Preterm birth: progress and prospects

Dr Dolan is Professor of Clinical Obstetrics & Gynecology and Women’s Health at the Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York, and a Medical Advisor to March of Dimes.

Dr McCabe is Senior Vice President and Chief Medical Officer at March of Dimes, White Plains, New York, Distinguished Professor Emeritus, Department of Pediatrics & Inaugural Mattel Executive Endowed Chair of Pediatrics, UCLA School of Medicine, Inaugural Physician-in-Chief, Mattel Children’s Hospital UCLA, and Professor Adjunct, Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut.

Neither author has a conflict of interest to disclose with respect to the content of this article.
The authors thank Motoko Oinuma for assistance with preparation of this article.

Much attention has been paid to the issue of preterm birth (PTB) in recent years due to more than 30 years of unrelenting increases in the annual rate of PTB, from 9.4% in the early 1980s, to 10.6% in 1990, to a peak of 12.8% in 2006
(Figure 1).¹ The good news is that the past 7 years have shown a reverse in this trend and modest progress has been made in decreasing the rate of PTB in the United States.

Data from 2013 showed that the US PTB rate decreased for the seventh consecutive year to 11.4%.² These decreases are good news for newborn health and reflect tremendous progress, with 231,000 fewer babies born preterm and $11.9 billion dollars saved.³

Consequences of PTB

The efforts around PTB prevention have helped clarify gestational age definitions, which are based on neonatal risks (Table 1). The definitions were affirmed by the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine in 2013.⁴

Ultimately, however, gestational age is a continuous variable. Data show that each week of gestation until full term makes a difference, bringing with it lower mortality rates as well as reduced rates of morbidity and improvement in a variety of health consequences, including respiratory and neurodevelopmental outcomes.⁵

Analyses from Utah showed an infant mortality rate (per 1000 live births) of 12.5 at 34 weeks, 8.7 at 35 weeks, 6.3 at 36 weeks, 3.4 at 37 weeks, 2.4 at 38 weeks, and 1.2 at 39 weeks.⁵ Thus, compared to infants born at 40 weeks, those born just 2 weeks earlier (at 38 weeks) were twice as likely to die in the first year of life, and those born at 36 weeks were more than 5 times as likely to die.

Due to the ongoing growth and maturation of the fetal lung throughout the third trimester, as well as surfactant production, which surges around 34 weeks, it is not surprising that rates of respiratory distress syndrome (RDS) in a US population from 2002 to 2008 decreased from 10.5% at 34 weeks to 6% at 35 weeks, 2.8% at 36 weeks, 1% at 37 weeks, and 0.3% at 38 weeks or greater.⁶ Other respiratory morbidities, including transient tachypnea of the newborn, pneumonia and respiratory failure, as well as respiratory interventions including oxygen supplementation, intubation, surfactant administration, support with a ventilator, and neonatal intensive care unit (NICU) admission, decreased with advancing gestational age, up to 39 weeks.⁶

Babies born preterm are at increased risk for hypothermia, hypoglycemia, hyperbilirubinemia, and feeding difficulties. Long-term outcomes associated with prematurity include neurodevelopmental delays, likely stemming from the dramatic brain growth that occurs close to term.⁵ Brain maturation appears to remain delayed, even in those born late preterm.^7,8 Studies have shown increased rates of intellectual, psychological, behavioral, and emotional disabilities, as well as vision and hearing deficits, in individuals born before 39 weeks.⁵

As all these data suggest, the relationship between prematurity and a wide variety of short- and long-term health outcomes follows a dose-response relationship: a little bit of prematurity confers a small risk of multiple adverse perinatal and long-term outcomes, and a greater degree of prematurity confers much greater risk. Therefore, successful efforts to reduce the rate of PTB must encompass the full spectrum of gestational ages, the notion of graded outcomes, and the incremental changes in risks and benefits that will determine the optimal timing of delivery.

Progress: Which interventions are working?

The progress in decreasing the rate of PTB can be attributed to many factors. Chief among them are quality improvement efforts aimed at eliminating early elective deliveries before 39 weeks.

According to clinical guidelines, early elective deliveries that do not have a medical indication should be avoided entirely before 39 weeks.9Efforts to increase adherence to these guidelines have been successful in decreasing non-medically indicated early term deliveries via induction or cesarean section in the 37- to 38-week window. They have also contributed to a decrease in the rate of late PTB (34 0/7 to 36 6/7 weeks), which has declined 11% since 2006.¹ Hospital quality improvement programs have engaged professional champions and have been complemented by significant public awareness and provider education campaigns undertaken by March of Dimes; ACOG; the American Academy of Pediatrics; the Association of Women’s Health, Obstetric and Neonatal Nurses; the Association of State and Territorial Health Officials; and many other organizations.

One multistate quality improvement program demonstrated a decline in elective early term deliveries from 27.8% to 4.8%.¹⁰ Another Utah-based study dropped rates from 28% to less than 3%,¹¹ and the Ohio Perinatal Collaborative’s early elective term delivery rate dropped from 15% to less than 5%.¹² A retrospective study at a large regional academic medical center found that the overall percentage of deliveries taking place before 39 weeks fell from 33.1% to 26.4% after a policy was implemented that limited elective delivery before 39 weeks.¹³ However, that study also found a modest increase in macrosomia and stillbirth. While it is imperative to monitor adverse outcomes in future studies, for the moment, it is clear that unless there is a maternal or fetal medical indication warranting delivery, women should wait for labor to begin and no elective inductions or cesarean sections should be scheduled before 39 weeks. A study of Medicaid singleton deliveries in 22 states in the period 2010–2012 found that almost 9% were early elective deliveries, so there is room for improvement according to this approach.¹⁴

Tobacco smoking during pregnancy contributes to a variety of adverse outcomes, including increased risk of miscarriage, stillbirth, PTB, low birth weight, and SIDS. A meta-analysis showed that women who smoked during pregnancy were more than 20% more likely to deliver preterm.¹⁵ Efforts to promote smoking cessation among reproductive-age women have led to decreases, but continued efforts are certainly worthwhile as approximately 20% of reproductive-age women continue to smoke (Figure 2).

Multiple births have shorter gestations, with 56.6% of twins and 93.4% of triplets or higher-order multiples delivering preterm in 2013¹⁶ (Figure 3).

Efforts to reduce the number of multiple births have focused on pregnancies conceived with the aid of fertility treatment, especially ovulation induction and assisted reproductive technology (ART). Nationwide in 2011, 45.6% of ART infants were multiples, the majority being twins, compared with only 3.4% of all infants.¹⁷ While the rate of twins conceived via ART has decreased just 2% between 2000 and 2011, the rate of triplets and higher-order multiple gestations has decreased dramatically (by 67%)¹⁷ since its peak in 2003 at 187.4 per 100,000 live births (Figure 4), largely due to professional guidelines recommending limiting the number of embryos transferred. This decrease has contributed to some of the improvement in the PTB rate.

The role of elective single embryo transfer (eSET) in the reduction of PTB rates is unclear. While eSET has led to a reduction in multiple gestations, which favorably affects the PTB rate, singletons born after IVF continue to be at increased risk of PTB. It is not clear if this is due to some combination of underlying infertility and ovarian stimulation, or additional factors that are not yet well understood. Furthermore, a recent observational study of 3125 eSET cycles performed from 2008 to 2009 showed that eSET alone resulted in an increased risk of PTB (17.6% vs 12%) in all pregnancies conceived via IVF.¹⁸ The composition of culture media, the timing of the transfer (blastocyst vs cleavage-stage), and the role of embryo freezing are all active areas of research that will lead to development of the safest practices for ART. Sorting out the relative contributions of eSET in limiting multiples versus the unexpected finding that eSET pregnancies were more likely to deliver preterm is an important area for future discovery and clarification.

A variety of other interventions have been demonstrated to decrease rates of PTB (Table 2).

Progesterone supplementation is an evidence-based intervention that prolongs gestation. When 17 alpha-hydroxyprogesterone caproate (17P) was used starting in the second trimester, PTB rates dropped approximately 34% in women with a singleton gestation and a history of PTB.¹⁹ Vaginal progesterone has been demonstrated in several studies to have similar efficacy.²⁰ A comparable risk reduction of 33% was demonstrated with group prenatal care emphasizing education and empowerment.²¹ Additional clinical interventions, which if fully implemented would be expected to contribute to a decrease in the rate of PTB, include appropriate use of cerclage for the management of cervical insufficiency and low-dose aspirin prophylaxis to reduce preeclampsia.^22,23 Preventive measures expected to contribute to reducing rates of PTB include educating women to help them achieve an optimal interpregnancy interval of 18–23 months and continuing efforts to reduce teen pregnancy.^24,25

Prospects for continued success

The primary prospects for success lie in full implementation of the evidence-based interventions described above. Were all of these clinical, educational, and public health interventions fully implemented, the rate of PTB would continue to decrease and more babies would get a healthy start in life.

Some aspects of PTB have remained especially challenging and resistant to change. These are areas for research and innovation with hopes for insights that will lead to additional success in decreasing the rate of PTB. A particularly difficult issue is the racial inequity seen in PTB, with African-American women experiencing much higher rates; the rate of PTB in 2013 was 16.3% for black women compared with 10.2% for white women (Figure 5).²

This racial inequity might be explained in part by environmental exposures such as stress and racism. Epigenetics provides a biological mechanism for understanding the cumulative impact of such environmental exposures over a lifetime and is an area of active research.²⁶ Understanding the basis of racial inequity and more importantly, developing interventions to restore equity, remain urgent priorities. March of Dimes supports transdisciplinary research centers,²⁷ which are focused on looking at the complex interplay of the many factors that contribute to PTB.

Another area of concern is the national epidemic of obesity. Overweight and obese women are more likely to deliver preterm,²⁸ and the rates of overweight and obesity continue to rise in the United States (Figure 6).

In the United States in 2013, 25.2% of women aged 18–44 were obese.²⁹ Thus, joining forces with national public health efforts to help women achieve a healthy weight before pregnancy and achieve optimal weight gain during pregnancy will likely contribute to improvements in the rate of PTB.

In addition, advocacy efforts are ongoing to ensure access to health insurance as well as preconception and prenatal care for all women. Programs aimed at reducing health inequities and community-based interventions to improve access to and quality of care will benefit all aspects of maternal-child health and are expected to contribute to lowering the rate of PTB.^30,31

Conclusion

Serious pregnancy complications, such as placenta previa with hemorrhage and severe preeclampsia, which are life-threatening for both mother and baby, warrant delivery when they occur in pregnancy and will likely always contribute to the occurrence of PTB.³² So the ideal PTB rate is not zero. Also, few if any studies adjust for the medical complications that led to PTB when assessing outcomes, so more research is needed to clarify the optimal timing of delivery in some medically complicated pregnancies. However, the surging PTB rate over the nearly 30 years prior to 2006 likely caused more harm than good, and recent clinical and public health efforts have demonstrated that many PTBs are preventable. The steady decline in the PTB rate over the past 7 years is good news, and the 2013 rate of 11.4% met the Healthy People 2020 goal 7 years early.³³ But there are more newborn lives to be saved and therefore, March of Dimes has set an ambitious goal of achieving a PTB rate of 5.5% by 2030.³ By implementing the evidence-based interventions described here and with outstanding prospects for additional research and breakthroughs, this number can be achieved, thereby giving the next generation a healthy start in life. 

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