NICHD Preterm Labor and Birth Research Information

Preterm birth, defined as the birth of a fetus before 37 weeks of gestation, is a major public health priority for the United States and an important research focus for NICHD. Preterm infants are at high risk for a variety of disorders, including cerebral palsy, intellectual and developmental disabilities, and vision impairment. These infants are also at high risk for long-term health issues, including cardiovascular disease (heart attack, stroke, and high blood pressure) and diabetes.

NICHD supports and conducts a large portfolio of research on preterm labor and birth. Among its comprehensive goals are the following:

• Preventing preterm labor and delaying birth until 39 weeks of gestation. Because women who have one preterm birth are considered to be at high risk for another preterm birth, investigators have focused much of their attention on trying to prevent preterm birth among these high-risk women. Current research efforts also are directed toward the significant problem of preterm labor and birth among women who have not given birth before (referred to as being "nulliparous").
• Understanding and preventing non-medically indicated preterm deliveries. NICHD is working with professional organizations to educate health care providers and the public about the significant risks to infants born even a few weeks early.
• Addressing health disparities in preterm birth. Race/ethnicity is an independent risk factor for preterm labor and birth. NICHD research is improving our understanding of health disparities and how they influence risk of preterm birth.
• Studying risk factors for preterm labor. NICHD-supported researchers are elucidating the effect of various risk factors—biological, environmental, genetic, and maternal.
• Improving outcomes for preterm infants. Infants born too early are at heightened risk for short- and long-term consequences. NICHD researchers are testing the safety and efficacy of interventions to see which ones work—and which ones don't.

Preterm labor and birth is the most common cause of infant death and is the leading cause of long-term neurological disability in the United States. NICHD conducts and supports research on preterm labor and birth, seeking ways to reduce the incidence, prevent adverse effects, and improve outcomes for mothers and infants.

• Institute Activities and Advances
• Other Activities and Advances

Institute Activities and Advances

NICHD supports a broad range of research on understanding the causes of preterm birth and reducing its incidence. Areas of research related to preterm birth include the following:

• Underlying Mechanisms
• Predicting Preterm Birth
• Preventing Preterm Birth
• Caring for Preterm Infants

Underlying Mechanisms

Past NICHD research has identified various causes of spontaneous preterm birth, including intrauterine inflammation or infection (PMID: 18240548, PMID: 22752762), uterine or vaginal bleeding (PMID: 21142755, PMID: 21890016), excessive uterine stretch (PMID: 19834610, PMID: 22811574), maternal or fetal stress (PMID: 21958433, PMID: 23447915, PMID: 21890014, PMID: 20195952), and premature rupture of fetal membranes (PMID: 10992202). Much of this research was supported through the Pregnancy and Perinatology Branch (PPB) in the Division of Extramural Research (DER).

PPB-supported researchers recently announced findings from their research on the association of bacteria and the risk of preterm birth. Infections in the mother's genital tract are thought to be a major cause of preterm birth, accounting for approximately 25% to 40% of all preterm births. Many different types of infections, caused by different combinations of micro-organisms, are apparently related to an increased risk of preterm birth. For example, a common infection called bacterial vaginosis (BV) has been associated with a sharp rise in the risk of preterm birth. However, scientists have found that although infections cause the risk of preterm birth to rise, treating an infection does not necessarily cause the risk to fall. To help understand why, researchers conducted a study to assess the relationship between preterm birth and selected vaginal bacteria.

Scientists collected vaginal fluid at 17 to 22 weeks' gestation from about 500 pregnant women who had previously had a preterm birth (and thus were at risk for another early delivery). The researchers found that several types of bacteria—mycoplasma, mobiluncus, and atopobium—were correlated with increased risk of preterm birth. However, the extent of the increased risk was sometimes different for women of different racial and ethnic groups. For example, the presence of mobiluncus bacteria is usually considered to indicate BV. Mobiluncus was associated with a nearly two-fold increase in the risk of preterm birth for Hispanic women, but there was no association between mobiluncus and preterm birth in the other racial and ethnic groups. By contrast, another organism also associated with BV appeared to decrease, rather than increase, the risk of preterm birth for all racial/ethnic groups. These findings help scientists understand why treating BV may not always reduce risk of preterm birth.  The results suggest that focusing on specific bacterial types, rather than the infections that may result, could help scientists develop new ways to prevent preterm deliveries. (PMID: 24096128)

Researchers in the Program in Perinatal Research and Obstetrics (PPRO), within the Division of Intramural Research (DIR), have proposed that allogeneic "rejection" of the fetus may be responsible for several obstetrical syndromes, including spontaneous preterm labor and delivery. (The mammalian fetus is a semi-allograft, as 50% of its genome is of paternal origin.) Program investigators have demonstrated that women with a type of inflammation of the fetal membranes known as chronic chorioamnionitis have circulating anti-fetal antibodies that cross the placenta and induce fetal inflammation and spontaneous preterm birth (PMID: 22092404). Future studies will focus on identifying biomarkers for this mechanism of disease.

Predicting Preterm Birth

Past and current NICHD research also aims to more accurately predict which women will experience preterm labor or who will deliver preterm. Reliable methods of prediction enable health care providers to provide interventions and treatments to prevent preterm delivery.

A recent study conducted by the PPRO evaluated the effectiveness of transabdominal sonography versus the gold standard of transvaginal ultrasound to determine cervical length in pregnant women. In the study, the transabdominal ultrasound screening correctly identified only 43% of women with a short cervix. Based on the results, the researchers recommend continuing use of the transvaginal ultrasound. (PMID: 22273078)

The Population Dynamics Branch, within the DER, supports research helping to identify the factors that do and do not contribute to the likelihood a woman will deliver preterm. Researchers analyzed data on birth outcomes in a large cohort of women who had been evaluated or treated for infertility, comparing the data with outcomes of infertile women who were able to achieve pregnancy without treatment and with fertile women. The researchers analyzed outcomes in women with singleton pregnancies in women who had not previously given birth.

The analysis showed that infertility treatment did not elevate the risk of preterm birth, although it did seem to increase the risk of low weight of an infant at birth. The researchers also found that women who were giving birth to their first child were at elevated risk of preterm birth, regardless of which group they were in. (PMID: 22633266)

Researchers in the Maternal-Fetal Medicine Units (MFMU) Network, which is funded by the PPB, analyzed the blood serum of women at the sixth and seventh weeks of their pregnancies, searching for possible protein anomalies that could warn of early, spontaneous labor. They identified three peptides (short sections of proteins) that were present in significantly lower concentrations in the serum of women who later delivered prematurely.

Specifically, two-thirds of the women with lower peptide concentrations were unable to carry their pregnancies to term. The researchers also found that concentrations of the peptides fell even lower as the women neared delivery. Early identification of pregnant patients who are more likely to experience preterm birth could help clinicians to take preventive measures. (PMID: 21074133)

Other work includes:

• Identifying the timing of cerclage to prolong pregnancy and improve infant survival rates
• Distinguishing women having true preterm labor from those having false labor
• Refining resuscitation methods for preterm infants to minimize lung injury

Preventing Preterm Birth

Women with a prior preterm birth are at increased risk for subsequent preterm birth. Some NICHD-supported research has focused on ways to prevent recurrent preterm births in this population.

An MFMU Network study that began in 2003 set out to determine whether injections of a synthetic type of progesterone called 17-alpha-hydroxyprogesterone caproate (17P) could reduce the number of preterm births among women who had already had one preterm birth. The results showed that, for women carrying one baby and with a history of preterm delivery, injections of 17P reduced preterm birth by one-third. Additionally, infants of women treated with 17P had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen. (PMID: 12802023)

A follow-up study, also conducted through the MFMU Network, tested the effectiveness of 17P for first-time mothers with a short cervix. The study found that it did not reduce the risk for preterm birth before 37 weeks of gestation. (PMID: 23010094) The MFMU investigators also learned that 17P did not reduce the rate of preterm births among women carrying twins or triplets. (PMID: 17671253)

Although the U.S. Food and Drug Administration (FDA) approved the use of 17P for preventing preterm birth in high-risk women in 2011, subsequent research did not show the same effectiveness. The FDA is currently reviewing the evidence to determine whether 17P will continue to be approved for this purpose.

Another study by MFMU collaborators demonstrated that the common recommendations to prevent preterm delivery—activity restriction and bed rest—did not reduce the rate of preterm birth among asymptomatic, nulliparous women with a short cervix. (PMID: 23812450) The researchers found that women who were at risk for preterm birth and who restricted their activity were actually more likely to deliver early than those who did not.

In 2012, the PPRO concluded a clinical trial that screened 30,000 women for short cervical length, a primary risk factor for premature delivery. Women who were found to have a shortened cervix were given either vaginal progesterone or a placebo. The progesterone reduced the rate of preterm birth at less than 28 weeks gestation by 50%. Learn more about PPRO research on preterm birth.

Caring for Preterm Infants

Getting adequate nutrition, preventing infection, and improving lung function are significant issues for preterm infants, particularly those born at very low birth weight (VLBW).

Researchers funded by NICHD's Obstetric and Pediatric Pharmacology and Therapeutics Branch (OPPTB) recently investigated the variable effect of medication to ease infants' breathing. Pregnant women who are in danger of giving birth too early are often treated with medications that help the baby's lungs mature faster. These medications can reduce the newborn's risk of a dangerous breathing difficulty called respiratory distress syndrome (RDS). However, the medicines seem to help babies of certain races and ethnicities more than others, even when other factors, like birth weight, are taken into account. The researchers suspected that this difference may be caused by genetics. They analyzed DNA samples and medical records from 117 mother-infant pairs in which the mother was treated with a specific anti-inflammatory medication before giving birth prematurely. In about half of the cases, the infants developed RDS. The scientists found that several specific variants in genes involved in the breakdown of the medication were also associated with the preterm newborns' risk of RDS. Some of the risk variants were in the mother, and others were in the fetus, meaning that the ways both the mother and the placenta break down the drug can affect how much of the drug reaches the developing fetus. The researchers are using this information to design a larger, more powerful study that will let them control for other factors that might be influencing the results and get a more accurate picture of the effects of these gene variants on infant health. This work could lead to the development of more personalized treatments. (PMID: 22445700)

Researchers in the Neonatal Research Network (NRN), funded by the PPB,recently reported that VLBW infants infected with methicillin-susceptible Staphylococcus aureus (MSSA) have similar morbidity and mortality rates as VLBW infants infected with methicillin-resistant S. aureus (MRSA). These study findings suggest that clinicians may consider applying prevention and treatment approaches for MRSA to MSSA among VLBW infants to improve their chances for survival and reduce complications. The findings are important for informing clinical practice because there is a general perception that MRSA leads to more complications than MSSA. (PMID: 22412036)

The NRN also completed a study showing that corticosteroids could be effective for improving infant survival and limiting brain injury when given to the mother as early as the 23rd week of pregnancy, although current recommendations suggest they not be prescribed until the 24th week. A MFMU trial showed that repeated courses of corticosteroids in pregnant women do not differ from a single course in their effects on child outcomes at 2 to 3 years of age. (PMID: 17881751)

A recent follow-up study on the benefits of higher oxygen levels for preterm infants found that the toddlers given the therapy as infants continued to thrive. Read more about the study.

NRN collaborators conducted a trial of whole-body hypothermia for treating neonatal hypoxic-ischemic encephalopathy (HIE). They found that the treatment was safe and effective and reduced the risk of death and disability among infants with moderate or severe encephalopathy. (PMID: 18829776).

Necrotizing enterocolitis (NEC) is the most common, serious gastrointestinal disease affecting newborn infants. It is most commonly seen in infants born preterm. Recent NRN studies included an observational trial of NEC that found survival was only 51% after hospital discharge in infants who had surgery for NEC or intestinal perforation. Follow-up at 18 months found continued poor outcomes. Children who underwent laparotomy, which involves making a large incision in the abdomen and removing dead tissue, were less likely to have neurodevelopmental impairment than were those who underwent intestinal drain placement, also called primary peritoneal drainage. The latter technique involves a small incision and the insertion of a 4-inch soft drain tube. A randomized trial comparing drain versus laparotomy is under way.

Late-preterm infants (born between 34 and 36 weeks of gestation) are more likely to suffer respiratory complications than infants born at term. Previous research by the NRN showed that a single course of antenatal corticosteroids improved lung function in very premature infants, but this therapy has not been evaluated in those born during the late preterm period. The NRN is currently evaluating whether treatment with antenatal steroids in the late-preterm period will improve infant outcomes. A previous NRN study previously found that weekly steroid treatments were harmful.

In addition, the PPB supported a study on the long-term effects of pain and stress in preterm infants. Researchers measured the level of cortisol in children who were born preterm and full-term and found that the children born preterm had higher levels of cortisol and were most likely to show symptoms of anxiety and depression in their daily lives. (PMID: 21298633)

Findings from the NICHD-supported MFMU also show that treating women at risk of preterm delivery with magnesium sulfate can reduce the risk of cerebral palsy in the infants born to these women. (PMID: 18753646) A third of all cases of cerebral palsy are associated with preterm birth. Read the ACOG Committee Opinion on the use of magnesium sulfate before anticipated early preterm birth for neuroprotection of the infant.

Other Activities and Advances

To achieve its goals for research on preterm labor and birth, NICHD supports a variety of other activities. Some of these activities are managed through the components listed above; others are part of NIH-wide or collaborative efforts in which NICHD participates. The following are a number of examples.

• Two research networks—the Neonatal Research Network and Maternal-Fetal Medicine Units Network—are funded through the Institute's PPB and conduct well-designed clinical trials in large enough populations to have adequate statistical power to answer many research questions.
• NICHD's Maternal and Pediatric Precision in Therapeutics (MPRINT) Hub provides the infrastructure needed to test therapeutic drugs during pregnancy.
• The National Child and Maternal Health Education Program Initiative to Reduce Elective Deliveries Before 39 Weeks of Pregnancy provides information to patients and health care providers about the additional risks to mother and child that accompany early delivery.
• Conferences related to preterm birth and preterm infants are a continuing part of the NICHD research agenda. These include the Surgeon General's Conference on the Prevention of Preterm Birth, the Timing of Indicated Late-Preterm and Early Term Birth Workshop, and the Neonatal Encephalopathy and Hypoxic Ischemic Encephalopathy: Advancing the Science and Improving Outcomes meeting.
• The NICHD NRN Extremely Preterm Birth Data Outcome Tool is intended to inform health care providers and families about possible infant outcomes. The tool is based on standardized assessment data collected through the Neonatal Research Network.
• Through the Neonatal Research Network, the Generic Database of Moderate Preterm Infants aims to establish a registry of moderate preterm infants, born alive at 29 to 33 weeks gestational age. The registry collects baseline data on both mothers and infants, the therapies used, and outcomes of the infants. The information collected is not specific to a disease or treatment (i.e., it is "generic"). Data are analyzed to find associations and trends between baseline information, treatments, and infant outcome, and to develop future trials.

The NICHD-funded Genomic and Proteomic Network for Preterm Birth Research is a research network that aims to accelerate the pace of preterm birth research by focusing on global genomic and molecular research strategies and to rapidly disseminate the data to the scientific community for secondary analyses. The network's projects consist of three collaborative core components: the clinical core, comprising three clinical sites; the analytical core; and the data management, statistics, and informatics core.