct for this in determining positive and negative predictive values, because this may significantly alter the values of the positive and negative tests. DR. SUZANNE R. TRUPIN, Champaign, Illinois. Were cervical examinations done on these patients? If so, were there any criteria for eliminating patients from the study or for determining a difference in responsiveness to the mammary stimulation test in patients with cervical effacement? Also, was there a difference between the multiparous patient and the nulligravid patient in response to this test? UNIDENTIFIED SPEAKER, St. Louis, Missouri. I enjoyed the presentation. It is refreshing to have the results of some form of testing for preteI'm labor that will not increase (and may decrease) the use of home uterine activity monitoring. I have two questions. One has to do with the incidence of preteI'm delivery in the group of patients from

Volume 164 Number 6. P"1l 1

the same clinic who dict not undergo any mammary stimulation testing. What is the baseline in the true control group? Second, preteI'm labor really results from a hodgepodge of different causes, and I would like to have a breakdown. if possible, regarding patients who had placental complications with bleeding manifestations in preteI'm labor, membrane rupture in preteI'm labor, and also intact membranes with preterm labor, because there may be different abilities to predict these different causes of the actual birth event. DR. EDEN (Closing). We like to thank the reviewers for their comments, especially that regarding alphabet soup. Because we believe that the mammary stimulation test will, in fact, prove to be clinically useful, we agree that it is imperative that the test be given a simple, catchy, and easy-to-remember name. Our biggest dilemma was, in fact, deciding on the name of this provocative new test. We also agree with the concerns raised regarding the predictive ability of the mammary stimulation test, and we are currently expanding the series considerably. Our fondest hope is that other institutions and investigators will attempt to verify our findings, and thus will enable the mammary stimulation test to take its place in prematurity prevention programs. Three minutes will not permit me enough time to comment on all the questions, but I would like to address a couple of Dr. Hill's queries first. We analyzed the patients who were delivered prematurely with respect tQ the negative mammary stimulation test. One patient was delivered at 34 weeks. The other two were in the thirty-fifth and thirty-sixth weeks of pregnancy, respectively, and all three of these premature infants weighed >2000 gm at birth. Of the 16 patients with positive mammary stimulation tests, 9 gave birth to infants weighing <2000 gm, with weights ranging between 1250 and 1920 gm. Ten of the infants of these 16 women were born at ~34 weeks' gestation. In positive mammary stimulation tests the interval from the time of the mammary stimulation test to delivery was about 4 weeks. In negative mammary stimulation tests, this interval was approximately 9 weeks. The regimen of tocolysis was basically a standard protocol that is used on the labor and delivery unit by residents. The diagnosis of preterm labor basically requires either cervical change or documentation of

Mammary stimulation test to predict preterm delivery

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uterine contractions (eight or more per hour) on the monitor. Intravenous tocolysis is accomplished by administering either magnesium sulfate or a [3sympathomimetic, such as terbutaline, followed by intravenous hydration. We had no evidence of uterine hyperstimulation in this small series. That is probably a result of light stimulation and cessation of the test when contractions occurred. The alternative would have been to go to the end of the contraction stress test, which requires three contractions in 10 minutes and additional stimulation." The earliest that we started patients on the mammary stimulation test protocol was 24 weeks. because that is probably the earliest time at which the test can be performed, as a result of the limitations of the equipment (specifically, the sensitivity of that equipment to detect uterine contractions). The data for twin gestations showed similar outcome measures. In fact. the two patients with twins who were delivered at term had negative mammary stimulation tests, although all patients who were delivered before term had positive mammary stimulation tests. Patients with premature rupture of the membranes had test results similar to those of patients without premature rupture of the membranes. The incidence of preterm delivery in our patient population is related to our location. We have a very interesting patient population in the city of Detroit, as a result of the problems associated with access to prenatal care. We have approximately a 20% to 25% incidence of preterm labor or preterm delivery, or both, which unfortunately is very, very high. We chose 5 weeks as the minimum because prenatal care usually requires that the patients be examined at 3- to 4-week intervals until late in gestation. Therefore a 5-week interval of time provides some degree of safety. In originating the mammary stimulation test, we felt strongly that nipple stimulation was preferable to the cumbersome technique of intravenous oxytocin administration, which patients do not readily accept. However, we do agree that knowing the oxytocin levels and being able to standardize oxytocin administration are preferable. All patients were seen after pelvic examination. In our preterm labor clinic all patients are examined by residents with staff supervision. No patient had advanced cervical dilatation, and there was minimal concern about gravidity.