Causes of premature birth probed.
Bette Hileman

Faced with a steady rise in premature births in the U.S., researchers are beginning to put pressure on federal agencies and Congress to take action. One possible cause may be exposure to chemicals that somehow affect gestation times. To study this, scientists are seeking changes in federal toxicology protocols that will give them the data they need.

Last month, the Institute of Medicine (IOM) sponsored a meeting on environmental causes of premature births. Speakers presented evidence that industrial chemicals, pesticides, and air pollutants could have contributed to the 23% rise in premature births in the U.S. since the early 1980s. However, they said, the evidence is not strong enough to blame premature births on environmental chemicals in general or on specific substances.

Speakers noted that changes are needed in the Environmental Protection Agency's and the National Toxicology Program's (NTP) chemical testing protocols so that the effects, if any, of specific chemicals on premature births can be identified. For example, in many rodent toxicity assays, the offspring are removed from the womb before birth, giving no indication if the compound could have affected gestation times.

In 1999 in the U.S., 11.8% of all babies, or about 440,000 infants, were born prematurely--that is, before the end of the 37th week of gestation. (The normal length of gestation is 40 weeks.) According to data from the National Center for Health Statistics, in 1981, 9.4% of live births were premature. Part of the increase can be attributed to the age of the women--women are becoming pregnant at older ages now than in 1981--and to fertility treatments, which often cause multiple births. But rates also rose among women under 35, from 10.8% in 1991 to 11.6% in 1999.

The problem of premature births is so severe that researchers and the March of Dimes hope to convince Congress to fund more studies in this area. IOM is preparing a report on the meeting that it hopes will raise Congressional awareness of the issue.

DESPITE SOME scientific advances in understanding prematurity, no progress has been made in lowering the rate of prematurity. "None of the interventions used to try to reduce prematurity actually is effective," Robert L. Goldenberg said at the meeting. Goldenberg is a professor in the department of obstetrics and gynecology at the University of Alabama, Birmingham. Illegal drugs, alcohol, and tobacco use have been found to contribute little to the problem, he explained. "The interventions which have been applied generally to populations and to specific targeted high-risk populations, such as home monitoring of fetal contractions, have not achieved any real reduction in the preterm birth rate," he explained.

Matthew P. Longnecker, an epidemiologist at the National Institute of Environmental Health Sciences (NIEHS), surveyed studies that attempted to gauge the effects of environmental chemicals on preterm births. In three studies of the effects of air pollution, sulfur dioxide and particulate matter were associated with a modest increase in the risk of preterm delivery, he said. But reaching definite conclusions from these studies was not possible because data on personal exposures were insufficient.

An epidemiological study implicates arsenic in drinking water as a cause of preterm births. But the levels in the arsenic study were about two times greater than the most highly contaminated areas of the U.S., Longnecker said. In occupational studies, maternal exposures to solvents and paternal exposures to pesticides were associated with preterm births, but only very general exposure data were available in these papers.

One of the strongest associations was found in a study by Longnecker. He measured the levels of DDE--a metabolite of DDT--in stored sera of mothers who gave birth between 1959 and 1966, when DDT was heavily used in the U.S. In a sample group of 2,380 babies born to these women, 361 were preterm and 221 were small for gestational age. The greater the level of DDE in the mother's blood, the higher was the risk for the infant [Lancet, 358, 110 (2001)]. "The findings of our study strongly suggest that DDT use increases preterm births," Longnecker said. Because the current levels of DDE in U.S. women are about 5% of what they were in the 1960s, DDT is probably not a factor in the recent rise in premature births, he said. But in the 25 countries where DDT is still used for malaria control, DDE levels can greatly exceed the range observed in this study, he said, and may cause early births or small babies. However, "none of the substances studied thus far is yet firmly established as a cause of preterm delivery," he concluded.

Xiaobin Wang, a professor of pediatrics at Boston University School of Medicine, discussed her recent work on shortened gestation times associated with benzene exposure. She studied 542 births to women working at a Beijing petrochemical plant to determine if there was an interaction between their genetic profile and susceptibility to benzene. She found that benzene shortened the pregnancies of those women with a genetic profile that prevented them from detoxifying benzene easily. Although these women were more highly exposed to benzene than the general population in the U.S., their exposures were low for an occupational setting--about one-fifth of the limit set by the U.S. Occupational Safety & Health Administration, she explained.

THE NEED FOR more data is obvious, but current federal testing guidelines for toxic substances are often poorly designed for measuring chemicals' effects on the length of gestation, said Carole A. Kimmel, senior scientist at EPA's National Center for Environmental Assessment.

EPA's and NTP's prenatal developmental toxicity studies are usually done in rats and rabbits. In both species, the pregnant animal is exposed to a chemical beginning at day six of gestation and sacrificed before the kits are born. So changes in the length of pregnancy can't be detected, Kimmel said.

However, in two studies, the developmental neurotoxicity and the two-generation toxicity protocol, a chemical's effect on the length of pregnancy might be detected, Kimmel noted. In these tests, primarily done in rats, chemical exposure begins at or before implantation and continues through pregnancy and birth and into the postnatal period.

One problem with nearly all of the tests is that chemicals' effects on gestation length in rats may not be relevant to humans because chemicals tend to lengthen, not shorten, a rat's gestation time. "We may need better animal models so we can be sure what we see in animals is relevant to humans," Kimmel explained.

Clearly, research has to advance on multiple fronts before the causes of the rise in preterm births can be nailed down. Areas mentioned at the conference include studies on cellular mechanisms to see how chemicals may affect uterine activity and research on the interaction between chemicals, the immune system, and inflammatory responses. Inflammation of the uterus is the proximate cause of many preterm births.

To help solve this mystery of rising premature birth rates, some are looking to Congress to direct NIEHS or EPA to spend more research dollars on studying the causes of premature births. "Given how little we know, a research initiative in that area would be appropriate at this time," says Mary M. Gant, assistant to the director for legislation at NIEHS. IOM's report on the meeting will be sent to Congress in early 2002.