By William W. Hay, Jr., MD
In 2003, 12.3 percent of births in the United States were preterm (less than 38 completed weeks of gestation). This represents a 31 percent increase in the preterm birth rate since 1981. As of 2010, the U.S. preterm birth rate has not declined significantly. The largest contribution to the increase in preterm births is from births between 34 and 38 completed weeks of gestation (term is after 38 weeks), known as late preterm births. Late preterm births have been increasing over at least the past two decades to a much greater extent than earlier preterm birth.
The U.S. singleton (one fetus) birth distribution of gestational age has been shifting toward earlier gestations and 39, not 40, weeks has become the most common length of gestation. Increasing rates of cesarean section and induced deliveries appear to be contributing to the shift toward earlier gestation deliveries among singleton births. And while multiple births, largely the result of reproductive technologies such as in vitro fertilization and cultured embryo implantation (usually of more than one embryo to ensure survival of at least one), have led to a marked increase in very preterm deliveries, singleton late preterm births comprise the fastest-growing segment of preterm births and the largest proportion (approximately 75 percent) of singleton preterm births.
Causes of Late Preterm Birth
At all gestational ages, the risks of continuing a pregnancy must be carefully balanced against the risks of delivery and the associated risks of preterm birth. Most preterm births are not elective and are due to problems beyond the mothers control or the discretion of her doctor. Although the factors contributing to increasing preterm birthsin the United States remain to be identified, plausible etiologiesinclude increasing proportion of pregnant women over 35 yearsof age, multiple births, medically indicated deliveries secondaryto better surveillance of the mother and the fetus, attemptsto reduce stillbirths, and stress from a variety of sources.
Some well-known medically indicated factors in the pregnant mother or the fetus leading to late-pretermbirths include placental abruption, placenta previa, bleeding,infection, hypertension, preeclampsia, idiopathic preterm labor,premature rupture of membranes, intrauterine growth restriction,and multiple gestation.
Compared with births before 34 weeks, late preterm births are more likely to be caused by spontaneous preterm labor or premature prolonged rupture of membranes than medical or pregnancy indications. The causes of indicated late preterm births are similar to that for all preterm births, including preeclampsia (46 percent), fetal indications (18 percent), placental abruption (14 percent), and other medical problems (20 percent). Maternal factors that are more common in the late-preterm group include chorioamnionitis, hypertension, diabetes, thrombophilia, primigravida (first pregnancy), and teenage pregnancy.
Unfortunately, however, increasing numbers of late preterm births are the result of non-medical conditions and are, thus, unintended. Unintended preterm delivery is an underappreciated contributor to the burden of preterm birth.
Unintentional preterm delivery may occur because of inaccurate gestational age assessment, which can be compounded if a planned elective delivery is proposed prior to 39 weeks of gestation. ACOG has proposed strict guidelines for gestational age assessment to minimize the risk of unintended preterm delivery. Furthermore, ACOG has mandated that elective delivery only take place after 39 weeks of gestation in well-dated pregnancies. An earlier elective delivery can only be considered after documentation of fetal lung maturity (FLM), with two exceptions in which elective delivery can be performed at 38 weeks without documentation of FLM: HIV and multiple pregnancies.
Despite these clear recommendations, some providers continue to offer a planned elective delivery prior to 39 weeks of gestation without documenting FLM. This is not only inappropriate, but potentially dangerous, because it can lead to unintentional late preterm birth with its accompanying complications.
What proportion of late preterm births are avoidable? For obvious reasons, elective preterm deliveries are likely underreported, but a recent study of late preterm births (34-37 weeks) at a single tertiary care institution showed that as much as 10 percent of late preterm births were purely elective. While the majority of the late preterm deliveries, therefore, were clearly unavoidable and due to the underlying medical or obstetrical condition that prompted the early delivery in the first place and not due to the gestational age at delivery alone, 10 percent still is a very high rate.
What are the medical problems in late preterm newborns?
Most people understand that extremely preterm infants, such as those born more than 8-10 weeks early, suffer major medical problems and have a very high chance of dying or surviving with long term disabilities. Many do not appreciate, however, that late preterm infants not only account for the vast majority of all preterm births, but also the majority of diseases that afflict all preterm infants and require care in neonatal intensive care units (NICUs).
Late preterm infants are not just a bit early and need only a few days to a few weeks to get bigger and stronger before they can go home. Every organ in the late preterm infant still is undergoing development, which is interrupted with their early birth and associated with unique disorders requiring care in NICUs.
Neonatal complications in late preterm infants are not infrequent or insignificant. Compared with normal term infants, late preterm infants have increased mortality and are at increased risk for complications including need for cardiopulmonary resuscitation at birth. Regarding specific disorders, approximately 8 percent of late preterm infants require supplemental oxygen support for at least 1 hour, almost three times the rate found in infants born at over 37 weeks. Among 35 to 36 week newborns who progressed to respiratory failure and who survived to 6 hours of age and did not have major congenital anomalies, the mortality rate is almost 1 percent, far greater than normal term infants.
Other major disorders that are greater in late preterm than term infants include generalized sepsis, specific infections (especially pneumonia), transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), persistent pulmonary hypertension (PPHN), unexplained respiratory failure including apnea (stopping breathing), temperature instability, hyperbilirubinemia with jaundice (even including the related neurological injury of kernicterus), seizures, feeding difficulties (especially for breast feeding), hypoglycemia (low blood sugar), and prolonged NICU stay.
In addition, late preterm infants experience multiple therapies, few of which have been formally evaluated for safety or efficacy in this gestational age group. One of the most concerning therapies is the use of antibiotics to treat presumed but not proven sepsis, a practice that his led to a major increase in opportunistic organisms that are very difficult to treat with usual antibiotics (methicillin resistant staphlococcus aureus or MRSA is a well known example).
Rates of rehospitalization after discharge from the birth hospital also are increased in late preterm infants. Jaundice, provenor suspected infections, feeding difficulties, and failure tothrive are the most common diagnoses at readmission, but higher rates of respiratory syncytial virus infection (RSV) causing bronchopneumonia and croup also occur, especially in such infants exposed to cigarette smoke. Even 1-2 weeks of gestation confer considerable improvement in the rates of significant diseases and thus the rates of admission to NICUs.
The financial burden of late preterm infants also increases with early birth, which, as with the incidence of disease and NICU admission, could be diminished significantly by even modest prolongation of pregnancy. For example a delay in delivery from 34 to 35 weeks provides a 42 percent decrease in the average neonatal cost, and a further delay from 35 to 36 weeks would result in an additional 38 percent decrease in cost. One study from California estimated that avoiding non-medicallyindicated births between 34 and 37 weeks of gestation couldhave saved $49.9 million.
Longer term outcomes
Late-preterm infants are at seven-fold higher risk for neonatal morbidity compared with term infants. More dramatically, the rates of morbidity double for each gestational week earlier than 38 weeks, such that even at 37 weeks the morbidity rates are twice those at 38 weeks. Compared with term infants, late-preterm infants are at higher risk for postneonatal mortality, sudden infant death syndrome, white matter injury in the brain (the clearest sign of later impaired mental deficiency and muscle weakness, including cerebral palsy), and neurodevelopmental problems well into school age.
In one study of nearly 1,000 preterm infants in a defined population of newborn infants, 20 percent of those born at 34 to 37 weeks of gestation had clinicallysignificant behavior problems at 8 years of age, a rate much higherthan those born at term from the same population of about 2-3 percent.
Future challenges
Fetal development and maturation represent a continuum, and any preset gestational age cannot be assumed to provide a clear separation between immaturity and maturity. Because all preterm infants carry finite, measurable risks, the indications for preterm deliveries need to be justified. In the presence of maternal or fetal illnesses, the risks and benefits of immediate delivery versus postponing it need to be closely assessed. Because late-preterm birth is the fastest growing subset, even a small increase in their morbidity rate can have a major impact on the health care burden. Despite much research, the reasons for the increasing number of preterm births are unclear, especially because there have been no reports of increasing prevalence of traditional risk factors such as preeclampsia, umbilical cord accidents, and chorioamnionitis.
Advancing maternal age, an often-cited factor for the increasing preterm birth rate, cannot explain all such increases. Increasing rates of multifetal gestation also cannot explain the increasing rate of late-preterm births among singleton pregnancies. Some investigators have suggested that nontraditional factors may need to be explored to explain increasing late-preterm birth rates. For example, women with no recorded indication for delivery are more likely to be older, white, have higher levels of education, and live outside the northeastern U.S., even though as with very preterm births, the frequency of late preterm births is two- to three-fold greater among African Americans and 20-30 percent greater among Hispanics than in whites (U.S. data).
Future research
One hopes that future research will yield answers to critical questions about late preterm birth. Do some health care providers use soft indications for induction of labor in late-preterm pregnancies? Have the improved standards of neonatal care led to a sense of complacency concerning late-preterm births? Do some patients request early labor inductions (and their health care providers oblige) for the sake of mutual conveniences? If so, how common are such practices? Are there variations in standards of care for late-preterm pregnancies among racial and ethnic groups, across regions or between academic versus nonacademic centers, in rural versus urban communities, and among those women with private versus public payer systems?
In the meantime, health care providers caring for pregnant women need to avoid delivery of infants in late-preterm pregnancy when it is not medically indicated. Those who care for late-preterm infants need to recognize that such infants are physiologically immature even when they appear clinically stable.
The American College of Obstetricians and Gynecologists recommends that no elective delivery should be performed before the gestational age of 39 weeks; however, studies report rates of 28-35.8 percent of elective deliveries occurring before 39 weeks and reveal that they also contribute to increased rates of late preterm births. Prevention of early-term elective deliveries has not demonstrated an increased risk for stillbirth, one of the more persistent reasons for performing elective deliveries before term. The implementation of hospital quality improvement programs has successfully reduced the occurrence of elective early-term and late-preterm deliveries, as well as associated neonatal morbidity and mortality.
Early origins of later life health and disease
There also is increasing evidence that disorders occurring at critical and sensitive developmental stages, including the late preterm period, can have lifelong impact on the health of individuals.
Interruptions of nutrition, insults to the lungs and heart and kidneys, disruption of normal brain development, and many other problems that occur in all preterm infants, but even in late preterm infants, are known risk factors for later life development of obesity, type 2 diabetes, cardiovascular disease (such as heart attacks and strokes), and intellectual impairment (lower IQs and cognitive capacity).
Thus, it is not just the immediate neonatal problems and their financial burden that are greater in late preterm infants, but the risk for lifelong complications of increased disease burden and related financial costs, which limit the opportunities for such infants to have normal development, participate in normal aspects of life, and contribute to personal economic well being. Prevention or reduction of late preterm birth, therefore, can have a major impact on improving the health of our citizens and our country.
This point could not have been said better, clear back in 1962, when then-President John F. Kennedy signed into law the National Institute of Child Health and Human Development:
. . . . The future health of our Nation rests on the care of our children and the development of our knowledge of the medical and biological sciences. . . . Research in recent years has established beyond question that adult behavior, intelligence, and motivation are established by the experience and patterns of response developed in the formative years of life. . .
William W. Hay, Jr., MD, is a professor of pediatrics (neonatology) and co-director (child and maternal health) at the Colorado Clinical and Translational Sciences Institute. He also is scientific director at the Perinatal Research Center of the University of Colorado School of Medicine.