**4. Corticosteroids**

Antenatal glucocorticoid treatment with corticosteroids is routinely used in women at risk of preterm delivery under 34 weeks of gestation [45]. Corticosteroids promote fetal lung development between the 24th and 34th week of gestation [46] and reduce mortality of the preterm infant after delivery [47]. An important consequence of lung immaturity in preterm birth is the respiratory distress syndrome (RDS), and it is the great responsibility for the early neonatal mortality and the high cost of neonatal intensive care [47]. Preterm babies present higher risk of neurological impairment [48], which is the reason why the strategies for reduction of the risk of neonatal RDS and IVH in preterm delivery have received considerable attention [49].

**3.3. Beta-agonists**

198 Multiple Pregnancy - New Challenges

more 12 hours [40].

initiated the treatment.

48 hours [40].

**3.5. Prophylactic tocolysis**

**4. Corticosteroids**

**3.4. Cyclooxygenase inhibitors**

The beta2-agonists cause relaxation of the myometrium, and the most studied drugs of this tocolytic class were terbutaline and ritodrine, which is no more commercialized in the United States.

Although efficient in postpone preterm labor, terbutaline is also known by many side effects to the mother (as tachycardia, tremor, palpitations, dyspnea, hyperglycemia and pulmonary edema) and to the fetus (tachycardia and neonatal hypoglycemia) [41, 42]. So, if possible, in

In UNIFESP, when necessary, for example, in the absence of calcium channel blockers and atosiban, terbutaline is used by continuous intravenous infusion. The starting dose is 2.5–5 mcg/min, increasing 2.5–5 mcg/min every 20–30 minutes until inhibition has been reached (maximum dose is 25 mcg/min), and maintain this dose for 12 hours. Then, the infusion can be decreased 2.5–5 mcg/min every 20–30 minutes, and the minimum dose of terbutaline is maintained for

Indomethacin is considered a first-line drug for acute preterm labor in multiple pregnancy by the ACOG [7], once it is known its efficacy in postpone delivery by at least 48 hours after

However, it is important to be aware of adverse effects related to indomethacin. During treatment period, the mother is at higher risk of gastritis, esophageal reflux, and platelet dysfunction. And, the major risk is the premature constriction of the ductus arteriosus of the fetus and

If necessary, indomethacin can be administered for a maximum period of 48 hours and should be avoided after 32 weeks of gestation; when these complications are more common, it is important to notice that before 32 weeks the risk decreases, but is not zero [37, 41].

Loading dose recommended is 100 mg per rectum and then 25 mg orally every 6 hours up to

There is no evidence of benefit in using prophylactic and long-term tocolytic drugs to avoid preterm birth in multifetal pregnancy. Besides, the prolonged use of these medications leads

Antenatal glucocorticoid treatment with corticosteroids is routinely used in women at risk of preterm delivery under 34 weeks of gestation [45]. Corticosteroids promote fetal lung

oligohydramnios due to reduction of fetal renal blood flow [43, 44].

to increase maternal side effects, including death [7].

multiple pregnancy, beta-agonists should be avoided to inhibit preterm labor.

A single course of corticosteroids reduces the risk of RDS from 40 to 21% in babies born before 32 weeks of gestation [46]. In recent publication (2017) of Cochrane Reviews*,* it was observed that treatment with antenatal corticosteroids was associated with an overall average reduction in IVH of 45%, average reduction in RDS of 34%, moderate to severe RDS was reduced to 41% compared with no exposure to antenatal corticosteroids, with less need for neonatal respiratory support, with a reduction in the need for mechanical ventilation/CPAP, fewer infants receiving corticosteroids needed surfactant, and was associated with a reduction in the incidence of necrotizing enterocolitis, as shown in **Table 4** [2].

However, an experimental study in Wistar rats in UNIFESP [50] evidenced that the groups presented different numbers of apoptotic neurons in the hippocampus, more precisely on the region named cornu ammonis 1 (CA1) and dentate gyrus (DG) after a single course of corticosteroids. The number of apoptotic neurons in the DG region was increased after corticosteroid use (by directly receptor activation), which caused, probably, the decrease in cell death in the CA1, as a compensatory reaction.

The increased apoptosis in DG and reduced cell death in the CA1 region can indicate the existence of an indirect compensatory pattern (statistically significant difference). A new balance was obtained in different areas of the hippocampus. There is no evidence in literature that the decrease in the number of apoptotic cells in CA1 is due to direct action of betamethasone, but the results suggest that this minor mortality is a compensation of a previous lesion in DG [50]. It is possible that inconclusive data referred to neurodevelopmental latency after corticosteroids (RR 0.64) described in Cochrane Review (**Table 4**), can be justified by abnormal neuronal apoptosis in the hippocampus.

Another important finding was described in a multicenter, cluster-randomized trial, within six countries (Argentina, Zambia, India, Kenya, Pakistan, and Guatemala) to standard care or an multifaceted intervention with teaching pregnant women how and when to use corticosteroids, including facilitation of the antenatal corticosteroid use with distribution of a kit with drug, material, and knowledge for application. The primary outcome was 28-day neonatal mortality among infants less than the 5th percentile for birthweight.

Fifty control clusters with 50,743 livebirths (2258 less than 5th percentile for birthweight [4%]) and 51 intervention clusters with 47,394 livebirths (2520 less than 5th percentile [5%]) completed follow-up. About 45% (1052/2327) of women in intervention clusters who delivered less-than-5th-percentile infants received antenatal corticosteroids compared with 10% (215/2062) in control clusters (p < 0·0001).


Despite the increased use of antenatal corticosteroids in low-birthweight infants in the intervention groups, neonatal mortality did not decrease in this group and increased in the population overall. For every 1000 women exposed to this strategy, an excess of 3·5 neonatal deaths

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The treatment consists in betamethasone administration intramuscularly two 12 mg doses

A single course of corticosteroids must be considered in twin pregnancy between 24th and 33rd week that have high risk of preterm delivery within 7 days, including for those with ruptured membranes and if the first course was administered previously more than 14 days. It also may be considered for pregnant women starting at 23 0/7 weeks of gestation who are at risk of preterm delivery within 7 days, based on a family's decision regarding resuscitation. A rescue course of corticosteroids can be considered before 7 days from the first dose if there is

A new recommendation from the ACOG suggests that in pregnancy during the 34–37th week, the use of corticosteroids could be beneficial, even during this late period of pregnancy,

Administration of corticosteroids can be considered in twin pregnancy between the 34th and 37th week which are in risk of preterm birth within 7 days and which have not received the

Unfortunately, according to the WHO, in Brazil only 30% of preterm birth received antenatal corticosteroids to lung maturation between 2010 and 2011 [53], whereas several pregnancies

In 1995, it was suggested that magnesium sulfate was a neuroprotector, decreasing the prevalence of cerebral palsy in very-low-birthweight newborns [55]. Since then, several studies

Despite clinical trials have failed proving reduction of infant death, the use of antenatal magnesium sulfate for neuroprotection statistically diminished the risk of cerebral palsy in the survivors [56, 57]. Therefore, its use is recommended in cases of high risk of imminent preterm birth, in single and multiple pregnancies, in gestations <32nd week, and after viability [7, 34]. Many mechanisms were proposed to explain the neuroprotective effect of magnesium sulfate, but the exact one is actually unknown. Other questions about magnesium sulfate that are not yet clarified are best dose regimen, treatment duration, and risks or benefits of retreatment. An interesting point that were recently approached is that the exposure to magnesium

received unnecessary corticosteroids, without real indication for that [54].

**5. Neuroprotection: the use of magnesium sulfate**

occurred, and the risk of maternal infection seems to have been increased [12].

24 hours apart or dexamethasone intramuscularly four 6 mg doses every 12 hours.

**4.1. When and how to use corticosteroids for lung maturation**

some clinical indication for that [51].

regardless of the number of fetuses [7, 52].

previous course of betamethasone [52].

have been conducted to elucidate this aspect.

**Table 4.** Correlation between complications of SPB and use of corticosteroids (Cochrane Review, 2017 [2]).

Among the less-than-5th-percentile infants, 28-day neonatal mortality was 225 per 1000 livebirths for the intervention group and 232 per 1000 livebirths for the control group (relative risk [RR] 0·96, 95% CI 0·87–1·06, p = 0·65), and suspected maternal infection was reported in 236/2361 (10%) women in the intervention group and 133/2094 (6%) in the control group (odds ratio [OR] 1·67, 1·33–2·09, p < 0·0001).

Among the whole population, 28-day neonatal mortality was 27·4 per 1000 livebirths for the intervention group and 23·9 per 1000 livebirths for the control group (RR 1·12, 1·02–1·22, p = 0·0127), and suspected maternal infection was reported in 1207/48219 (3%) women in the intervention group and 867/51523 (2%) in the control group (OR 1·45, 1·33–1·58, p < 0·0001).

Despite the increased use of antenatal corticosteroids in low-birthweight infants in the intervention groups, neonatal mortality did not decrease in this group and increased in the population overall. For every 1000 women exposed to this strategy, an excess of 3·5 neonatal deaths occurred, and the risk of maternal infection seems to have been increased [12].
