Special Feature

Preterm Birth — A Synopsis of Current Methods of Prediction and Prevention

By John C. Hobbins, MD, Professor, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Denver, is Associate Editor for OB/GYN Clinical Alert.

Dr. Hobbins reports no financial relationship to this field of study.

The latest figure for the rate of preterm birth (PTB) in the United States is 12.7%,1 which represents a rise of more than 20% since 1980, despite concerted efforts to address the problem. This is particularly unsettling since the global rate of prematurity has leveled at 10%. One major factor for the rise has been a doubling of twins and a 400% rise in multiple order gestation, mostly through assisted reproductive technology. However, this is not the only factor. For the last 2 years of data collection, there has been a slight decrease in multiples, while the rate of PTB has continued to rise.

With this backdrop one might expect an increase in neonatal mortality, but this has leveled off, mostly because neonatologists are now better able to keep very early preterm babies alive. However, unfortunately, this comes with a concomitant increase in immediate neonatal morbidity and long-term disabilities.

The Pathogenesis of Preterm Labor

If there were one cause of preterm labor (PTL), it would be easier to concentrate on an effective therapy, but, unfortunately, there are many causes, including uterine anomalies, abruption, over-distention of the uterus in multiple gestation, cervical insufficiency, and the big unknown. However, the current thinking is that infection/inflammation is the major contributor.

Vaginal bacteria can gain access to an extra membranous site within the uterus where they initiate a maternal inflammatory response that results in the release of cytokines and prostaglandins. These soften the cervix and eventually stimulate uterine contractions. If the process continues, bacteria then get into the amniotic cavity where they cause fetal cytokines to be released. These have been implicated in the development of periventricular leukomalacia, and sometimes cerebral palsy. Inflammation alone (without evidence of intra-amniotic infection) is enough to set the process in motion.

Identification of Patients at Risk for PTB

History.One factor for patients at risk is having a history of previous PTB — about 15% of PTB occurs in patients having already had at least one prior PTB. This risk increases with every prior PTB and is higher in those when the pregnancy has ended before 32 weeks. If a term pregnancy occurs between pregnancies, then the risk of PTB drops somewhat.

Iams and Berghella2 recently resurrected a method based on an earlier concept3 to roughly calculate the risk of PTB for a given patient passed on three variables: race (African Americans have the highest rate), number of preterm deliveries, and the gestational age of the prior PTB(s). If the patient is an African American, the risk is 1.5-fold above the background rate. With each prior PTB, the risk is increased by 1.5 and if the prior delivery occurred prior to 32 weeks, the risk is also raised by 1.5. For example, the authors have assumed a background risk of 11%, so for an African American with one prior PTB at less than 32 weeks, the risk would be 11% x 1.5 (black) x 1.5 (one prior PTB) x 1.5 (less than 32 weeks) = 35%.

Other factors increasing the risk of PTB include:

  • Multiple gestation
  • Bleeding during pregnancy
  • Bacteriuria in the current pregnancy
  • Cervical conization (but not cryo cautery)
  • Uterine anomalies
  • Bacterial vaginosis (but this has been questioned)
  • Smoking

The Role of Cervical Length

Cervical length (CL) obtained by transvaginal ultrasound has become an extremely useful tool to assess risk for PTB and also to determine who might benefit from preventive measures. Its predictive ability appears to be best when measured between 18 and 24 weeks. The median CL during this time is about 3.5 cm and the 10th percentile is 2.5 cm. In Iams' original study,4 the chances of a PTB prior to 35 weeks in those with adequate CL was about 4.3% (which is low, but in those with CL of less than 2.5 cm, it was 17.3%). Two other studies5,6 showed similar results in different populations, and both found that 50% of those delivering prior to 35 weeks of gestation has CL < 1.5 cm. The relationship of CL was refined beautifully in a review by Iams and Berghella2 in which they laid out in table form the probabilities of PTB based on cervical length and the time in gestation when the examination was made. For example, with a CL of 2.5 cm at 20 weeks, the probability of PTB at < 32 weeks was 16.2%. At 24 weeks, this probability with the same CL was 9.9%.

Fetal Fibronectin

In many cases of PTB, there is disruption of the placental/decidual margin, either as a result of inflammation or another disruptive process. Under these circumstances, fetal fibronectin is released from this area and finds its way into the cervix and vagina. This has been used after 20 weeks with and without CL to predict PTB2 or to identify which patients with preterm contractions later in pregnancy are in true labor.7 This test may be useful in the latter category, especially when used in conjunction with CL, but at 20 to 24 weeks the method is fraught with false positives and logistic problems, and I feel is of limited value.

Prevention

Progesterone. For years, investigators had dabbled with the concept of using progesterone to inhibit uterine contractions because of its quieting effect on uterine muscle. Also, since progesterone levels drop just before patients go into spontaneous labor, thereby essentially removing the "progesterone block," there seemed to be a cogent reason to try some form of progesterone to head off impending labor. 17 alpha-hydroxyprogesterone caproate (17P) had been used before, and in a landmark NIH-supported randomized trial, Meis et al8 reported in 2003 that weekly injections of 250 mg of 17P reduced the rate of PTB in those with a history of a prior PTB by 35%. Now there are six trials showing similar results. The current wisdom is that progesterone's action is more related to a direct anti-inflammatory effect, since the inflammatory process starts long before uterine contractions occur.

It is important to point out that there is no evidence that 17P is beneficial in patients who have not had a prior PTB, and thus far studies have shown no benefit in twin pregnancies.9

Can daily vaginal progesterone be used instead of weekly intramuscular 17P injections? Two Brazilian trials10-11 suggest the benefit of vaginal progesterone in patients with short CLs or history of PTB. There are some compelling data soon to be published that will demonstrate significant benefit of vaginal progesterone. Fortunately, this comes out at a time when one company has somehow gotten FDA approval (which appears to be an exclusive) to sell a branded version of 17P.12 Currently, it is being made by compounding pharmacies at an average cost of about $10 a dose, but, according to Time Inc., these compounding pharmacies have been warned that they will face FDA action if their non-branded versions are sold. The company initially sold the product for $1,500. However, in an example of how sometimes organized resistance can work, the price was reduced to $600 after ACOG and SMFM (and others) protested against this outrageous example of gouging. Nevertheless, $600 is still too expensive for a drug that required no pre-marketing R&D, and could cost up to $12,000 for a full course for each pregnancy.

In summary:

  1. 17P has been shown to decrease rates of PTB when given by IM injection of 250 mg once a week.
  2. Vaginal progesterone may work as well, but the dosage and vehicle may vary from the dosage used in the two Brazilian studies.
  3. So far, there is no evidence of benefit with 17P in multiple gestation.9
  4. 17P has not been shown to have additional benefit in patients who have had a cerclage.

Cerclage

Since Shirodkar first described a primitive version of cerclage to treat an "incompetent cervix," obstetricians have been attempting to prevent PTB, especially in those with a history of silent, early PTB, with modified versions of the original procedure. For a time, it was in vogue to do the procedures at about 13 weeks, once there was ultrasound assurance of a viable and non-anomalous start to the pregnancy. When CL examinations became popular, the obvious option was to utilize cerclage in those with short cervices. However, until recently, there were few studies available to indicate which types of patients would actually benefit from this procedure. In fact, randomized trials up until 2001 showed no benefit of cerclage for any reason despite its continued use.13

Althuisius was the first to show potential benefit of cerclage in a randomized trial involving patients with a history of preterm birth and short cervices.14 Then, in 2005, Berghella and colleagues added the above study to a meta-analysis which then suggested the benefit of cerclage in those patients with cervical length of less than 2.5 cm.15 An NIH-supported trial that surfaced in 2009 showed a trend toward benefit in this group of patients (CL < 2.5 cm), but statistical significance was only achieved when the CL was < 1.5 cm.16 Last, Berghella17 very recently added the Owen et al randomized trial to a new meta-analysis, and finally found significant benefit in patients with a history of preterm birth and whose CL was in the "middle ground" (1.5-2.5 cm).16 The effect was seen in only two categories: PTB < 37 weeks (47.5% vs 62%) and pregnancy loss < 24 weeks (2.9% vs 8.9%).

The contemporary rationale is that in patients with a prior PTB and cervices < 2.5 cm, cerclage is not necessarily a method to shore up an inherently weak cervix, but rather, to create a thicker (longer) barrier to ascending infection/inflammation. Anyone with a prior PTB with a CL < 1.5 cm might be encouraged to have a cerclage, and those with a CL of 1.5-2.5 cm could be offered this procedure. Categories of patients in whom no benefit has yet been demonstrated from cerclage:

  1. Multiple gestation — actually, a sub-analysis of the Berghella 2005 trial data showed an increase in adverse outcome with cerclage (vs no treatment).15
  2. Patients with no history of PTB. There are no solid data to suggest benefit of cerclage with or without a short cervix.
  3. Patients already on 17P. This question has not been addressed yet. However, it is now being recommended that if patients on 17P develop a short cervix, they should be offered cerclage.2 Thus far, there is no evidence showing benefit of adding 17P to patients having had cerclages.

Since one study suggested that patients with evidence of the inflammatory changes (interleukin-8) in cervical mucus did worse with cerclage,18 every effort must be made to rule out infection/inflammation before considering cerclage. Suggested protocol for patients with a history of PTB between 17 and 34 weeks:

  1. Standard workup in early pregnancy would include: urine culture, check for bacterial vaginosis, rule out uterine anomalies.
  2. Start progesterone prophylaxis at 16 weeks.
  3. Begin CL exams, using a regimen outlined in the Owen et al study,16 of every two weeks after 16 weeks, and if CL is between 2.5–2.9 cm, then it should be done every week until 24 weeks.
  4. If the CL is < 2.5 cm, offer cerclage, but look for evidence of intrauterine infection/inflammation. Non-invasive help is on the way through new techniques of assessing cervical interleukins and other proteins,19 but, as of now, amniocentesis might be considered.
  5. Early cerclage (13 to 14 weeks) is not advised unless there is an extremely strong suspicion of cervical insufficiency (3 PTBs and/or losses prior to 20 weeks).

Other preventive measures studied include:

  1. Smoking cessation. This has been shown to decrease the rate of PTB by 16%.20
  2. Omega-3 fatty acids may decrease the risk of PTB,21 but in one trial it did not show benefit to patients who were started on 17P.22
  3. Vitamin supplements and calcium supplements are of questionable value.2
  4. Weekly office visits with digital pelvic exams do not decrease the incidence of PTB.23
  5. Screening for bacteriuria with follow-up treatment is of benefit.24
  6. Monitoring uterine contractions is not preventive.25
  7. Restriction of activity, although commonly recommended, has not been shown to be of any benefit.26

With newer methods of surveillance and careful selection of patients for interventions, we may well start to make a dent in the ever increasing, and, frankly, embarrassing rise of PTB in the United States.

References

  1. Hamilton BE, et al. Births: Preliminary data for 2007. National Vital Statistics Reports. Web release, vol. 57, no. 12. Hyattsville, MD: National Center for Health Statistics. Released March 18, 2009.
  2. Iams JD, Berghella V. Care for women with prior preterm birth. Am J Obstet Gynecol 2010;203:89-100.
  3. Iams JD, et al. The Preterm Prediction Study: Recurrence risk of spontaneous preterm birth. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 1998;178:1035-1040.
  4. Iams JD, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit Network. N Engl J Med 1996;334:567-572.
  5. Heath VC, et al. Cervical length at 23 weeks of gestation: Prediction of spontaneous preterm delivery. Ultrasound Obstet Gynecol 1998;12:312-317.
  6. Hassan SS, et al. Patients with an ultrasonographic cervical length < 15 mm have nearly a 50% risk of early spontaneous preterm delivery. Am J Obstet Gynecol 2000;182:1458-1467.
  7. Gomez R, et al. Cervicovaginal fetal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes. Am J Obstet Gynecol 2005;192:350-359.
  8. Meis PJ, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348;2379-2385.
  9. Rouse DJ, et al. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med 2007;357:454-461.
  10. da Fonseca EB, et al. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: A randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003;188:419-424.
  11. da Fonseca EB, et al. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007;357:462-469.
  12. Szalavitz M. Can patients get around the exorbitant new cost of a pregnancy drug? Accessed March 10, 2011. http://healthland.time.com.
  13. Rush RW, et al. A randomized controlled trial of cervical cerclage in women at high risk of spontaneous preterm delivery. Br J Obstet Gynaecol1984;91:724-730.
  14. Althuisius SM, et al. Final results of the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): Therapeutic cerclage with bed rest versus bed rest alone. Am J Obstet Gynecol 2001;185:1106-1112.
  15. Berghella V, et al. Cerclage for short cervix on ultrasonography: Meta-analysis on trials using individual patient-level data. Obstet Gynecol2005;106:181-189.
  16. Owen J, et al. Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length. Am J Obstet Gynecol 2009;201:375.e1-8.
  17. Berghella V, et al. Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth. A meta-analysis. Obstet Gynecol 2011;117:663-671.
  18. Sakai M, et al. Evaluation of effectiveness of prophylactic cerclage of a short cervix according to interleukin-8 in cervical mucus. Am J Obstet Gynecol2006;194:14-19.
  19. Holst RM, et al. Prediction of microbial invasion of the amniotic cavity in women with preterm labour: Analysis of multiple proteins in amniotic and cervical fluids. BJOG 2011;118:240-249.
  20. Polakowski LL, et al. Prenatal smoking cessation and the risk of delivering preterm and small-for-gestational-age newborns. Obstet Gynecol2009;114(2 Pt 1):318-325.
  21. Olsen SF, et al. Randomised clinical trials of fish oil supplementation in high risk pregnancies. Fish Oil Trials in Pregnancy (FOTIP) Team. BJOG2000;107:382-395.
  22. Harper M, et al. Omega-3 fatty acid supplementation to prevent recurrent preterm birth: A randomized controlled trial. Obstet Gynecol 2010;115(2 Pt 1):234-242.
  23. Main DM, et al. Controlled trial of a Preterm Labor Detection program: Efficacy and costs. Obstet Gynecol 1989;74:873-877.
  24. Smaill F, Vazquez JC. Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev 2007; 2: CD000490.
  25. Dyson DC, et al. Monitoring women at risk for preterm labor. N Engl J Med 1998;228:15-19.
  26. Sosa C, et al. Bed rest in singleton pregnancies for preventing preterm birth. Cochrane Database Syst Rev 2004;1:CD003581.