P retenu birth is a significant contributor to neonatal and infant morbidity and mortality in both developed and developing countries.1 In the United States, preterm birth accounts fot more than 70% of neonatal morbidity and 35% to 40% of infant deaths.2 Over the past 30 years, improvements in maternal child health have significantly reduced other causes. However, preterm birth and its sequelae continue to be significant problems.3 Between 1970 and 1980, the incidence of preterm low birthweight for all races declined 7.1%.4 However, according to recent vital statistic data, preterm births in the United States have increased from 9.4% in 1981 to 10.6% in 1991.5 Between 1980 and 1992, the infant mortality rate for white infants declined by 37% to 6.9 infant deaths per 1000 live births, while the mortality rate fot black infants declined only 24% to 16.8, widening the gap between the two races.6 Because prematurity is a leading cause of infant mortality, the prevention of prematurity has become a high priority. To meet the Year 2000 Objective, the overall infant mortality in the United States must be reduced to no more than 7 per 1000 live births and the black infant mortality to no more than 11 per 1000 live births.7
What is the cause of preterm birth?
The development of a strategy for the prevention of preterm birth requires an understandinq of its etiology, and the etiology is complex.8 Little attention has been directed toward the identification of specific causal pathways. Instead, investigators focus on predisposing factors associated with preterm birth. New plausible hypotheses must be developed.
In the first half of this century, the most complete review of the literature to establish an etiologic classification was performed by Anderson and Lyon9 in 1939. These investigators observed that nearly one half (41%) of the factors related to preterm birth fell into the category of indicated preterm deliveries, only a few cases (9%) were due to premature rupture of the membranes, and the remainder were idiopathic with no identified cause (50%). The authors concluded that there are many predisposing factors that impair the health and nutrition of mothers, thus causing preterm birth. Anderson and Lyon were the first in the United States to suggest that social and environmental conditions were probably responsible for variations in the studies they reviewed. During the next 15 years, the advent of antibiotics to treat syphilis and tuberculosis caused these chronic infections to almost disappear from the list of causes. After World War II, Nicholas Eastman, known as the father of obstetrics in the United States, noted that only one fourth of preterm deliveries were indicated. He recommended three strategies the obstetrician could use to reduce the effects of prematurity on mortality: improved nutrition, administration of vitamins (including vitamin K}, and a nonintervention strategy in premature rupture of the membranes.
Etiology of Preteriti Birth
Not until the mid 1970s was attention directed toward identifying women at risk for preterm birth. Fredrick and Anderson in England, Kaltreider and Johnson in the United States, and Papiemik in France began a search for factors associated with spontaneous preterm birth. They wanted to identify patients at risk for early prenatal care and intervene to improve outcome.11' These studies recognized specific subtypes of causation as spontaneous preterm birth, preterm premature rupture of the membranes, and medically indicated early delivery.
In 1976, a National Institute of Child Health and Human Development workshop on prematurity presented an update on the problem of prematurity. There, Boldman and Reed1^ reviewed the indicator variables for 21 countries, showed that the variables were highly correlated with each other, and concluded that the causes of low birthweight and prematurity are embedded in the environment.
Arias and Tomich15 in 1982 were the first to estimate the subtype contributions to preterm birth (after 1940) as depicted in Table 1. They noted that each subtype - spontaneous preterm labor (idiopathic), preterm premature rupture of the membranes, and medical indications - accounted for approximately one third of preterm births. Meis et al revealed interesting differences between these three subgroups for private versus public patients. Private patients have a much higher proportion of idiopathic preterm labor while public black patients have a higher proportion of deliveries due to premature rupture of the membranes. Recently, Savitz et al17 concluded that the subcategories listed in Table 1 need to be considered in future studies of etiology and prevention.
A scientific approach to prevention of prematurity requires a hypothesis. In 1982, prior to initiating our Los Angeles Premature Prevention Project, we formulated the one illustrated in the Figure.18 The central focus was stress using Selye's concept that a hypothesis does not attempt to "be right" in the sense of a mathematical solution. Rather, a hypothesis should be useful in discovering new information.19 Our hypothesis was consistent with the impressions of Anderson and Lyon, Eastman, and those of Boldman and Reed assuming the cause is complex and embedded in our environment. Now almost 12 years later, we have reassessed our hypothesis and from the "big picture" point of view it remains on target, but several modifications need to be considered.
First, infection has emerged as a separate focus.20 Infection appears to be an important cause of premature rupture of the membranes, and it occurs in a significant proportion of idiopathic cases. In a comprehensive evaluation of 50 patients admitted with idiopathic preterm labor, Lettieri et al21 found that 38% had an intrauterine infection by examination of the placenta. Prior to 1940, the percentage of cases due to premature rupture of the membranes was low, but today premature rupture of the membranes occurs in at least 25% of private cases, 35% of public white cases, and 50% of public black cases. Our original proposal included infection as it relates to maternal behaviors and characteristics, and pointed out the rote that stress may play in susceptibility to infection.18 The role of silent infections as a contributing or direct causal factor has become an important concept.22
Another change in our hypothesis is the importance of separating cognitive (mental) and workrelated stress. Both are receiving considerable attention in the literature.23-25 Even though the end effect may be an alteration in uteroplacental perfusion, future studies should focus on the separate or combined effects of both types of stress on preterm labor and fetal growth.
Figure. A hypothesis for the muftifactorial etiology of preterm labor. Stages I and II are asymptomatic stages. Stage HI-A is the beginning of symptoms suggestive of an increased risk of preterm labor. Stage IH-B is the beginning of preterm labor. (Reprinted with permission from Bragonier JR, Cushner IM, Hobel CJ. Social and personal factors in the etiology of preterm birth. In: Fuchs F, Stubblefield PG, eds. Preterm Birth, Causes, Prevention, and Management Copyright ©1984, MacMlllan Publishing Co.)
A growing body of evidence reveals that uteroplacental dysfunction plays a role in idiopathic preterm labor as well as being part of maternal complications (such as hypertension) that may lead to early delivery. Infants bom preterm have evidence of poor growth several weeks prior to the onset of labor, evidenced by reduced abdominal circumference (site of glycogen storage) and measurements of asymmetric intrauterine growth,26'27 The cause of this decrease in growth is complex but could be secondary to placental localization and to decreased uterine perfusion during prolonged standing or work. Recently, we have shown that unilaterally located placentas (when compared with centrally located placentas) are associated with a significant decrease in fetal weight at birth.28
A third revision of our causal diagram should address the role that the fetus and placenta may play in the initiation of preterm labor. Recent studies suggest the placenta may release "placental corticotropin releasing hormone" prior to preterm labor.29 The mechanism that signals the production of this peptide is unknown; however, infection, alteration in uterine blood flow, or reduced fetal growth are plausible. What is apparent is that the onset of preterm labor is not the acute event that it appears to be clinically, but is preceded by maternal behaviors weeks prior to onset. Thus, we should have time to identify the patient at risk and provide interventions to prevent poor fetal growth and perhaps preterm birth.
Can women at risk be identified?
Papiernik13 in 1979 proposed the concept of identifying patients at risk for preterm birth and its application for focused care to prevent this adverse outcome by various interventions. At about the same time, Fredrick30 in England proposed a scoring system to identify patients at risk. In the United States, Creasy used Papiernik's risk assessment scheme to apply an education program to high-risk patients for the early detection of preterm labor and the institution of tocolytic therapy. His study, published in 1983, launched several prospective studies.31 Unfortunately, the application of his scheme by subsequent investigators to identify populations at risk for intervention programs has been disappointing.32'34 In general, screening using various historical and developing factors has low sensitivity and poor predictive power in identifying women who will deliver preterm infants. This subject has been reviewed by Main et al.35 Risk assessment schemes to apply interventions such as early tocolytic therapy may not be effective because the patient's destiny has already been determined. Once preterm labor is initiated, it is difficult to stop. Table 2 lists the most predictive risk factors used in the various assessment schemes.36,37
According to Kramer, modifiable factors with large effects on fetal growth and the duration of gestation should be targeted for public health interventions. These include maternal work, physical activity, antenatal care, genital tract infections, and stress.37 Papiernik believes that primary prevention schemes used in France, such as work leave, will only be effective when applied to nulligravida patients. Investigators are searching for new ways to improve risk assessment with a focus on primigrávida patients who may not yet have the classical historical risk factors. Unfortunately, the paradox remains: can we afford to screen all patients and are we committed to apply new technology to a selected group of high-risk patients but risk missing at least half who deliver preterm births from low-risk or nonscreened group? Biophysical and biochemical parameters currently under study may improve our ability to identify the patient at risk for delivering a preterm infant.
Biophysical Screening: The Importance of Uterine Activity, in 1957, Bruns et el38 published data indicating that preteriti birth is associated with an increase in uterine activity and a reduced effective uterine circulation. These investigators were the first to recognize the value of uterine activity as an early sign of preterm labor. The strategy to monitor uterine activity is based on three tenants:
* excessive uterine activity precedes idiopathic preterm delivery,
* uterine activity prior to preterm birth occurs during a rather short period (days to 1 or 2 weeks, and if excessive uterine activity is to be identified on a timely basis, the patient would need to be monitored more frequently than at routine clinic or office visits, and
* the majority of patients do not easily perceive uterine activity.
Therefore, an electronic device used daily to identity excess uterine activity could improve the identification of a patient with excessive uterine activity.39
The clinical application of monitoring uterine activity initially was called "ambulatory monitoring" by Katz et al*^ in 1986. With the commercial development of a monitoring device, signal storage, and the ability to transmit data easily for interpretations, this technology was rapidly picked up by investigators to identify patients at risk. "4^ Unfortunately, the designs of these early studies did not take into consideration the impact of the additional perinatal support of the nurses who provide this service. However, a multicenter randomized trial by Mov at al43 suggested that home uterine activity monitoring in the absence of nursing support significantly improved the detection of preterm labor and the opportunity to institute early therapy. As a result of these studies, home monitoring has been widely accepted. This has led to controversy regarding the early application of costly tech' nology, which had not yet been shown conclusively to prevent preterm birth. Grimes and Schulz44 reviewed five early randomized trials of home monitoring (Mov et al not included) and found all to have serious méthodologie deficiencies. They suggested this technology not be used clinically until its efficacy has been clearly established.
This one form of biophysical assessment cannot be evaluated easily in isolation of other risk factors such as historical, developing problems, or other biophysical or biochemical assessments. How can clinicians use this technology in a timely fashion and for a period of sufficient duration to be of value? Only a total program of risk assessment and the application of specific interventions including a device may ultimately have an impact on preterm birth.
Cervical Change. Considerable attention has been focused on the identification of early cervical change. Wood et at45 in 1965 followed 259 pregnancies prospectively with cervical examinations every Z weeks and found that 28% of women with cervical change delivered preterm while only 0.4% without cervical change delivered preterm. In addition, they noted that those with uterine activity plus early cervical change were more likely to deliver preterm. A similar study was performed in 1969 by Anderson and Tumbull,46 and even though their data were equally impressive, they were not convinced that cervical change and uterine activity could be used as an index of pathology. However, these investigators did show a significant relationship between both cervical dilation and uterine contractility in patients.
Possible Risk Factors for Pretorili and Low Blithwelght Births*
In 1979, our group suggested the use of ultrasound as a biophysical parameter to measure early cervical dilation as a risk factor requiring close surveuance.47 As a result of several descriptive studies between 1981 and 1988, various investigators described the use of ultrasound in the diagnosis and management of patients at risk.48-49 Using the endovaginal technique in a prospective study, Anderson et al ° recently showed that cervical length measurement of <3.9 cm prior to 30 completed weeks was associated with a significant increased risk of preterm birth. They detected 76% of preterm births and found it predictive regardless of the parity or level of risk by history.
Biochemical Screening. Until recently, little attention has been directed toward the development of a biochemical screening test to identify the patient at risk. Because progesterone plays an important role in the maintenance of pregnancy, several investigators in the late 1970s found that low maternal serum progesterone was associated with preterm birth.51'52 Johnson et al reported preliminary success in correcting low matemal serum progesterone levels with progestins.52 However, other investigators were not able to show the value of serum progesterone levels to improve risk prediction.
In 1971, Lockwood et al54 postulated that because fetal fibronectin is present in amniotic fluid and placental tissues, mechanical damage (uterine contractions) or inflammatory mediated damage to the membranes might result in the release of this substance into the cervix and vagina and thereby provide a marker for the risk of preterm delivery. These investigators first defined the natural history of this substance in uncomplicated patients who delivered at term. They identified a window between 20 and 36 weeks gestational age in which positive tests are rare, and if the test becomes positive, the result may indicate a biochemical disruption of the relationship of the extracellular matrix of the membranes, decidua, or placenta due to uterine contractions or inflammation. Their preliminary results showed that cervical or vaginal fetal fibronectin was present in 50.4% of women with preterm uterine contractions and intact membranes, and its presence identified women who delivered before term with a sensitivity of 81.7% and specificity of 82.5%.
Subsequently, Nageotte et al55 studied 87 patients at risk for preterm birth with a history of a previous preterm birth, a uterine malformation, the presence of a cervical cerclage, or multiple gestation, and showed that those with a positive test for fetal fibronectin were at significant risk for preterm birth. The presence of fetal fibronectin had a sensitivity of 92.8% and a specificity of 51.7% for predicting preterm birth. Another recent multicenter study found that a positive test significantly improved prediction of preterm delivery.56 This test promises to provide new information about the pathophysiologic changes in the uterus and cervix prior to preterm delivery, and become another marker of risk. However, the value of such a test is dependent on the availability of effective interventions to prevent preterm birth.
Corticotropin-Releasing Hormone (CRH). This hormone, initially identified in the hypothalamus, is thought to be a mediator of the stress response. Corticotropin-releasing hormone is released into the hypophyseal portal blood and stimulates the secretion of adrenocorticotropic hormone (ACTH).57 Because ACTH and endorphins also are produced in the placenta, placental CRH may promote the release of ACTH and endorphins from the placenta or from the fetal or maternal pituitary gland. Sasaki et al58 were the first investigators to find a considerable increase in CRH in maternal plasma during pregnancy with advancing gestational age. The significance of high circulating levels of CRH toward the end of pregnancy is unknown. In 1987, Campbell et al59 reported that CRH levels were significantly elevated in women with pregnancy- induced hypertension and in women who subsequently went into preterm labor. This observation opened the possibility of another marker for women at risk for preterm birth.
Recently, Warren et al29 confirmed that CRH levels are elevated prior to preterm labor but did not find an elevation when preterm labor was associated with infection. Goland et al showed that umbilical cord levels of CRH are extremely elevated in growthretarded fetuses, suggesting that chronic stress may modulate fetal pituitary-adrenal function in high-risk pregnancies. The above studies suggest elevated maternal CRH levels are probably mediated through important physiologic pathways in high-risk pregnancies and may be a marker of chronic stress.
What prevention strategies work?
Interest in the prevention of preterm birth began in the early 1980s as a result of the early work of Papiernik61 in France who demonstrated a progressive decrease in the incidence of preterm birth between 1971 and 1982. The basis of Papiemik's program was patient and provider education, social support, work leave, and prophylactic interventions such as progestins, cervical cerclage, and tocolytics. Unfortunate-Iy, Papiemik's program was not designed to determine which interventions were most effective. In 1983, Herrón et al31 in the United States reported a significant reduction in the preterm birth rate with patient education for the early detection of preterm labor symptoms. This stimulated others to implement similar programs using patient education for the early detection of preterm labor based on the hypothesis that early detection of preterm labor and its treatment will reduce preterm delivery. Subsequently, several investigators initiated randomized trials to test this hypothesis.
In 1985, Main et al reported the randomization of a group of 132 high'risk patients to test the effectiveness of patient education and close follow-up. This program was ineffective even though more women from the preterm prevention clinic were admitted with complaints suggestive of preterm labor. Another study by Mueller-Heubach et al3* randomized 831 patients so half received intensive education; again, no difference in preterm birth was observed between the intervention and the control group. These investigators attributed this failure to a spillover of the prevention program to the control patients: during the next 2 years of their prevention project, preterm births fell significantly in both the control and experimental clinics. A somewhat different approach was used by Heins et al whereby highrisk patients who were at risk for low birthweight were randomized to receive standard care by obstetricians or by nurse midwives who provided education to identify signs and symptoms, performed frequent pelvic examinations, and applied stress reduction, nutrition, and substance abuse counseling. This study showed no reduction in low birthweight. However, a post hoc analysis showed that black women had a lower incidence of very low birthweight infants, suggesting these interventions were effective in this subgroup.
The results of the March of Dimes trials initiated in 1984 in five centers also were not encouraging. The first March of Dimes study published by Goldenberg et al34 in 1990 studied the effectiveness of weekly observations and detailed education about prêterai labor signs and symptoms. Approximately 1000 patients were randomized into either a study or control group. Even though more patients with preterm labor were diagnosed and treated in the study group, their prêterai birth rate was slightly greater compared with the controls. The final result of the March of Dimes multicenter trials, published in 1993, suggested patient education for the early recognition of signs and symptoms of preterm labor and hospitalization for tocolytic therapy were not effective in reducing preterm births.62 This outcome is at best disappointing after the encouraging study by Herrón et al. The assumption that patient education for the early identification of preterm labor and early admission/tocolytic therapy can decrease preterm delivery is not supported by these studies.
Because several of Papiernik's interventions have not been properly evaluated, we initiated the Los Angeles Preterm Birth Prevention Program in 1983.63 We randomized eight West Los Angeles clinics into five experimental clinics and three control clinics. This design attempted to avoid spillover of education and interventions from study to control patients. In the experimental clinics, all high-risk patients received prenatal education that focused on the modification of behavior that could cause preterm labor, such as work, prolonged standing, stress-strain, and smoking. In addition, we encouraged patients to develop a support system. We also focused on education to help patients recognize early signs and symptoms of preterm labor. Finally, we randomized highrisk patients into one of five intervention groups: 1) psychosocial support to reduce stress, 2) bed rest to improve uterine blood flow, 3) oral progestin to cause uterine quiescence, 4) a matched placebo, and 5) a group to receive only education. After 5 years and entering 10,294 patients, this study showed a 19% reduction in preterm births between high-risk patients in the experimental (7-4%) versus control clinics (9.1%). None of the specific interventions were found to be additive to the overall effect of education to prevent preterm labor. However, patients who were randomized to bed rest and those who were compliant in taking the progestational agent had the lowest preterm birth rates. It should be noted that the 19% reduction in the preterm birth rate in the West Los Angeles Project occurred during a period when preterm rates were increasing in Los Angeles and in the United States. A cost benefit analysis comparing our focus on prevention rather than the early treatment of preterm labor saved $1768 per high-risk patient.64 We believe our success was due to our more focused education, increased visits, and the extra time spent by health-care workers while applying the interventions.
What is the role of prenatal care in preventing low birthweight and prematurity?
The overall effectiveness of prenatal care recently was reviewed by Alexander and Korenbrot.65 Evidence regarding the efficacy of prenatal care to prevent low birthweight continues to be mixed, but certain interventions appear promising. These interventions are psychosocial (primarily aimed at smoking), nutritional (aimed at low pre-pregnancy weight and inadequate weight gain), and medical (reducing morbidity). These investigators believe that the success of prenatal care will depend on a much broader and a more focused risk specific type of care.
How can primary care physicians help?
Primary care physicians, whether an obstetriciangynecologist, pediatrician, family practitioner, or generalist, must incorporate a strategy for prevention of preterm birth into their practices. Preconceptional counseling must become a part of all practice constructs.66 Every woman should complete a structured questionnaire regarding their plans for pregnancy and identifying what they should consider doing before becoming pregnant.6 Women who smoke must be educated about the hazards of smoking to themselves and others, especially their children. Smoking cessation intervention should be available in all practices. Approximately 25% of low birthweight deliveries could be prevented if women could stop smoking during pregnancy. Approximately 20% of women who participate in these programs will stop smoking, and an additional 25% will reduce the amount smoked.65 Pre-pregnancy counseling also can provide an opportunity to begin folie acid supplementation to prevent neural tube defects, which also are associated with a greater risk of early delivery and prenatal mortality.68
The preconceptional questionnaire also should focus on nutrition to identify the women who are underweight by body mass index based on the Institute of Medicine recommendations for nutrition in pregnancy.69 Women who report poor nutrition habits should be guided toward making adjustments prior to becoming pregnant and then maintaining them during pregnancy.
For the primary care physician who provides newborn care, he or she must work closely with those providing obstetrical care to plan care for preterm labor. There are two important areas. First, it has become a standard in most centers to treat women in preterm labor with antibiotics. The use of antibiotics, primarily ampicillin, may be given to prevent the newborn from being colonized with group B streptococcus: preterm labor and preterm premature rupture of the membranes <37 weeks are two risk factors that have been identified that justify chemoprophylaxis against group B streptococcus.70 The second area of this collaborative effort is to consider giving the mother corticosteroids prior to delivery to reduce the incidence of respiratory distress syndrome and to increase neonatal survival rates.71 Studies suggest that corticosteroids are underused. It also is important to counsel the mother in preterm labor regarding risks to her infant, especially when the fetus is in the very low birthweight category (<1500g).
My final recommendation for all primary care providers is to recognize the important role that you play in the continuum of women's health care from the preconception period through pregnancy and then postconceptional care. Prenatal care must focus on the maternal behaviors that are thought to cause preterm birth. Many women who cease smoking during pregnancy relapse soon after delivery.65 All women who smoked at the beginning of pregnancy should be encouraged to continue to curb this serious habit postpartum, not only for their own health but for the health of their newborn.72 Women who deliver preterm infants require a special commitment: since the risk of delivering a second preterm infant is significantly greater in subsequent pregnancies, we need to give these women focused care to prevent a recurrence if they have more children. The preterm newborn also requires special care and selected interventions to reduce long-term disabilities. Remember, preterm prevention must be a team effort if we are going to make advances to meet our Year 2000 objectives. Time is running out.
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Etiology of Preteriti Birth
Possible Risk Factors for Pretorili and Low Blithwelght Births*