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Delivery prior to 20 weeks of gestation is considered a Natural abortion.1 The survival rate of low birth weight infants has significantly increased from 15-80% in the last 20 years. However, the incidence of prematurity has not seen any change, neither decrease nor increase. Currently the average incidence is 10-11%.1 There are noticeable sex and race differences in incidence and survival rates. In African-Americans the incidence of preterm births is 18.9% compared to 8.8% of Caucasian births. Also, there are differences in survival rates, with male infants having a mortality rate twice that of females, twin infants having a mortality rate 4 times greater than that of singletons, and African-Americans generally having higher survival rates. After 29 weeks of gestation differences are no longer significant. 1 Some factors that have been proposed in order to explain race differences are lower socio-economic status (SES), availability and quality of prenatal care and residence in urban neighborhoods. 2 Traditionally, SES is the focus of arguments that try to explain the differences. However, in a study carried out, SES was not found as a major factor, rather, Bacterial Vaginosis was the center of attention. 3 It was found that among black pregnant women, there was a higher incidence of Bacterial Vaginosis, an infection which will be discussed later. It is difficult to understand how there has been such a drastic improvement in the survival rate but no change in the incidence of preterm birth. The main reason that the incidence has remained static is that there has been no clear definition of the chain of events that result in pre-term birth. Without an understanding of how it happens, there can be no way of stopping the process, and further, of stopping the process once it has begun being that there is no way of knowing exactly at what stage it is. There has recently been a strong theory proposed which needs to be given more attention, the prostaglandin theory. Briefly, pro-inflammatory cytokines and other immunomodulatory proteins produced by either overt or sub-clinical infection stimulate prostaglandin synthesis and release. This ultimately induces the synthesis and release of metalloproteases, which bring on cervical ripening and membrane weakening and rupture. 4 The increased survival rate with a static incidence means that there are more people with problems in society, more NICU’s being filled, more families are having to learn to live with someone that is handicapped, more problems arise with health care funding as more people have chronic health problems, and with a little creativity and a careful eye, the rest of this paper could be a list of the problems that are arising. Some known morbidities of preterm birth include Cerebral Palsy, ADHD, growth retardation, respiratory distress syndrom, decreased cognitive ability, decreased academic skills, decreased visual and gross motor function, and decreased adaptive functions. 5 In a study conducted in Japan, 81 out of 152 patients with Cerebral palsy were type Periventricular Leukomalacia (PVL) and were preterm. There were 90 total PVL cases, that indicates that 90% of the PVL cases had been preterm. 6 Something that has been accomplished is the identification of many risk factors, and risk factors of risk factors. Some factors that do not appear in this chart are untimely prenatal care, Bacterial Vaginosis and urinary tract infections. A risk factor for premature birth is late entry into prenatal care. This is a risk factor not in itself, but indirectly, as it leads to neglect of other risk factors that could be treatable. The other reason that there is a need for focus on this issue is that attitude towards prenatal care is reflective of attitude towards pediatric care. In efforts to explain delayed initiation of prenatal care some logistical risk factors have been designated, the only significant one is transportation, affecting a meek 8% of low-income women in a study carried out in California. 7 The more significant risk factors are more pervasive and require serious health and social reform. In the same study, it was found that of the 28% of women who received untimely care, only 6% of them were unaware of their pregnancies. The women selected for this study were postpartum and had Medicaid or private coverage throughout the duration of their pregnancy. A disturbing 22% of the women blatantly ignored the available care. The significant risk factors identified in this study were unwanted or unplanned pregnancy, no regular provider of care, and no schooling beyond high school, respectively affecting 43%, 66%, 22%, and 76% of women. Unlike transportation, these issues cannot be dealt with easily because they are out of the control o f the care giver during pregnancy, they are events that have already taken place. In another study conducted a major risk factor was residence in a distressed urban neighborhood. 2 Both these studies emphasize the need for outreach and care management for pregnant women, the value of social and health policies, and the importance of encouraging use of prenatal care in Medicaid managed care. Bacterial Vaginosis is another new risk factor, first correlated with spontaneous preterm birth in 1991. 8 There has been much work done on the subject, but with the advent of the Prostaglandin theory, it is beginning to gain force in the field of etiology. Bacterial Vaginosis is an infection in which the normal hydrogen peroxide producing Lactobacillus sp. in the vagina are replaced with high concentrations of characteristic sets of aerobic and anaerobic bacteria. 8,9 Positive amniotic fluid cultures were reported in 20-30% of women with preterm labor. 10 In two other studies, it is predicted that anywhere from 10-41% of women have Bacterial Vaginosis and 50% of those are asymptomatic. 9,11 There is still debate about how these microbes arise within the uterus. Some argue that the microbes ascend through the dilated cervix after the parturial process has initiated as a result of a change in the uteroplacental endocrine interface. Others argue that the microbes ascend to the deciduas, membranes and amniotic fluid primarily through the vagina and initiate inflammatory response in the deciduas, membranes and fetus. A third and most valid theory is that the micro organisms responsible are present in the endometrium before conception and initiate a sub clinical infection of the deciduas , chorioamnion, and fetus weeks or even months before the preterm labor. 10 This last theory fits best with the prostaglandin pathway. The sub clinical or clinical infections caused by the microbes have the same result of producing proinflammatory cytokines and other immunomodulatory proteins. 9,10 These cytokines stimulate prostaglandin synthesis, advancing the evolution of events that lead to cervical ripening, membrane weakening and eventual membrane rupture. In discussing prediction and prevention indices, it is important to keep in mind that “Premature delivery is an end-stage symptom of a multi-factorial disease. Pre-tem labor is one of the last symptoms in a cascade of biochemical events that lead to preterm delivery. The most appropriate way to end preterm delivery would be to prevent the causes that initiate the cascade that ends in pre-term labor.” 12 Another issue to restate is that there is a lack of understanding of the pathogenesis of preterm birth. The effectiveness of the predictions and preventions are limited by our lack of knowledge as to where they fit in. The new hope provided by the prostaglandin theory is a shimmer of light in the right direction, yet it research must continue before it can be accepted. The current indices of prediction of Spontaneous preterm birth fall mainly along two lines, biophysical and biochemical factors. There are also ‘risk scoring’ indices by which the risk is evaluated. According to these measurements 50% of spontaneous preterm births occur in women without apparent risks, a reflection of the low accuracy of these methods. 13 The two main biophysical predictors involve the cervix and the uterus. The three methods for examination and prediction of the risk of preterm birth with the cervix are the Bishop score (Digital examination), the Cervical score (Digital examination; cervix length in centimeters minus dilation in centimeters), and an endovaginal ultrasound to measure the length of the cervix. In general, it has been suggested that there is an increased risk of preterm delivery as cervical length decreases. In a study carried out all of these methods yielded low sensitivities and low positive predictive values. 14, 15 In the uterus, a preterm delivery is predicted if uterine activity is above normal. The uterus is monitored at home by a a tocodynamometer. However, the differences are not large enough to be of clinical value. 14, 15 Biochemical indices are highly sought, a simple litmus test would be a quick way to determine the risk level of a pregnant woman. Plasma and serum markers have been searched for but unfortunately there has been no success. Elevated levels of estradiol, progesterone, prostaglandin, and its metabolites have all been measured prior to the onset of preterm labor, all resulting in differences with no diagnostic significance. 13 Cervicovaginal secretions have been tested, primarily for fetal fibronectin. Fetal Fibronectin is a high molecular weight glycoprotein produce by the chorioamniotic membranes and trophoblasts. It is hypothesized that it functions as a biologic glue that maintains the integrity of the Chorionic-decidual interface. 16 Levels are often elevated until 20 weeks of gestation and beyond that they are miniscule or undetectable in the cervix or vagina, most likely because of the tight application of the membranes to the decidua. 16 Many studies have found a correlation between detection of fibronectin and preterm birth. Its presence not being considered the cause of preterm delivery, rather the result of a disruption (by inflammation or bleeding), in the chorionic-decidual interface from which it leaks out. 16, 17 The value of fibronectin as a predictor is further supported by a screening conducted by the US National Institute of Child Health and Human Development (NICHD) in which women with a positive fetal fibronectin test at 24 weeks had a 60-fold increase in the risk of preterm delivery within 4 weeks after being screened. 16 Prevention against premature birth is the most important issue at hand in terms of improving infant mortality and morbidity. Research has focused on pharmacologic therapy. It is justifiable. It would be ideal to prescribe a pill and make all the problems go away. We have not gotten to the point where preterm birth can be prevented, however, there have been some improvements in morbidity and short delay of labor. 18, 19 The process of stopping labor is called Tocolysis. There are some grave side effects of tocolytics. Their use must be monitored and depends on careful assessment of the mother and fetus. The most commonly used tocolytics are beta-mimetics and Magnesium Sulfate. They both have noticeable side effects, but Magnesium Sulfate is less harmful. 18 In three articles the use of Magnesium sulfate was approved in stopping acute preterm labor. Maintenance therapy, the use Magnesium Sulfate to prevent recurrent preterm labor or preterm delivery, is ineffective and not recommended. Studies have shown that maintenance therapy does not reduce mortality or morbidity. 18, 19, 20 Some long-term side effects include harm to the mother’s cardiovascular system, carbohydrate metabolism, and the fetus’s cardiovascular system. 12 The use of Magnesium Sulfate with indomethecin (a Prostaglandin inhibitor) is approved as long as the gestation period is less than 32 weeks and for less than 48 hours. 12 Labor is postponed for the same amount of time of most known tocolytics, 48-72 hours. There are many other drugs which are considered “investigational drugs,” including Calcium Antagonists, Oxytocin Antagonists and Prostaglandin inhibitors, that require more research to determine possible side effects and effectiveness. 18 Interventions that are less clinical include education programs, bed rest, and precautions regarding coitus. 21 Coitus later in pregnancy can contribute to the pathogenesis of intrauterine infection. Also, orgasmic activity involves contraction of the uterus and semen contains prostaglandins. Preterm labor can theoretically be triggered by either of these two means. Presently, there are a number of recognized and treatable risk-factors, “Known medical and obstetric risk factors for preterm birth should be avoided, eliminated, or reduced, when possible, without undue cost or risk.” 22 A good policy proposal for the present would involve better diagnosis and treatment of Urinary Tract Infections (UTI’s). The incidence of UTI’s among pregnant women at 16 weeks gestation is 6%. Half of the known UTI’s are asymptomatic. If women with UTI’s go untreated, 40% of them will develop polynephritis and 20-50% of these will develop prematurity. 23 UTI’s are easy to treat with proper anti-biotics and antipyretic treatment. The issue is that currently, only Urinalysis is required. Asymptomatic UTI’s will no be discovered by this method. Urinary cultures must be taken instead of Urinalysis. For example, the diagnosis of the presence of Asymptomatic Bacteriuria requires 100,00 colonies/ml of urine on 2 consecutive clean, mid-stream voided specimens in the absence of signs or symptoms of UTI. 23 Urinary culture necessary in order to detect the greatest number of UTI’s. If the issue of cost arises, it is important to remember, ‘The most effective medicine is preventive medicine.’ The costs of the urinary cultures and treatment of UTI’s will be covered with money to spare. The average cost of the first year of care of an infant of *1500g is $93,800 (1987 constant dollars). The actual costs range from $58,000 to $273,900 in first year medical expenses. The preterm birth does not even have to be prevented in order to yield savings. If an infant that would have weighed at least 750g increases 250g, the savings in first year medical expenses range from $12,000-$16,000. If the increase is 500g savings are $28,000. 24 These savings are definitely significant and should be taken into consideration when questioning the price of a certain prenatal care policy. Policy makers have it in their hands to take prenatal and neonatal care in any direction they choose. There is much research to be done in many areas of this field. Three recommended areas requiring significant research are Pathogenesis, Bacterial Vaginosis and fetal fibronectin. They are very promising, but in order to proceed results are needed quickly. Policy makers should focus first on funding research on the pathogenesis of preterm birth. The Prostaglandin pathway is the first solid pathogenesis proposal and as Eastman stated way back in 1947, “Only when the factors underlying prematurity are completely understood can any progress toward prevention be made.” 25 In this light research on the link between Bacterial Vaginosis and intrauterine microbes must be solidified. There should also be a focus on delineating quick screening methods and preparing kits for physicians in order to facilitate diagnosis of Bacterial Vaginosis. Lastly, a more standardized way of measuring fibronectin levels need to be instituted. Currently an readings above 50 ng/ml after 20 weeks gestation are considered indicators of impending preterm birth. Multiple studies have found a strong correlation between positive fibronectin test results and spontaneous preterm birth. Recall the study by the NICHD which found a 60-fold increase in the chances of a spontaneous preterm birth within 4 weeks of sampling. This is a promising biochemical predictor of preterm birth. The survival of premature infants has significantly improved, but the number of infants being born preterm has remained steady for the last few decades. This increased survival rate with the stable, high incidence is yielding a greater amount of neonates with chronic health problems. There is need to further research the proposed pathogenesis and prediction pathways, but presently there are possibilities for treatment that should be implemented. Bibliography: Key: A. Creasy R.K., Resnik R.: Maternal-Fetal Medicine 4th Edition (Philadelphia; W.B. Saunders Company, 1999) - Creasy R.K., Iams J.D.: Chapter 32, “Preterm Labor and Delivery” B. Davis C (Editor): Clinics in Perinatology June 2000, Volume 27, Number 2 (Philadelphia; W.B. Saunders Company) -Lu G.C., Goldenberg R.L.: “Current Concepts on the Pathogenesis and Markers of Preterm Births” C. Creasy R.K., Resnik R.: Maternal-Fetal Medicine 4th Edition (Philadelphia; W.B. Saunders Company, 1999) - Gibbs R.S., Sweet R.L.: Chapter 41, “Maternal and Fetal Infectious Disorders” PubMed: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?CMD=search&DB=PubMed 1. A, pg. 498 2. Perloff J.D., Jaffee K.D.: Late entry into prenatal care: the neighborhood context (PubMed; 1999) 3. A, pg. 503 4. B, pg. 267 5. A, pgs. 499-500 6. Okumura A., Hayakawa F., Kato T., Kuno K., Watanabe K.: MRI findings in patients with spastic cerebral palsy. I: Correlation with gestational age at birth (PubMed; 1997) 7. Braveman P., Marchi K., Egerter S., Pearl M., Neuhaus J.: Barriers to timely prenatal care among women with insurance: the importance of prepregnancy factors (PubMed; 2000) 8. A, pg 502 9. McGregor J.A., French J.I.: Bacterial Vaginosis in pregnancy (PubMed; 2000) 10. A, pg. 503 11. B, pg. 270 12. Katz V.L., Farmer R.M.: Controversies in tocolytics therapy (PubMed; 1999) 13. A, pg. 507 14. A, pgs. 508-509 15. B, pgs. 273-274 16. B, pg. 271 17. A, pg. 513 18. Higby K., Suiter C.R.: A risk-benefit assessment of therapies for premature labour (PubMed; 1999) 19. Crowther C.A., Moore V.: Magnesium for preventing preterm birth after threatened preterm labour (PubMed; 2000) 20. Sanchez-Ramos L., Kaunitz A.M., Gaudier F.L., Delke I.: Efficacy of maintenance therapy after acute Tocolysis: a meta-analysis (PubMed; 1999) 21. A, pg. 510 22. A, pg. 509 23. C, pgs.659-660 24. Rogowski J.: Cost-effectiveness of care for very low birth weight infants (PubMed, 1998) 25. A, pg. 509 Figure 1: B, pg. 267 Figure 2: A, pg. 507 Word Count: 2641
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