Naiara Brocal Madrid
Madrid
Updated Tuesday, February 6, 2024-02:08
Obstetrics The WHO sounds the alarm about a "silent emergency": 13.4 million babies were premature in 2020 worldwide
The lack of medications to prevent premature birth is an issue that worries health authorities. Prematurity is the leading cause of neonatal mortality and is a major cause of complications and disability. In Spain, according to the Spanish Society of Neonatology,
7% of babies are born before the 37th week of gestation
.
The World Health Organization
(WHO) recognizes that there is "an urgent need
for new agents to prevent preterm birth and reduce adverse outcomes for newborns." For this reason, it published a
technical document
in December to guide developers and regulators on the characteristics that these medications must potentially meet.
The US agency
FDA also wants to promote
research in the area. A few weeks ago, the FDA
brought together
experts from various disciplines to discuss how to address the challenges involved in developing these compounds.
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Since the withdrawal last year in the United States (US) of hydroxyprogesterone caproate (
Makena
) for spontaneous premature birth, there is no authorized medication in the country for this indication. This injectable progestin had been on the market for more than a decade after obtaining accelerated approval, but the post-marketing clinical trial required by the regulator did not confirm its effectiveness.
In the US there are only seven drugs authorized for Obstetrics: "No other specialty in Medicine has
such a short list
of drug approvals with so few indications, and this is the panorama that at the FDA we want to change," declared
Christina Chang
, director of the Division of Urology, Obstetrics and Gynecology, according to the specialized media
Biopharmadive
.
José Luis Bartha
, head of the Gynecology and Obstetrics Service at La Paz Hospital, explains that preterm birth and spontaneous abortion "are end results of very different clinical conditions." For the specialist, "The issue is treating or preventing the cause or the way by which that end is reached, and not treating the symptom itself."
Bartha identifies "four major pathways" that lead to spontaneous premature birth that require a specific approach: "inflammation, uterine overdistention, hemorrhage and stress in its most varied forms," says the specialist. "
It is and will be very difficult
to find a global solution for premature birth, which is not only giving birth before week 37 but that point is reached in many different ways. Until this is understood we will not be able to continue moving forward ".
What drugs are used in the threat of premature birth?
The only medication that is prescribed in certain cases to prevent preterm birth in asymptomatic women is
vaginal progesterone
, such as the presence of a short cervix or a history of preterm birth.
María Goya
, senior consultant in Maternal-Fetal Medicine, of the Gynecology and Obstetrics Service of the Vall d'Hebron Hospital, warns that, however, this treatment "is not effective in preventing premature birth and improving perinatal outcomes if there are symptoms and labor has started."
Among tocolytics, only
atosiban
and
ritodrine
have a recognized indication in the technical specifications. But the most used according to obstetricians are atosiban and nifedipine: the first, administered intravenously, has a better safety profile than the second, an oral calcium channel blocker.
Indomethacin
is also used as a tocolytic
, although its use is limited to short periods of time and especially to the first and second trimesters. "It is not recommended after week 28 due to the risks of adverse effects for the fetus," says Goya. "It is the drug of choice when symptoms appear at early gestational ages, below 24 weeks. However, administered beyond 32 weeks of gestation it is associated with premature closure of the ductus arteriosus," adds Miriam Turiel
,
coordinator of the Obstetrics Area of the Department of Gynecology of the Clínica Universidad de Navarra.
As for ritodrine, like terbutaline, "its use is limited by the cardiovascular side effects that it can produce in both the mother and the fetus," says Goya.
What are the medications to mature the baby's lungs?
The goal of treatment with tocolytics is to allow the administration of corticosteroids and magnesium sulfate, which are also used off-label and have been shown to improve neonatal outcomes.
Glucocorticoids, such as
betamethasone and dexamethasone
, accelerate fetal lung maturation. "Evidence from multiple clinical trials and meta-analyses suggests that they significantly reduce the risk of neonatal respiratory morbidities, including hyaline membrane disease, as well as other complications such as intraventricular hemorrhage and necrotizing enterocolitis in premature neonates," Goya clarifies.
Magnesium sulfate is administered for the prevention of perinatal neurological damage. "In a Cochrane review, it was found that magnesium sulfate reduces the risk of cerebral palsy by approximately 30%, and of gross motor dysfunction, by 40%. The protective effect is greater at earlier gestational ages," adds Turiel.
WHAT COMPOUNDS AGAINST PREMATURITY ARE UNDER RESEARCH?
Against this background, a study published last year in
BMC Pregnancy and Chilbirth
identifies
178 compounds under investigation
for the prevention of spontaneous premature birth and preterm labor, of which 71 were in clinical development.
Of these candidates, the authors highlight the potential of ten, six for prevention (
omega-3 fatty acids
, aspirin, vaginal progesterone, oral progesterone, L-arginine and selenium), and four for treatment: nicorandil, isosorbide dinitrate, nicardipine. and celecoxib.
One of the most studied are omega 3, Turiel points out. While encouraging results from a
meta-analysis of trials
and a
Cochrane systematic review
were published in
2015
and
2016
, a clinical trial in 2019 in the
New England of Journal of Medicine
found no significant difference in the rate of preterm births. The conclusion, explains the specialist, is that although there is not enough evidence to recommend this supplementation, "it could be beneficial in populations with low levels, such as in states of malnutrition or patients with
anorexia nervosa
."
The focus of research on medications in preterm birth is on asymptomatic women and women with risk factors "because when there are symptoms, it is more complex to act," warns Goya. Among the strategies under study, interventions are being investigated to modify the vaginal and gastrointestinal
microbiota
with the aim of reducing inflammation and the risk of infections that can advance labor. Other lines of interest are "
stress
management
and the identification of biochemical and genetic biomarkers," she says.
WHAT ARE THE BARRIERS TO FINDING NEW DRUGS?
Why haven't there been more clinical trials in this indications? At the FDA meeting they recognized that it is another sign of the
historical lack of investment
in the development of medications for pathologies that exclusively or mainly affect women.
There are many ethical and regulatory challenges involved in research on pregnant women, apart from the need for financial investment and the interests of the promoters, Turiel acknowledges: "Research resources can be limited and, sometimes, areas with greater visibility are prioritized. or market potential".
Another barrier is the difficulty in measuring certain outcomes of interventions, "especially when looking for long-term effects on the health of children born prematurely." The biological complexity of this phenomenon does not help either, "with
multiple causes and risk factors
, which make the development of effective interventions difficult," explains the CUN expert.