Preterm birth is defined as the birth of a baby before 37 completed weeks (term gestation is between 37-40 weeks). Over the past decade, preterm births have risen by more than 30% and in 2011, they accounted for 12.5% of all births, according to data published by March of Dimes. This is a steady increase from 8% before 1980 and 10.4% in 2002. To put this in real numbers, the Centers for Disease Control reports that more than half a million babies are born prematurely every year. That is, for every 7 babies born at term, there will be 1 baby that is born prematurely. What’s more, prematurity is most frequent in African American and Hispanic women as well those that are economically disadvantaged.
Prematurity - A public health problem
Prematurity poses a tremendous public health problem, where not only racial and socioeconomic disparities are concerned, but more concerning are the short and long term complications associated with preterm birth. The silver lining is that fetal deaths due to prematurity have declined significantly thanks to medical advances in perinatal and neonatal care.
Preterm infants born after 32 weeks now have a 100% chance of surviving. Despite this great achievement, the downside is that preterm infants who survive are likely to develop long-term complications, such as cerebral palsy, developmental problems, mental retardation, visual impairment, and hearing loss. Other complications that are often less apparent are language and learning disabilities and behavioral and psychological problems. Ten years ago, more births were occurring post term (after 40 weeks) but for unclear reasons, this has now shifted to more preterm infants being delivered close to term (34-36 weeks). These babies represent about 74% of all preterm births and though they are mistakenly disregarded as healthy, they still remain at high risk of developing long-term complications. Infants born less than 32 weeks (very preterm) are less occurring, but they have the highest risk of developing life-threatening and chronic conditions.
The impact of preterm birth on the infant and the family
Preterm birth not only impacts the quality of life for the infant, but it can also be financially and emotionally tolling on the family members involved. Furthermore, prematurity impacts the health of the adult-to-be by increasing the risk for such chronic diseases as heart disease, diabetes, hypertension, stroke, cancer and premature death.
It is estimated that $51,000 to $150,000 is spent on each preterm infant for inpatient care and hospital visits, depending on the region where the baby is born. This does not include the expenses incurred for outpatient diagnostic testing and subsequent infant support treatments. In 2005, the US healthcare system spent $26.2 billion on prematurity for medical care, intervention programs, and early education, all of which have failed in preventing preterm birth and improving perinatal outcomes. To put this in perspective, this costs each working man and woman in the USA $600 annually. This is $1,200 per working couple, and if we consider that currently the median household income in the USA is $52,000, it accounts for more than 2% of the median household income. This is a lot of money for a family of four with two working parents.
Despite research, problems with prevention, diagnosis and treatment persist
Given the increase in research over the past decade, not to mention the severity of the problem, it is alarming that we have not made any major improvements in the prevention, diagnosis, and treatment of preterm births.At best and a good step forward by any means, is the limited body of information that suggests a multitude of causes for which there are wide ranges of solutions. The causes, more often than not, co-exist with a combination of other risk factors, such as race and socioeconomic status, genetic susceptibility, environmental exposure to toxins and carcinogens, and behavioral factors such as smoking, drinking, and illicit drug use. This indicates that preterm birth is not the result of a distinct disease but the result of many abnormal conditions that share a common denominator, inflammation.
The past 2 decades have also seen an influx of assisted reproductive technologies (ART) that have led to an increase in pregnancies by older mothers and multiple gestations (twins, triplets, etc). Assisted pregnancies, older age, and multiple gestations greatly increase risk of preterm delivery. It is significant to note here that the largest contribution to prematurity from ART is not from the multiple gestations but from the singleton ones. A potential reason for this problem is that most sub-fertile couples suffer from genetic and acquired thrombophilias, which interfere with placental development, leading to poor neonatal outcomes, including prematurity and growth retardation among others. Fetal demise in pregnancies conceived by ART is 4X that of spontaneously conceived pregnancies.
Why is tocolysis not improving neonatal outcomes?
Clinically, the causes associated with preterm birth are most commonly attributed to conditions such as spontaneous preterm labor, preterm premature rupture of membranes, hypertension, intrauterine growth restriction, antepartum haemorrhage, and cervical incompetence or uterine malformation. Luckily, most of these conditions can be detected weeks before delivery, which allows doctors to intervene with the proper treatment. Paradoxically, while current interventions do their best at addressing the symptoms that lead to preterm labor, they have proven to be less than successful for a variety of reasons. For one, little is known about the physiological and pathological mechanisms underlying preterm labor and the complications associated with prematurity.
This may explain why methods of tocolysis (inhibition of contractions) are not always successful in improving neonatal outcomes. Tocolytic drugs such as beta-mimetics, atosiban, and nifedipine effectively delay labor for more than 24-48 hours, but studies have shown that these drugs do not significantly improve outcomes, such as infant death, respiratory distress syndrome, birth weight, seizures, and developmental delays. Other data show that while tocolysis is beneficial in reducing infant mortality (death), it is associated with an increase in severe neonatal brain scan abnormalities and severe chronic lung disease.
Indomethacin underutilized in clinical practice
Unfortunately, despite the well proven superiority of indomethacin in reducing prematurity, which is the most desirable outcome as opposed to simply delaying the time of delivery by a few days, very few specialists use indomethacin in clinical practice. The reason for this failure has to do with the lack of expertise in proper fetal heart monitoring in order to protect the fetus from the risk of premature closure of the ductus arteriosus, a potential indomethacin related complication. This risk remains a theoretical one if the medication is used according to strict protocols and in the appropriate gestational ages.
Indomethacin is the safest and most efficient tocolytic drug, and as of the time of this writing, it can reduce prematurity by as much as 90% in patients with early signs of preterm labor as measured by progressive cervical shortening. No other tocolytic drug can achieve this feat.
Why is indomethacin superior to progesterone?
The most fashionable tocolytic drug currently is synthetic or natural progesterone in oral, intravaginal, and injectable forms. The best study that propelled synthetic progesterone (17-α- hydroxy- progesterone caproate) to fame was heavily criticized, and rightly so, for the unnaturally high rate of preterm birth in the study’s control group, which allowed the researches to claim that they were able to reduce prematurity by 50%. However, the fact that the treated group experienced a prematurity rate of 30%, which was 3 times higher than the average prematurity rate in the US at the time of the study was totally ignored. To put it in a different way, if one compares a criminal who killed only 30 people to a criminal who killed 60 people one should have the right then to claim that the criminal who committed the fewer murders is a nice person.
Progesterone in all its forms and fashions is a poor alternative to indomethacin, which according to our recently published study it reduced prematurity by almost 90%.
The only advantage of progesterone is that it has no serious side effects for the baby and its use does not require any particular skill, unlike indomethacin that requires excellent knowledge of fetal cardiovascular physiology as well as fetal cardiac Doppler skills. However, because the use of progesterone in any form is idiot-proof, it has rapidly gained prominence and is currently the most commonly employed tocolytic drug, nevermind that it has done nothing to reduce prematurity.
Administering glucocorticoids in high-risk pregnancies
The use of glucocorticoids in high-risk pregnancies before 34 weeks of gestation has been shown to reduce mortality (death), respiratory distress syndrome, and intraventricular haemorrhage in preterm infants; however, no beneficial effect has been reported when administered before 28 weeks of gestation. The use of single dose glucocorticoids in premature fetuses has been associated with increased risk of insulin resistance and diabetes in early adulthood. Importantly, little is known about the potentially harmful effects of repeated doses vs single-course doses on the developing fetus.There is strong evidence that 3 or more doses of glucocorticoids administered to premature fetuses can cause significant restriction in brain growth. Therefore, further randomized control data is needed in order to establish a definitive and safe protocol that will guide better clinical practice.
Antibiotics can prolong pregnancy and improve neonatal outcomes
Antibiotics have also been effective in the treatment of infections that increase risk of preterm labor. Results from a substantially large randomized control trial of the antibiotic, erythromycin, have shown that it significantly prolongs pregnancy and improves neonatal outcomes, but it also failed to make a dent in the reduction of prematurity. Studies show that treatment of bacterial vaginosis with intravaginal clindamycin cream (antibiotic) did not show any improvements in reducing preterm birth and may even be harmful when used in the first trimester.
Other interventions like cervical cerclage (stitches to close the cervix) have been beneficial in preventing preterm birth mainly in women with cervical incompetence and previous risk factors for preterm labor. However, study results on neonatal and perinatal outcomes are conflicting and inconclusive because the obstetrical community has not found a way yet to accurately define which patient has cervical weakness and which one has preterm labor.
At Kofinas Perinatal we have exploited the benefits of Indomethacin as a diagnostic and therapeutic tool in order to better identify the patients who would benefit from cervical cerclage. Our method helped us reduce the need for cerclage by 70% and reduce prematurity in patients with persistently short cervix by 90% in comparison to other institutions, which refuse to use any kind of intervention due to “lack of evidence”.
Promoting antenatal care and providing enhanced social support systems
Enhanced social support systems and promotion of antenatal care are additional interventions that target socioeconomic factors that increase the risk of preterm birth. Studies have observed improvements in the number of antenatal visits, bed rest programs, home visits by midwives, counseling, and nutritional education.
Unfortunately, these interventions have not resulted in a significant advantage in terms of perinatal and neonatal outcomes, simply because they have never addressed the real common denominator, poor placental development and poor maternal health overall.
The challenge - accurate diagnosis and detecting conditions that lead to preterm labor early enough
Although these various interventions are in place to prevent preterm birth, the rate continues to rise indiscriminately. The possible explanations that can be drawn out of this predicament is that not only the treatments themselves are defective, but there is a constraint in the ability to correctly diagnose conditions that end in preterm labor and detect them early enough for interventions to work efficiently.
In the field of obstetrics, this has been one of the most difficult problems to tackle. Like most obstetrical problems, the causes of preterm birth are complicated and involve the interplay of various biological, environmental, genetic, and even socioeconomic factors.
Currently, no single tests or assessment can accurately predict all preterm births. Serial cervical measurements by means of endovaginal ultrasound in the first half of pregnancy seem to be the best predictor of preterm birth, and if used properly according to our protocol, it can reduce prematurity by 90%. (https://kofinasperinatal.org/resources/file-library-/dr-kofinas-publications)
We need larger controlled trials and improved assessments
The inadequate body of information available on this subject calls to attention an urgent need for additional clinical research with a focus on improved assessments and larger controlled trials.
Furthermore, there is a need for more multi-disciplinary research that explores the molecular and biological mechanisms underlying preterm labor as well as gene expression during labor (term and preterm), which could enhance understanding of how preterm birth occurs as well as aid in new developments in effective and targeted treatments.
The IOM even reports a need for improved and accurate collection of perinatal data and surveillance, which is essential for assessing the causes, mechanisms, and outcomes of preterm birth.
The prospect of achieving these goals is ambitious; however, it remains a long-standing and persistent issue of profound importance, not only in terms of improved obstetrical practice, but also for the future health of infants at risk of the adversities that commonly follow preterm birth. Preterm birth can be devastating for family members and also present a huge economic cost to society.
Further research, randomized control data, and improvements in the diagnosis, early detection, and treatment of preterm birth will greatly improve perinatal and neonatal care as well as the future health of the adult.
