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NEJM Editorial-Volume 346:282-284 January 24, 2002 Number 4

Predicting Premature Delivery - No Easy Task

Premature delivery is a leading cause of infant death. Approximately 5000 infants die each year in the United States from complications of prematurity and low birth weight. During the past decade, mechanisms contributing to prematurity have been identified.1 The observation that several pathways are involved in its pathogenesis may explain why premature delivery has proved so difficult to predict and prevent.

Premature activation of the fetal hypothalamic-pituitary-adrenal axis may result from maternal psychosocial or fetal physiological stress (for example, when there is insufficient uteroplacental blood flow). This mechanism may account for up to one third of premature births.1,2 The critical mediator of stress-induced prematurity appears to be corticotropin-releasing hormone, a 41-amino-acid peptide initially localized to the hypothalamus but also expressed by cells in the placenta, chorion, amnion, and uterine decidua.1,2 The maternal plasma concentration of corticotropin-releasing hormone rises during the second half of pregnancy and peaks during labor.3 This hormone stimulates the production of prostaglandins by cells of the amnion, chorion, and decidua.1,2 Prostaglandins then directly stimulate uterine contractions and cause cervical ripening.1 Prostaglandins also stimulate the release of corticotropin-releasing hormone in the placenta, fetal membranes, and decidua, resulting in a positive paracrine feedback loop, that drives preterm delivery.1,2

Whereas glucocorticoids inhibit the hypothalamic release of corticotropin-releasing hormone, stress-induced increases in fetal or maternal cortisol production enhance placental production of this hormone.1,2 The production stimulates the release of adrenocorticotropin from the fetal pituitary gland, which, in turn, stimulates fetal adrenal cortisol production. Cortisol also directly increases the production of corticotropin-releasing hormone by the placenta and fetal membranes and has local effects that stimulate the synthesis of prostaglandins in the fetal membranes.2

Increased production of dehydroepiandrosterone accompanies the increase in fetal adrenal cortisol production.1 This and related androgens are converted by the placenta to estrogens that activate the myometrium by enhancing the expression of proteins involved in activating uterine contraction, such as connexins and oxytocin receptors.1 In addition, corticotropin-releasing hormone can act directly on the fetal adrenal gland to stimulate dehydroepiandrosterone production.4

Ascending genital tract infections contribute to up to 50 percent of premature deliveries, particularly those occurring before 30 weeks of gestation.1,2 Intraamniotic infections are associated with the activation of interleukin-1 and tumor necrosis factor in the genital tract. These cytokines directly and indirectly stimulate prostaglandin synthesis in the fetal membranes and decidua and inhibit prostaglandin breakdown.1,2,5 Similarly, interleukin-1 and tumor necrosis factor enhance the expression of matrix metalloproteinases and interleukin-8 in the chorion, decidua, and cervix; this increased expression leads to the breakdown of the extracellular matrix of the fetal membranes and cervix.1,6 Tumor necrosis factor and matrix metalloproteinases also promote programmed death of amniotic cells.1,6 The combined effect of these mechanisms may promote premature delivery.

Placental abruption (hemorrhage into the uterine decidua) is apparent on histologic examination in up to 60 percent of premature deliveries but is clinically recognized as recurrent vaginal bleeding in only one fifth of cases.1 The decidua is extraordinarily rich in tissue factor, which is the primary initiator of hemostasis.1,7 After hemorrhage, membrane-bound tissue factor from the decidual cells forms a complex with activated factor VII to activate factor X, which generates thrombin. The binding of thrombin to its receptors enhances the production of enzymes that break down the decidua and fetal membranes.7 Thrombin also binds to myometrial receptors, resulting in the stimulation of uterine contractions.7,8

Premature delivery may also be precipitated by the mechanical stretching of the myometrium caused by increases in uterine size that exceed the ability of the uterus to compensate. This occurs, for example, in multifetal gestations and in cases of polyhydramnios (excess amniotic fluid). Stretching promotes premature labor by increasing the formation of myometrial gap junctions, the activation of oxytocin receptors, and the synthesis of prostaglandin in amnionic, myometrial, and cervical cells.1

The elaboration of these pathogenic mechanisms has led to the hope that biologic markers associated with the specific pathways involved might be useful predictors of premature delivery. However, several proposed markers have proved disappointing. For example, maternal serum corticotropin-releasing hormone concentrations higher than 1.9 times the median value between 15 and 20 weeks of gestation had a sensitivity of 73.0 percent but a positive predictive value of only 3.6 percent for premature delivery.9 Elevated maternal salivary levels of estriol, a proposed marker of premature activation of the fetal hypothalamic-pituitary-adrenal axis, had a low positive predictive value for premature delivery,10 as did cervical levels of interleukin-6.1 The presence of recurrent vaginal bleeding and the identification of a multifetal gestation also have poor sensitivity (10 to 20 percent) for predicting prematurity. The low predictive accuracy of these pathway-specific markers can be explained, in large part, by the multifactorial pathogenesis of prematurity.

Markers associated with the common final pathways of prematurity - uterine contractions and the disruption of the extracellular matrix within the cervical and fetal membranes - have been proposed as another approach to predicting premature delivery. In this issue of the Journal, Iams and colleagues11 report on the value of home monitoring of uterine activity, estimates of cervical length based on ultrasonographic examination, and measurement of the fetal-membrane protein fibronectin in cervicovaginal secretions in predicting spontaneous preterm delivery at less than 35 weeks of gestation. They assessed the mean and maximal daily frequency of uterine contractions among 306 women at variable risk of premature delivery, recording more than 34,000 hours of uterine activity. Although uterine activity was increased among women who subsequently gave birth prematurely, there was only a weak relation between the maximal frequency of uterine contractions during the daytime and at night and premature delivery. The generally accepted cutoff of more than four contractions per hour was insensitive and had a low positive predictive value for premature delivery.

These findings provide an explanation for the results of randomized clinical trials that failed to demonstrate a beneficial effect of home monitoring of uterine activity on the rate of preterm delivery, birth weight, or perinatal mortality.11,12,13 Both the American College of Obstetricians and Gynecologists13 and the U.S. Preventive Services Task Force14 concluded that home monitoring of uterine activity was not of value in predicting premature delivery.

Iams and colleagues found that elevated levels of fetal fibronectin in cervicovaginal secretions and ultrasonographically detected cervical shortening were only marginally more clinically useful than the results on home monitoring of uterine activity. The positive predictive value of the cervicovaginal fibronectin level ranged from 30.0 to 35.0 percent, and the positive predictive value of the cervical length ranged from 20.9 to 37.0 percent.

Our limited ability to stop preterm labor once it has started is even more disheartening than our frustrated efforts to predict it. The U.S. Preventive Services Task Force report14 concluded that the use of tocolytic agents, such as terbutaline and magnesium sulfate, to reduce uterine contractions produced only a slight prolongation of pregnancy. Long-term tocolysis (usually with oral agents) has not been shown to prolong pregnancy or improve perinatal outcome. Although antibiotics may prolong pregnancy in women with preterm rupture of fetal membranes, they have not been effective in preventing premature delivery in these women, and they do not prolong pregnancy or prevent premature delivery in women with preterm labor whose fetal membranes are intact.

The prevention of preterm delivery will require intervention at an earlier stage in the processes that lead to it. Strategies are needed to prevent ascending genital tract infections and to reduce excessive cytokine responses to normal genital tract flora. Prophylactic heparin therapy should be rigorously evaluated in women with inherited or acquired thrombophilia who have recurrent premature deliveries due to placental abruptions or uteroplacental thrombosis. Finally, since the induction of ovulation and in vitro fertilization are major causes of multifetal gestations, we must refine our assisted reproductive techniques to reduce the occurrence of twin and higher-order multifetal pregnancies.

Although several biomarkers are associated with premature delivery, the findings of Iams et al. reinforce the conclusion that the practical usefulness of these markers in the case of an individual woman is limited. Although we have come a long way in understanding the mechanisms involved in the pathogenesis of prematurity, we have a long way to go.

Charles J. Lockwood, M.D.

New York University School of Medicine

New York, NY 10016

References

1.Lockwood CJ, Kuczynski E. Markers of risk for preterm delivery. J Perinat Med 1999;27:5-20.

2.Challis JR, Lye SJ, Gibb W, Whittle W, Patel F, Alfaidy N. Understanding preterm labor. Ann N Y Acad Sci 2001;943:225-234.

3.McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R. A placental clock controlling the length of human pregnancy. Nat Med 1995;1:460-463.

4.Smith R, Mesiano S, Chan EC, Brown S, Jaffe RB. Corticotropin-releasing hormone directly and preferentially stimulates dehydroepiandrosterone sulfate secretion by human fetal adrenal cortical cells. J Clin Endocrinol Metab 1998;83:2916-2920.

5.Van Meir CA, Sangha RK, Walton JC, Mathews SG, Keirse MJ, Challis JR. Immunoreactive 15-hydroxyprostaglandin dehydrogenase (PGDH) is reduced in fetal membranes from patients at preterm delivery in the presence of infection. Placenta 1996;17:291-297.

6.Lei H, Furth EE, Kalluri R, et al. A program of cell death and extracellular matrix degradation is activated in the amnion before the onset of labor. J Clin Invest 1996;98:1971-1978.

7.Lockwood CJ, Krikun G, Aigner S, Schatz F. Effects of thrombin on steroid-modulated cultured endometrial stromal cell fibrinolytic potential. J Clin Endocrinol Metab 1996;81:107-112.

8.Elovitz MA, Saunders T, Ascher-Landsberg J, Phillippe M. Effects of thrombin on myometrial contractions in vitro and in vivo. Am J Obstet Gynecol 2000;183:799-804.

9.Leung TN, Chung TK, Madsen G, McLean M, Chang AM, Smith R. Elevated mid-trimester maternal corticotrophin-releasing hormone levels in pregnancies that delivered before 34 weeks. Br J Obstet Gynaecol 1999;106:1041-1046.

10.McGregor JA, Jackson GM, Lachelin GC, et al. Salivary estriol as risk assessment for preterm labor: a prospective trial. Am J Obstet Gynecol 1995;173:1337-1342.

11.Iams JD, Newman RB, Thom EA, et al. Frequency of uterine contractions and the risk of spontaneous preterm delivery. N Engl J Med 2001;346:250-255.

12.Grimes DA, Schulz KF. Randomized controlled trials of home uterine activity monitoring: a review and critique. Obstet Gynecol 1992;79:137-142.

13.American College of Obstetricians and Gynecologists. ACOG Practice Bulletin: assessment of risk factors for preterm birth: clinical management guidelines for obstetrician-gynecologists. No. 31, October 2001. Obstet Gynecol 2001;98:709-716.

14.U. S. Preventive Services Task Force. Home uterine activity monitoring for preterm labor. JAMA 1993;270:371-376.