Reducing Preterm Birth Rates: New Strategies and Interventions

Preterm birth (PTB) is a global problem, with 15 million babies born prematurely each year, putting them at greater risk of mortality and lifelong health problems. Currently, the only therapeutic option to prevent PTB in the U.S. is Makena, an intramuscular progestin injection given to women who have had a preterm birth in the past. However, recently, Makena failed a confirmatory trial, which resulted in the Center for Drug Evaluation and Research (CDER) recommending that the FDA withdraw the approval of Makena.

This recommendation would leave doctors without therapeutic options to prevent PTB.In order to improve the health outcomes of these newborn babies, the World Health Organization has published updates for two interventions. A set of recommendations focuses on the use of prenatal corticosteroids. These drugs cross the placenta and improve the structural maturity of the fetus's developing lungs, helping to prevent airway-related morbidity and mortality in preterm infants.Recently, interdisciplinary efforts involving doctors, pharmacists, biologists, chemists, and engineers have been made to understand the risk factors associated with PTB, the mechanisms that contribute to PTB, and to develop next-generation therapies to prevent PTB. These advances have the potential to better identify women at risk of PTB, prevent the onset of preterm birth and, ultimately, save the lives of babies.Childbirth is a complicated process by which a fetus is born.

Successful delivery requires biological signals that coordinate maternal cervical remodeling and uterine contraction to give birth to offspring. Birth is preceded by fertilization, implantation, and development of the fetus and surrounding gestational tissues. Once an oocyte has been fertilized, cells begin to divide until they are eventually implanted in the uterine wall through cell invasion in the deciduous one (Figure). These cells differentiate and form the amnion, chorion, yolk sac, and placenta (Figure).

During pregnancy, amniotic fluid surrounds and protects the developing fetus within the amnion.Early in pregnancy, the yolk sac and later, the chorion and placenta participate in maternal-fetal exchange of nutrients and waste. The maternal cervical mucus plug forms to protect the uterus (Figure). As pregnancy nears its end, the cervix begins to soften and mature to prepare for the fetus to pass through the vaginal canal. It is then that contractions begin signaling labor.During these complicated processes of pregnancy and delivery there is a possibility of a number of complications especially when delivery occurs early.

Clinically progesterone is currently approved by the FDA for prevention of PTB; however based on historical trials it is clear that further work must be done to understand optimal formulation and mechanism of action of progesterone in context of PTB.In addition to pharmaceutical trials recent studies have investigated how diet can affect PTB rates. The ADORE study investigated how docosahexaenoic acid (DHA) supplementation can reduce early PTB (preclinical animal models of PTB have been useful in understanding mechanisms of PTB as well as testing therapies capable of preventing PTB).A summary of candidate drugs and formulations used in recent clinical and preclinical studies for prevention of PTB is provided. Further work must be done to understand mechanisms of drugs and optimal formulations to better prevent PTB. Drug administration during pregnancy is altered due to changes in maternal physiology; these changes should be considered when considering medications formulations and dosing regimens for prevention of PTB.Our group has recently highlighted need to administer drugs that effectively target female reproductive tract while preserving homeostasis of vaginal environment.

Improvement of drug delivery to target cells and tissues allows better characterization of molecular mechanisms that may contribute to PTB. Future studies should continue using rationally designed formulations that improve pharmacokinetics and pharmacodynamics of new treatments paying special attention to safety and unwanted side effects.Through ongoing collaborative efforts scientific community will surely have an impact on preterm births and pregnancy outcomes. If governments were to adopt universal coverage of interventions (95%) ensuring all women and children who need an intervention receive it then according LiST analysis (table) and historical data this could result in reduction in preterm births by up to 50%.

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