Risks Versus Benefits of Using Aspirin, Magnesium Sulfate, Corticosteroids, and Progesterone during Pregnancy

Abstract

This chapter will discuss various prophylactic and therapeutic strategies based on a review of the literature that is based on the best evidence. In this way, we will know the effect of aspirin as a prophylactic measure in the prevention of severe preeclampsia. Then, we treat the impact of magnesium sulfate to significantly reduce intracranial hemorrhage and cerebral palsy. Following this, we examine the impact of corticosteroids in premature pregnancies in different clinical scenarios, demonstrating their efficacy in improving neonatal prognosis. Finally, we will see the effect of progesterone in reducing premature labor. The use of these strategies has allowed for an improvement in perinatal morbidity and mortality due to the intrinsic beneficial effects of these drugs, as well as a decrease in prematurity (aspirin and progesterone).

1. Introduction

Recently, several prophylactic strategies for preventing poor perinatal outcomes have been studied. Thus, in this chapter we will share the four biomedical interventions that have proven to be safe and effective for improving neonatal prognosis, despite their contradictory evidence, and except for when corticosteroids are indicated. Next, we will review the effect of corticosteroids, progesterone, aspirin and magnesium sulfate by reviewing the literature based on the available evidence.

2. Aspirin: Acetylsalicylic acid

2.1 History

Aspirin is one of the oldest medications still in use in the modern world. The first records of “salix”, a component of aspirin derived from willow bark, were found in papyri used by Egyptian physicians in 1534 BC [1]. Hippocrates also recommended herbal tea made from white willow leaves for pain and fever. Hundreds of years later, in 1829, Pierre Leroux obtained salicin crystals by boiling white willow bark powder. Later, in 1842, Raffaele Piria synthesized salicylic acid for the first time, however, it had many adverse effects. In 1953, Gerhardt was the first to isolate acetylsalicylic acid as we know it today [2].

In 1971, Vane, Samuelson, and Bergstrom were awarded the Nobel Prize for elucidating aspirin’s mechanism of action and they initiated the clinical research on its antiplatelet effects [1]. This last effect has made aspirin one of the most prescribed medications in the world and it is taken by more than 50 million people to prevent cardiovascular disease.

In the field of prenatal care, aspirin appeared for the first time in 1978 in a case reported by Goodlin et al. They describe a patient with a history of two premature births due to hypertensive crises and thrombocytopenia (currently HELLP syndrome) who was undergoing her third pregnancy with similar characteristics. At 15 weeks, she already presented thrombocytopenia, so after a course of heparin with no favorable results, aspirin was started given its antiplatelet effect. The patient had a remission of her plateletopenia and reached 34 weeks of gestation resulting in a live newborn weighing 1410 grams [3]. Shortly thereafter, in 1978, in the wake of this case report, Crandon et al. published a retrospective study that demonstrated that aspirin could have a role in the prevention of preeclampsia [4]. In the following years, multiple studies were published on the protective role of aspirin in hypertensive disorders of pregnancy.

2.2 Preeclampsia

Preeclampsia is a multifactorial systemic disorder, which occurs syndromatically. It is characterized by high blood pressure associated with proteinuria and/or the dysfunction of an organ or system. It affects between 3 to 5% of all pregnancies, representing one of the main causes of maternal morbidity and mortality, especially when it begins early on in pregnancy [5, 6]. Of all premature births, one-sixth are due to preeclampsia; and out of all preeclampsias, a third must be interrupted before term with all the morbidity and mortality associated with newborn prematurity [6]. This is the reason why it is important to have predictive methods for preeclampsia and, concomitantly, to have a prevention strategy, which is where the role of aspirin arises.

2.3 Pathophysiology of preeclampsia and mechanism of action of aspirin

PE is characterized by a systemic proinflammatory state in which cytokines, free radicals, oxidized lipids, oxygen reactive species, and sFlt-1 are released into circulation, among other molecules that cause the clinical characteristics observed in PE. This endothelial dysfunction causes an increase in the peroxidation of endothelial lipids and these, in turn, activate the cyclooxygenase (COX) enzyme and inhibit prostacyclin synthase, enzymes that regulate the production of prostaglandins that play a leading role in the pathophysiology of PE [7]. Prostaglandins are fat-soluble molecules that participate in multiple biological processes, both physiological and pathological. They are synthesized from arachidonic acid (AA) which is present in practically all cells by means of the COX enzyme. This enzyme converts AA into prostaglandin H₂ which is metabolized into several other types of prostaglandins depending on the cell type in which the reaction occurs and the type of enzyme that acts upon it. Prostacyclin synthase, present mainly in endothelial cells, transforms AA into prostacyclins (prostaglandin I2) which have a vasodilatory effect and inhibit platelet aggregation and adhesion. On the other hand, thromboxane synthase produces thromboxane from AA. It is found mainly in platelets and causes a vasoconstrictor effect, contrary to prostacyclins [8]. Aspirin induces the acetylation of a serine in the COX enzyme, binding irreversibly to its catalytic site. This prevents the binding of AA which causes an inhibition of its action. Although aspirin irreversibly blocks the action of COX in its production of endothelial prostacyclin as platelet thromboxane, endothelial cells quickly activate gene mechanisms that allow new COX to be produced, which allows normal levels of prostacyclins to be maintained. On the other hand, platelets that do not have a nucleus cannot activate genetic mechanisms that generate new COX molecules for the production of thromboxane. This imbalance causes disequilibrium in the thromboxane/prostacyclin balance in favor of the latter, which would generate a protective effect by reducing the inflammation previously described in the pathophysiology of PE [7, 9]. These findings have been corroborated in studies that show that patients with PE have high levels of thromboxane and low levels of prostacyclins [10]. This imbalance can already be seen during the first trimester of pregnancy, and studies show that when aspirin is administered, this imbalance is reversed after 2 weeks, favoring vasodilation in the systemic circulation, specifically in the remodeling of the spiral arteries. In addition, there is a decrease in antiangiogenic factors such as sFlt-1 and an increase in circulating levels of PlGF [2].

In summary, the effect of aspirin in the prevention of preeclampsia is due to an improvement in the placentation process, the inhibition of platelet aggregation, and its antithrombotic effect which leads to lower levels of placental infarction, its anti-inflammatory effects, and endothelial stabilization [6].

2.4 Aspirin and prevention of preeclampsia

As already mentioned, since the late 1970s, multiple studies have been published regarding the prevention of preeclampsia with the use of aspirin, however, the results have varied, and even contradictory. This variation in results is likely due to the heterogeneity in the methodology of the studies in addition to the multifactorial etiopathogenesis of preeclampsia. This heterogeneity includes:

• Patient selection: There are several ways to stratify the risk of developing preeclampsia and therefore prescribe the use of aspirin to a particular patient. Different studies and international societies apply very diverse criteria to classify patients who are at risk. For example, some are founded on assigning a score based on major risk factors or a sum of lesser risk factors [11, 12, 13]. Other guidelines have assigned value to an altered uterine artery Doppler in the first trimester, without considering other risk factors [14]. In other latitudes, patients are stratified based on an algorithm that assigns a specific risk according to the presence or absence of several environmental and biophysical variables [15].

• Aspirin dose: another possible cause of the variation of the results is that the only thing that all the studies coincide on is to administrate of low doses of aspirin. However, these low doses have been studied with 50 mg, 60 mg, 75 mg, 81, 100 mg, or 150 mg [15, 16, 17, 18, 19].

• Gestational age at the time of indicating or stopping aspirin: another point of controversy is when the indication of aspirin starts. Several authors indicated the use of aspirin anytime a risk factor for preeclampsia was observed, regardless of gestational age. Others, on the other hand, started aspirin in the first trimester, and others before 16 or 20 weeks [15, 18, 20, 21]. In the 2010s, important meta-analyses were published regarding the use of aspirin in PE prevention, one of them showed that a greater decrease in the appearance of preeclampsia is achieved when aspirin is started before 16 weeks of gestation [22]. The same group later went on to demonstrate through another meta-analysis that starting aspirin before 16 weeks only achieves the desired effect in preventing the preeclampsia that appears before term (37 weeks) and does not influence the prevention of preeclampsia that begins after this gestational age [23]. Finally, a more recent meta-analysis by the same group reported that the dose of aspirin does influence the results, demonstrating greater benefits in studies that used higher doses of aspirin (150 mg) [24]. In 2017, as a result of the publications of these meta-analyses, a large randomized controlled trial was published, which showed that in patients at a high risk of preeclampsia, the use of aspirin indicated before 16 weeks of pregnancy, at a dose of 150 mg per night (circadian effect), decreased the rate of preterm preeclampsia by 62% (OR 0.38; 95% CI, 0.20–0.74; p = .004) [15].

Despite the evidence shown in the prior paragraph, the different large obstetrics and gynecology societies still have not agreed on the criteria regarding when aspirin should be initiated, what the recommended dose is, and when its use should be stopped, as shown in Table 1.

Guide	Start of aspirin use	Dose	Cessation of use
ACOG	12–28 weeks. Ideally before 16 weeks	81 mg	Until childbirth
RCOG	12 weeks	150 mg or 2 tablets of 81 mg (acceptable)	Until childbirth
WHO	<20 weeks	75 mg	Unspecified
FIGO	11–14 + 6 weeks	150 mg	Up to 36 weeks, or when preeclampsia is diagnosed
NICE	12 weeks	75 mg at moderate risk and 150 mg at high risk	Until childbirth

Table 1.

Recommendations from different scientific societies regarding the use of aspirin.

ACOG: American College of Obstetricians and Gynecologist, RCOG: Royal College of Obstetricians and Gynecologist; WHO: World Health Organization; FIGO: International Federation of Gynecology and Obstetrics; and NICE: National Institute of Health Organization. Adapted from Horgan et al. [25].

Other beneficial effects of aspirin have been studied and have demonstrated a decrease in poor obstetric outcomes such as the restriction of intrauterine growth, in-utero fetal death, and admission to neonatal intensive care units. However, the studies have more biases and less statistical power, so better quality studies are required in order to be able to provide a recommendation [6].

3. Magnesium sulfate

Magnesium Sulfate in the obstetric field is relevant due to its tocolytic effect (prevention of premature birth), prophylaxis, and treatment of eclampsia in severe hypertensive conditions (effect on maternal morbidity) as well as its role in reducing cerebral palsy in premature newborns. This section will focus on this last role.

3.1 Cerebral paralysis

It is a spectrum of non-progressive movement and posture disorders that have multiple causes, clinical types, and degrees of severity. It is also associated with intellectual disability, autism, epilepsy, and visual impairment [26]. It has an approximate incidence between 2 and 2.5/1000 births, with a relationship that is inversely proportional to the gestational age at birth, both in its incidence and in its degree of severity. Some series reported that a quarter of newborns with cerebral palsy were born before 34 weeks and a third of babies with cerebral palsy born before 26 weeks cannot walk [26, 27, 28]. Neonatal encephalopathy secondary to injury or acute peripartum hypoxia is often attributed as the cause of cerebral palsy; however, only 13% of term newborns diagnosed with neonatal encephalopathy subsequently developed cerebral palsy [29]. In its pathophysiology, cerebral palsy is observed in the context of a diffuse white matter lesion or cystic periventricular leukomalacia, or both. It may also be seen as intraventricular hemorrhage. Lesions have been described in the corticospinal tract, as well as in the posterior thalamic radiations connecting the thalamus with the occipital and posterior parietal cortex. Neuronal loss has also been described in the subplate, basal ganglia, and cerebellum [30].

Risk factors associated with cerebral palsy are, as already mentioned, premature birth, coexisting congenital anomalies, intrauterine infections, abnormal fetal inflammatory response, thrombophilia, intrauterine growth restriction, multiple pregnancies, circular nuchal cord tension during childbirth, prolonged shoulder dystocia, placental pathology, congenital errors of metabolism, genetic factors that cause intrinsic brain damage or increased susceptibility to brain injury, and finally a greater association with the male sex [26].

3.2 Magnesium sulfate as cerebral palsy prophylaxis

Magnesium Sulfate has been used for several decades in the prevention and treatment of eclampsia. In the early 1990s, a retrospective observational study described that women who received magnesium sulfate, in the context of a hypertensive syndrome of pregnancy, demonstrated a decrease in the incidence of cerebral palsy in premature babies, particularly those patients who did not have preeclampsia [31]. Based on these findings, the role of magnesium sulfate in the prophylaxis of cerebral palsy began to be actively studied. Thus, in the 2000s, 5 large studies appeared that tried to demonstrate the relationship in the decrease of cerebral palsy with magnesium sulfate when it was administered in the context of premature birth [32, 33, 34, 35, 36]. In most of them, the primary results that tried to demonstrate that magnesium sulfate decreased cerebral palsy were not met. However, a meta-analysis that included these 5 large trials demonstrated that there were no differences in terms of pediatric mortality between exposed and unexposed children (RR 1.04, 95% CI, 0.82–1.17). However, evidence of a relative decrease in cerebral palsy of 32% was observed (RR 0.68, 95% CI, 0.54–0.87). Sixty-three had to be treated to prevent one case of cerebral palsy (95% CI, 39–172) [37]. In addition, there was evidence of a significant decrease in gross motor dysfunction (RR 0.61, 95% CI, 0.44–0.85).

Subsequent follow-up studies in school-aged children did not demonstrate harmful effects in children exposed to magnesium sulfate, which is why it is currently considered a safe therapy [35, 38]. A more recent Cochrane review that evaluated different measures for preventing cerebral palsy reported that the use of magnesium sulfate has high-quality evidence in fetal neuroprotection, unlike other prophylactic measures [39].

Regarding its physiological mechanism of action, magnesium is an important mediator in cellular apoptosis pathways that occur during inflammatory processes. It competitively reduces calcium entry into the cell, blocks glutamate and other excitatory neurotransmitters, and modulates the actions of proinflammatory cytokines and oxygen free radicals. Furthermore, magnesium is considered a vasoactive agent, with hemodynamic benefits in the fetus and newborn which include the stabilization of blood pressure and cerebral arterial perfusion [40].

3.3 Practical considerations regarding magnesium sulfate

There are no clear definitions regarding the time when magnesium sulfate should be administrated given the heterogeneity of the different studies; however, most international guidelines agree on administering it in the face of imminent delivery before 30–32 weeks of gestation. The doses also usually vary, nevertheless, the most commonly used corresponds to a loading dose of 4 grams to be administered in 30 minutes followed by a continuous infusion of 1 gram/hour administered for 24 hours or until the child is born. As an exception, its use can be extended in cases of prophylaxis for postpartum eclampsia. It is recommended to monitor the mother with clinical parameters due to the risk of poisoning, through the serial assessment of diuresis, tendon reflexes, respiratory rate, and state of consciousness. Regarding its concomitant use with other tocolytics, recommendations differ [41].

4. Corticosteroids

The beneficial effect of corticosteroids in animals has been recognized for more than 50 years. Liggins was the first to conduct experiments on sheep, concluding that premature lambs exposed to corticosteroids had a better survival prognosis than those that had not received them. In 1972, this same author, together with Howie, published the first randomized controlled study of the effect of corticosteroids in humans concluding that corticosteroids not only reduced the risk of respiratory distress syndrome (RDS) (from 25.8 to 9%) but also significantly reduced neonatal mortality (15 to 3.2%) [42]. Finally, it is interesting to note that a meta-analysis that included more than 1400 pregnant women with premature rupture of membranes (PROM) who received a single dose of corticosteroids showed that RDS decreased significantly (RR 0.56, 95% CI 46–70), HIV (RR 0.47, 98% CI 0.31–0.70 CI) and EN (RR 0.21, 95% CI 0.05–0.82) [43]. The evidence with the most statistical power and with a high degree of recommendation is a Cochrane systematic review that included 30 studies that encompassed 7774 pregnant women and 8158 neonates whose mothers had mostly received a course of corticosteroids (betamethasone, dexamethasone, or hydrocortisone) except 9 trials in which a second course was administered 7 days apart compared with a placebo or no treatment. This regimen was indicated for women with a single or multiple pregnancy, before premature birth occurred (elective or after spontaneous labor), regardless of another comorbidity. This meta-analysis highlights that prenatal corticosteroid treatment (compared with a placebo or no treatment) is associated with a decrease in the most serious adverse outcomes related to prematurity which include: perinatal death, neonatal death, RDS, wet lung, necrotizing enterocolitis, periventricular leukomalacia and less need for mechanical ventilation (less use of surfactant and neonatal infections in the first 48 hours) [42, 43, 44].

4.1 Physiological effect of antenatal corticosteroids

The use of corticosteroids in premature pregnancies decreases mortality and respiratory distress syndrome. The physiological mechanism of how corticosteroid therapy would act would be through the stimulation of surfactant production by type 2 pneumocytes, the maturing of connective tissue, and the stimulation the synthesis of elastin.

Betamethasone (two doses of 12 mg intramuscularly every 24 hours) and dexamethasone (four doses of 6 mg every 12 hours) are the corticosteroids prescribed for the prenatal period due to a series of advantages. The most noteworthy are that these corticosteroids pass through the placenta without losing effectiveness and this lasts even after delivery since newborns respond better to the effect of postnatal surfactant and furthermore, the effect on neonatal plasma is short, no more than 40 hours after delivery.

Betamethasone and dexamethasone are the most widely studied corticosteroids and, in general, have been preferred as prenatal treatment to decrease neonatal death and to accelerate the maturing of other fetal organs (not only the fetal lung) since a decrease in HIV, periventricular leukomalacia and necrotizing enterocolitis became evident. Both pass through the placenta in their active form and have almost identical biological activity.

4.2 Impact of corticosteroids on perinatal outcome

The accumulated evidence advises the use of a course of corticosteroids in pregnant women who have a threat of premature birth between 24/0 weeks and 33/6 weeks of pregnancy and who have a real risk of delivering within 7 days [43, 44].

Besides, the use of corticosteroids in patients with premature rupture of membranes (RPM) between the weeks already indicated has proven its indication, not only in improving respiratory morbidity. If not, mortality, intraventricular hemorrhage, and necrotizing enterocolitis have also decreased [45, 46, 47].

In relation to the probable risk that corticosteroids have in facilitating infectious processes, it has been published that their use in pregnant women with PROM does not increase infection in the mother-child binomial, and their indication can even be considered from week 230/7 and that they are giving birth within 7 days [43, 48]. .Repetitive use or a rescue course of corticosteroids with preterm PROM is controversial, as there is not enough evidence to make a recommendation for or against it.

The studies that support the use of corticosteroids in pregnancy are contradictory; in fact, Cochrane concludes that more studies are needed to suggest their indication. Despite the above, a retrospective study was recently published that indicated that prenatal corticosteroids in twin pregnancies within 7 days before delivery were associated with a significant reduction in premature neonatal pathology (neonatal mortality, neurological injury, and respiratory distress) [43, 44, 49, 50].

In relation to imminent late preterm birth, recent data also suggest that betamethasone may be beneficial in pregnant women at high risk of late preterm birth, between 34 0/7 weeks and 36 6/7 weeks of gestation who have not received a prior course of prenatal. To answer this hypothesis, a study led by The Maternal-Fetal Medicine Units Network Antenatal Late Preterm Steroids Trial was carried out. This study was a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the use of prenatal betamethasone in pregnant women at a high risk of delivery in the late preterm period. Women were identified as being high risk if they were in preterm labor, had preterm PROM, or had a planned delivery in the late preterm period, with the indication at the discretion of the obstetrician-gynecologist or other health care provider. Tocolysis was not used as part of this trial and delivery was not delayed due to obstetric or medical indications. The study found that betamethasone administration led to a significant decrease in the primary outcome, which was the need for respiratory support. A greater decrease was demonstrated for serious respiratory complications, from 12.1% in the placebo group to 8.1% in the betamethasone group (RR, 0.67; 95% CI, 0.53–0.84; P < 0.001). There were also significant decreases in rates of transient tachypnea in newborns; bronchopulmonary dysplasia; a combination of respiratory distress syndrome (RDS), transient tachypnea in the newborn and RDS; and the need for postnatal surfactant. Infants exposed to betamethasone were less likely to require immediate postnatal resuscitation. There was no increase in proven neonatal sepsis, chorioamnionitis, or endometritis with betamethasone in the late preterm period. Hypoglycemia was more common in betamethasone-exposed infants 24.0% versus 14.9% (RR, 1.61; 95% CI, 1.38–1.88); however, no adverse events related to hypoglycemia were reported, and neither an increase in the length of hospital stay. The rates of hypoglycemia found in the trial are similar to those reported in the general population of late preterm infants [51, 52, 53]. Currently, there is greater evidence supporting the use of corticosteroids in late preterm infants, particularly in those women who had not received a prior course.

Finally, ACOG recommended that elective cesarean sections should be performed at 39 weeks to reduce potential risks associated with prematurity in newborns at 38 weeks. Therefore, we hypothesize that the 38-week-old fetus needs labor to release corticosteroids and other mediators that would reduce neonatal complications associated with prematurity. In this way, the authors of this chapter carried out a randomized case-control study in which some patients received a course of corticosteroids at 37 + 5 and 37 + 6 and were operated on at 38 weeks, and the controls at 39 weeks who did not receive this indication. The results of this study are encouraging, because they show that in selected cases and exceptionally, the administration of corticosteroids at 38 weeks prior to an elective cesarean section does not have worse results than an elective cesarean section at 39 weeks (RDS 0% vs. 1.1%, p = 1.0, transient tachypnea 0% vs. 0% and admission to neonatal intensive care unit 8.8% vs. 6.3%, p = 0.7) [54].

Finally, there are still no methodologically well-done studies in the literature to advise that cycles less than or equal to two doses present any risk of alteration of neurobehavioral development. Therefore, the 2000 NICHD consensus panel concluded that studies on the possible benefits and risks of repeated courses of prenatal corticosteroids are limited due to their designs and “methodological inconsistencies.” It also noted that while there is a suggestion of a possible benefit of repeated courses (especially in the decrease and severity of respiratory distress), there is also data in animals and humans suggesting deleterious effects on the fetus with regards to myelination of the brain, lungs, growth, and function of the hypothalamic-pituitary-adrenal axis. Follow-up of children at 2 years of age who were exposed to repeated courses of prenatal corticosteroids showed no significant differences in physical or neurocognitive measurements in two studies [55, 56], and the same result was found in younger children in a third study. Although not statistically significant, the relative risk of cerebral palsy in infants exposed to a series of prenatal corticosteroids (RR, 5.7; 95% confidence interval, 0.7–46.7; P = 0.12) as observed in one study is a cause for concern and warrants further study. Maternal effects include a greater risk of infection and suppression of the hypothalamic-pituitary-adrenal axis [57]. Regularly scheduled repeat cycles or serial cycles (more than two) are currently not recommended [58].

5. Progesterone

Preterm birth is the most frequent complication in Maternal-Fetal Medicine with an incidence ranging from 6.5% to 12.5% depending on the different regions of the world and it is the main cause of morbidity and mortality in the neonate. Research on this condition is a priority for the World Health Organization (WHO) and it is considered key for decreasing prenatal deaths by the United Nations [59].

Despite being controversial, one of the strategies that has proven its effectiveness is progesterone.

This hormone, in both its presentations as micronized natural progesterone and 17 alpha hydroxyprogesterone caproate (c17-OHP), has as a possible mechanism of action, an anti-inflammatory effect. It may also maintain the myometrium quiescent, decrease the degradation of the cervical stroma, decrease the contractile frequency of the uterus, attenuate the decidual hemorrhage/inflammation response, and inhibit connexin-43. However, it should be kept in mind that although both presentations are types of progesterone, current evidence concludes that only micronized natural progesterone decreases the contractility of the myometrium and prevents cervical modifications whereas c17-OHP would not do so since it would act by different pathophysiological mechanisms [59].

5.1 Impact of progesterone in pregnant women with a prior history of premature birth

Regarding c17-OHP, in pregnant women with a previous history of preterm birth and singleton pregnancy, both the first clinical trials [30] and a subsequent meta-analysis reported a significant decrease in delivery <37 weeks and in perinatal morbidity after the prophylactic administration of c17-OHP (intramuscular [IM] at a dose of 250 mg every 7 days). The greatest effectiveness was observed when its administration was started before 21 weeks of gestation (usually from 16 to 20 weeks to week 36). Notwithstanding, the risk of gestational diabetes tripled in the pregnant women who were studied [31].

The study that refuted the efficacy and safety of the latter was the one published in 2020 (PROLONG [32], a randomized, multicenter, placebo-controlled trial that evaluates the safety and efficacy of c17-OHP injections in 1707 pregnant women with a singleton pregnancy and a history of prior preterm delivery. This study did not demonstrate that c17-OHP decreases delivery <35 weeks (11.0 vs. 11.5%; RR 0.95; 95% CI: 0.71–1.26), nor neonatal morbidity (5.6 vs. 5.0%; RR 1.12; 95% CI: 0.68–1.61), nor fetal/early infant death (1.7 vs. 1.9%; RR 0.87; 95% CI: 0.40–1.81). Maternal outcomes were also similar between the 2 groups.

In twin pregnancies, two randomized (double-blind, placebo-controlled) studies revealed that c17-OHP did not reduce the risk of preterm birth nor improve fetal or neonatal outcomes [33, 34].

On the other hand, natural micronized progesterone would not reduce the risk of birth <34, <37 weeks nor improve neonatal morbidity and mortality in pregnant women with a history of prior preterm birth and normal cervical length [35, 36]. Supporting this conclusion, the PROGRESS study [37] (randomizing 787 pregnant women with a single or twin pregnancy and a history of prior preterm birth) evaluated the effectiveness of a progesterone pessary (equivalent to 100 mg of vaginal micronized progesterone) vs. a placebo and did not observe a decrease in labor <37 weeks (adjusted RR 0.97; 95% CI: 0.81–1.17), nor in the risk of neonatal respiratory distress (adjusted RR 0.98; 95% CI: 0.82–1.17) or other neonatal or maternal outcomes related to preterm birth (adjusted RR 1.35; 95% CI: 0.85–2.15).

Finally, in the OPPTIMUM study [35] no differences were observed when the efficacy of progesterone was evaluated in pregnant women at a high risk of preterm birth (odds ratio [OR] 0.86 [95% CI: 0.61–1.22]). Therefore, administration of c17-OHP or vaginal micronized natural progesterone to prevent preterm birth is not recommended solely because of the history of previous preterm birth.

5.2 Impact of progesterone in singleton pregnancies and short cervix

c17-OHP does not decrease the risk of preterm birth in pregnancies with a short cervix (cervical length ≤ 25 mm) [60]. Regarding natural micronized vaginal progesterone, in pregnant women with a short cervix, with or without a history of preterm birth, it has been reported that progesterone is effective in decreasing preterm birth <34 weeks [35, 38] (RR 0.60; 95% CI: 0.44–0.82) neonatal complications (neonatal respiratory distress (RR 0.47; 95% CI: 0.27–0.81) and neonatal morbidity and mortality (RR 0.59; 95% CI: 0 .38–0.91) with the number of pregnant women that need to be treated being 10 (95% CI: 7–28), 18 (95% CI: 13–51) and 18 (95% CI: 12–81) respectively [61]. The benefit would not depend on the maternal age, BMI, race, or ethnicity.

However, the OPPTIMUM [60] study published later contradicts the results of previous meta-analyses. In said study, the pregnant women who were selected had a high risk of preterm birth (history of preterm birth <34 weeks and/or cervix <25 mm). They were randomized to receive 200 mg daily of vaginal progesterone vs. placebo with administration starting at weeks 22–24 through week 34. The study did not observe a decrease in preterm birth nor any improvement in perinatal outcomes in the vaginal progesterone group. Subsequently, another meta-analysis [62] (5 studies, 974 pregnant women) confirmed the results of the previous meta-analyses regarding the benefit of progesterone in reducing labor <34 weeks (RR 0.72; 95% CI: 0.55–0.95). No differences were observed regarding the neurodevelopment of those born after 2 years of follow-up. Therefore, the administration of natural micronized progesterone (200 mg/24 h vaginally) is recommended in asymptomatic pregnant women with singleton pregnancies and a short cervix (≤ 25 mm) to prevent preterm birth, regardless of whether they have a history of previous preterm birth or not.

5.3 Impact of progesterone in twin pregnancies

If the current evidence is taken into account, progesterone has not been shown to decrease preterm birth in twin pregnancies [63]. This conclusion is supported by a Cochrane review [64] that analyzed the effectiveness of progesterone (both vaginal and IM) as prophylaxis in twin pregnancies (16 randomized studies with placebo, 4548 pregnant women). A higher percentage of delivery <34 weeks was observed in the group treated with c17-OHP than in the placebo group (RR 1.54; 95% CI: 1.06–2.26). With regards to vaginal progesterone, no significant differences were observed in the risk of preterm birth (RR 0.90; 95% CI: 0.66–1.23), nor in neonatal morbidity-mortality. Finally, in pregnant women with twin pregnancies and a short cervix, Romero et al. [58], in a meta-analysis with six randomized clinical trials that included pregnant women with twin pregnancies and cervical length < 25 mm, observed that vaginal progesterone decreased labor <33 weeks (31.4% vs. 43.1%; RR 0 .69; 95% CI: 0.51–0.93) and neonatal morbidity and mortality, without finding differences in the neurodevelopment of these children at 4–5 years of follow-up. Currently, the data from this study is being analyzed once again and these results are pending. For now, there is not enough evidence to recommend the use of vaginal micronized progesterone in twin pregnancies.

6. Conclusions

The use of the interventions described in this chapter has been shown to decrease perinatal morbidity and mortality. Their application is recommended in all clinical settings due to their easy applicability, and excellent cost-effectiveness due to the low cost of these pharmacological therapies compared to the great expense generated by caring for a premature newborn, both in the short and long term.

With regards to the use of aspirin, there is a consensus that its use started before 16 weeks, in a high-risk population, with doses greater than 100 mg, significantly reduces the risk of preeclampsia, and to a lesser extent the risk of restriction of fetal growth.

Regarding the use of magnesium sulfate, although the evidence is more limited, its use is currently suggested to reduce the risk of cerebral palsy, when there is an imminent risk of premature birth before 32 weeks. After this gestational age, its use does not have significant benefits.

Regarding corticosteroids, a single course of corticosteroids has immediate and substantial benefits in immature fetuses between 24 and 33 + 6 days in pregnant women who present a high risk of giving birth within 7 days, both in the premature rupture of membranes as well as in twin pregnancies. A second course or a rescue dose in pregnancies less than 34 weeks, at risk of delivering within 7 days, whose first course was indicated 7 to 14 days after receiving the first dose, has also been seen to be beneficial. The indication of a second dose in pregnant women with PROM, as well as its use in pregnancies between 34 + 0–36 + 6 weeks, still has limited evidence. Finally, there is evidence in the literature that supports the indication of a course of corticosteroids in women undergoing an elective cesarean section at 38 weeks in exceptional situations.

Finally, the use of vaginal progesterone has been shown to reduce the incidence of premature birth in those women who have a singleton pregnancy, with a history of premature birth and a short cervix. The use of progesterone in twin pregnancies does not have enough evidence to make a recommendation.

Conflict of interest

The authors declare no conflict of interest.