If a pregnant woman rushes into a hospital with labor pains, one of the first questions she’s asked is how long she’s been pregnant. If the answer is much less than the usual nine months, then the normal course of action — wheeling the soon-to-be mother to a labor and delivery room — is set aside. Instead, doctors immediately begin giving her drugs to stop contractions that could deliver the baby too soon, then inject her with steroids that speed the development of the infant’s underdeveloped lungs. Finally, they alert the neonatal intensive care unit that there may be a premature baby on its way soon, one who needs extra attention.

“If we can delay labor by even a few days in a mom who comes in beginning preterm labor, it makes our job treating that newborn exponentially easier,” says pediatrics professor William Benitz, MD, who cares for babies in intensive care at Lucile Packard Children’s Hospital at Stanford.

Those few extra days matter so much because babies born too early are at the crux of the lamentable rate of infant mortality in the United States.

This year in the United States, more than 25,000 babies will take their last breath after only hours, days or months of life. Twenty-five thousand tiny bodies, many hidden beneath bright lights, monitors and tangles of tubes as they die. Twenty-five thousand grieving families. This is what an infant mortality rate of six in 1,000 in a country of 4.3 million babies born per year means in real terms.

Considered from another perspective, for every six infants who die before their first birthday in this country, 994 will live. But those numbers — like flowers and cards — don’t lessen the losses. And compared with most of the developed world, the statistics aren’t something to brag about. According to a 2011 World Bank report, the United States ranks 46th when it comes to infant mortality, coming in behind the vast majority of Europe, behind Australia, New Zealand and Canada, behind Korea and Cuba. Every year twice the number of U.S. babies die on their first day alive than in all 27 European Union nations combined, although 1 million more are born there (4.3 million versus 5.3 million respectively). This is one of many disconcerting statistics in Save the Children’s State of the World’s Mothers report published this year.

It would be comforting to attribute the poor ranking to a quirk in how the deaths are calculated. After all, not all countries define birth the same way. For example, in the United States, arrivals of all living infants are counted as births, but a few European countries (the Czech Republic, France, Ireland, the Netherlands, Norway and Poland) have more restrictive definitions. For example, France and the Netherlands report live births only if the infant weighs at least 500 grams — a little more than a pound — or were born at 22 weeks’ gestation or later.

‘The reporting differences are a minor part of the story but not an excuse for why the U.S. has such a high mortality rate.’

But these reporting differences cannot account for the full extent of the gap between countries, says Paul Wise, MD, a pediatrician at Packard Children’s and a health policy analyst at Stanford. “The reporting differences are a minor part of the story but not an excuse for why the U.S has such a high mortality rate.”

Because even when researchers look only at births that meet the criteria for all European countries — 500-gram babies born at 22 weeks and later — the United States doesn’t fare any better. In 2009, Marian MacDorman, PhD, a statistician at the Centers for Disease Control and Prevention’s National Center for Health Statistics drew up a new ranking list, comparing the United States with 20 European countries and excluding the deaths of all babies born before 22 weeks’ gestation. The United States still ranked below most European countries.

So the problem is real, which begs the questions: What’s going on? And what’s to be done about it?

The root cause

Over most of the 20th century, infant mortality rates in the United States and other industrialized nations steadily declined thanks to improving medical knowledge and technology. Hospitals established neonatal intensive care units for infants born with health problems, women began taking folate supplements to decrease the occurrence of certain birth defects and pediatricians learned the best sleeping positions for babies to prevent sudden infant death syndrome. And compared with much of the world — African countries like Somalia and Mali with infant mortality rates around 10 percent and South American countries like Honduras and Ecuador with rates over 2 percent — the United States wasn’t faring poorly.

But by the end of the century, the declines had slowed, the United States lagged behind other developed countries, and it was becoming clear that a drastic socioeconomic divide existed even within the United States when it came to infant mortality. According to the CDC, African Americans had — and continue to have — almost double the rate of infant deaths as Caucasians, and babies born in Mississippi and Alabama are more than twice as likely to die in their first year of life as babies born in Massachusetts and Vermont. (The differences between states reflect, in part, differences in the racial and ethnic makeup of their populations.)

Five main causes of mortality play into the statistics for babies under a year old: birth defects, sudden infant death syndrome, maternal health complications, unintentional injuries and preterm-related causes of death. But when scientists, including Wise and MacDorman, have crunched the numbers on infant mortality, they find that one factor is the biggest difference maker between the United States and other industrialized countries: premature births.

The poor infant-survival rates in the United States are intrinsically linked to high rates of preterm births, those that occur when a woman is between 22 and 37 weeks pregnant, rather than full-term — 37 to 41 weeks. And the same socioeconomic divides seen in infant mortality rates are seen with preterm birth rates — mothers who are African American, live in certain states or experience high levels of emotional stress during their pregnancy are more likely to give birth preterm. And although fertility treatments and teenage pregnancies both raise the risk of preterm births, neither explains the diversity in infant mortality rates — states with high infant mortality have no higher rates of either.

In fact, the analysis published in 2009 by MacDorman and her colleagues at the CDC found that if the United States had the same rate of preterm births as Sweden, our infant mortality rate would be 33 percent lower. Instead of six deaths per 1,000 births, it would be four, closer to Sweden’s rate of three per 1,000.

To save infants’ lives in this country, says David Stevenson, MD, Stanford professor of neonatal and developmental medicine, researchers must first understand the complex causes of preterm birth.

“Over the past 30 years, the rate of preterm births has remained an intractable problem,” says Stevenson. “I think that we now need to take a different kind of approach to solving it.” The approach that’s needed, he says, is one that integrates scientists from many disciplines. To understand the biology of preterm birth and the effects of stress and environmental exposures on that biology, and to develop ways that the U.S. health-care system can address the problem, clinicians can’t work alone. Instead, they need to collaborate with statisticians and mathematicians, with social scientists and ecologists.

Connecting the dots

The challenge in understanding preterm births isn’t making the link between preterm births and mortality rates; that much is already clear to anyone who has worked with premature infants.

“From a clinical standpoint, infectious diseases are going to adversely affect preterm births because these babies don’t yet have fully developed immune systems,” says Stevenson, who also directs the Johnson Center for Pregnancy and Newborn Services at Packard Children’s Hospital. “And they’re also more vulnerable to many other stressors due to their incredibly fragile bodies.”

At 22 weeks’ gestation, a fetus doesn’t yet have fully formed lungs, its nervous system and brain connections aren’t established, its senses are still maturing and its bones aren’t hardened. By 37 weeks, though, these organ systems are mature. Between these two time points, even a few extra days’ gestation can make a difference in which body systems are formed and in a baby’s likelihood of survival — there’s been found to be a 3 to 4 percent increase in survival odds per day in babies at the youngest end of that spectrum. A 2010 study led by Stanford pediatrician Henry Lee, MD, using data from the California Perinatal Quality Care Collaborative on more than 4,000 babies born between 22 and 25 weeks’ gestation found that mortality could be predicted by birth weight, sex and whether the baby was part of a set of twins or triplets. (Heavier babies and females have better survival rates; twins and triplets have worse rates.)

‘Over the past 30 years, the rate of preterm births has remained an intractable problem.’

In the United States, almost one in eight babies is born between 22 and 37 weeks’ gestation. That’s nearly the highest rate in the industrialized world — second only to Cyprus. The U.S. prematurity rate is double that of Finland, Japan, Norway and Sweden, according to the 2013 report by Save the Children.

At any given gestational age, doctors in the United States are as good as doctors in other developed countries at keeping babies alive.

“If you look at a baby born at 25 weeks in the United States and any other developed country, we do really well,” says neonatologist Philip Sunshine, MD, who has cared for more than 30,000 premature babies during his career at Stanford and Packard Children’s. “We have the technology and we have the resources.”

Some causes and risk factors for preterm births are well-established: smoking cigarettes or drinking during pregnancy, infections, high blood pressure or diabetes. But even when studies take these risk factors into account, there are still unexplained differences in infant mortality between different populations. Women on Medicaid, for example, are more likely to deliver preterm, as are women in lower income brackets. And single women, those who induce labor, as well as women with a husband deployed with the military, are more likely to have a preterm baby.

Changing the Odds

In 2011, the March of Dimes, a nonprofit focused on improving maternal and child health, turned to Stanford researchers to help decrease the rate of preterm births in the United States. The organization promised $20 million — $2 million a year for 10 years — to create the March of Dimes Prematurity Research Center at Stanford University School of Medicine. The center, led by Stevenson; Wise; pediatrics researcher Gary Shaw, PhD; and Maurice Druzin, MD, a gynecologist and obstetrician, aims to bring together scientists from disparate fields to study both the clinical causes of preterm births — what happens in the body that causes a woman to go into labor — as well as how environmental and sociological factors can impact this biology.

The center has established teams of researchers to tackle the issues, and is looking at not only the possible genetic factors involved in preterm births, but how bacteria in the gut could play a role, why infections increase the risk of preterm births and whether any molecules in a mother’s blood can predict her risk of going into labor early. Already, they’ve discovered a link between proximity to pollution in California’s Central Valley and preterm births; the data are not yet published.

‘Some of these defects happen so early that they’ve already occurred by the time a woman even finds out she’s pregnant.’

“Right now, we don’t understand the ultimate clinical mechanisms of premature birth,” says Wise. “We don’t understand what triggers the onset of early labor, and that makes it hard to make sense of these social forces.” That lack of scientific knowledge makes it hard to untangle the factors that play into the high rate of preterm births in the United States, he says, but also means that it’s important to study all angles of the problem. A breakthrough could come as easily from the discovery of a new environmental factor — such as pollution — as from an experiment in a biochemistry lab. And the best breakthrough, they all agree, would be a discovery that offers a way not to better treat premature babies once they’re born, but to stop preterm births from the outset.

Over the 20th century, small improvements in technology and approaches to treating preterm babies were constantly pushing earlier the gestational age at which babies were considered viable, and raising the survival rate for these tiniest babies.

“Now we’re at a plateau,” says Stevenson. “The outcomes haven’t been improving; we can’t push them beyond a certain limit in terms of survival.”

So lowering infant mortality, he says, will require preventing preterm births. And even when it comes to many known risk factors for preterm births — substance abuse, diabetes and high blood pressure, for example — physicians can do better at intervening early in pregnancy to optimize women’s health and reduce this risk.

A major focus in the field, Sunshine says, is to encourage at-risk women — such as those with diabetes — to see a doctor earlier in their pregnancy, get their health under control, and continue careful monitoring and regular doctor’s visits throughout pregnancy. “If we can get them in early pregnancy and get them in better condition, that can make a difference.”

In 2011, Kaiser Permanente revealed data from almost two decades of the Kaiser Permanente Northern California Early Start Program, an initiative aimed at getting care to at-risk women as early in pregnancy as possible. Women enrolled in the program, they found, were less likely to give birth preterm, have a stillbirth or a low-birth-weight baby. If the program were expanded to reach women across the nation, Kaiser calculated, it could save $2 billion in health-care costs.

“Our problem with premature births is a problem with the poor health of women of reproductive age in our country and the lack of access to health care that many women in this group have,” says Wise. “Young women tend to have highly fragmented care.” Many of them lack health insurance, he says, and don’t see a doctor regularly enough for any clinician to even know that they have risk factors that lead to preterm births.

According to a 2010 report by the CDC, Americans in their 20s — peak childbearing years for women — were almost twice as likely to lack health care as older adults, and 12 percent of people in that age group had been unable to fill a prescription they needed because of cost.

Although the 2013 Save the Children report focuses on how to improve infant mortality rates in the developing world, several of its recommendations, including improving female education and nutrition, would have positive effects in the United States. Researchers like Wise and MacDorman emphasize the importance of both providing easier access to care for young women as well as educating them better about health during pregnancy.

Birth defects are another cause of infant mortality, and as is the case with preterm births, scientists don’t know many of the risk factors, or the developmental causes at a molecular level.

“Some of these defects happen so early that they’ve already occurred by the time a woman even finds out she’s pregnant,” says Shaw, whose research centers on structural birth defects such as spina bifida and congenital heart malformations. “That’s a window of time that’s very hard for us to study but critical to give scientists ideas about their causes and therefore potentially lead to prevention methods.”

The good news is that the latest numbers on infant mortality in the United States offer the first glimmer of improvement: Data released in April 2013 showed a drop in infant mortality rates between 2005 and 2011, after a plateau from 2000 to 2005. The overall rate dropped from 6.87 deaths per 1,000 births to 6.05, and drops were seen in nearly all causes of mortality, including birth defects and preterm births. The CDC report on the new data hypothesized that part of the drop is likely due to fewer doctors performing non-medically indicated early caesarean sections or inductions of labor, although more data is needed to be sure. And the 6.05 rate still keeps the United States low on the list of international infant-mortality rankings.

“The takeaway message is that the status quo is unacceptable,” says Wise. “The infant mortality rate in many ways is a synoptic judgment on our health-care system and our society. It’s telling us that we must do better — and we can do better, especially when it comes to eliminating social disparities in medicine.”

 

E-mail Sarah C.P. Williams