**3.2. Oxytocin receptor antagonists**

Atosiban is an oxytocin receptor antagonist and presents minimum side effects to both mother and fetus in inhibition of preterm labor. This is a positive aspect, since it leads to a better acceptance and compliance to treatment [39].

to approve it as a tocolytic due to the results of one trial, which questioned safety of this drug in pregnancies before 28 weeks. Perhaps, these findings can be explained by the concentration

**Table 3.** Principal drugs used nowadays in tocolysis, with recommended regimen dose and important characteristics

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In UNIFESP, as in Europe, this tocolytic class is considered an interesting choice, and its administration begins with a bolus of 6.75 mg followed by a 300 mcg/min infusion for 3 hours

of oxytocin receptors that increases as more advanced the pregnancy is [41].

and then 100 mcg/min for up to 45 hours [40].

of them.

Meanwhile, this medication has a high cost and is administered intravenously. In the United States, atosiban is not available, because the US Food and Drug Administration (FDA) refused


The main goal of tocolysis is not to prevent preterm delivery, once the effectiveness for it is not proven [33]. However, tocolytic drugs can postpone delivery in 48 hours to 7 days, which is essential to manage antenatal corticosteroids to accelerate fetal pulmonary maturation and

Tocolytic drugs should be administered when there is a clear benefit to the newborn, once the majority of these drugs has side effects to the mother and, sometimes, also to the fetus. So, it can be used from viability (23–24 weeks of pregnancy) until the 34th week, as most guideline recommendations propose. In special cases, they can also be used before viability, for example, in patients after an intra-abdominal surgery, when the cause of preterm labor is

Contraindications for tocolytics include lethal fetal anomaly, preterm premature rupture of membranes, chorioamnionitis, severe preeclampsia and eclampsia, maternal hemorrhage with hemodynamic instability, suspected placental abruption, intrauterine fetal demise, and

Nowadays, the main drugs used in tocolysis are beta-agonists (as terbutaline), calcium channel blockers (as nifedipine), cyclooxygenase inhibitors (as indomethacin), and oxytocin recep-

The ACOG recommends as first-line treatment in acute preterm labor in multiple pregnancy calcium channel blockers and cyclooxygenase inhibitors due to fewer side effects of these drugs [7]. In UNIFESP, the preference is for calcium channel blockers and oxytocin receptor

The main drug of this class used in preterm birth inhibition is nifedipine, and many dosing regimens were proposed. Among tocolytics, nifedipine was the only drug that seems to statis-

In addition to being inexpensive, nifedipine is also administered orally and has less adverse maternal effects when compared to beta-agonists. When present, hypotension, flush, and

The recommendation in UNIFESP is an initial dose of 10 mg orally every 20 minutes (maximum of 30 mg in 1 hour) until inhibition is reached, followed by 20 mg orally every 8 hours

Atosiban is an oxytocin receptor antagonist and presents minimum side effects to both mother and fetus in inhibition of preterm labor. This is a positive aspect, since it leads to a better

Meanwhile, this medication has a high cost and is administered intravenously. In the United States, atosiban is not available, because the US Food and Drug Administration (FDA) refused

tically reduce neonatal morbidity and to increase gestational age at birth [38, 39].

to transfer the patients to a tertiary care center when necessary [34, 35].

self-limited [34, 36, 37].

196 Multiple Pregnancy - New Challenges

antagonists.

compromised fetal status [34].

**3.1. Calcium channel blockers**

for up to 48 hours [40].

headaches usually are not severe [37, 39].

**3.2. Oxytocin receptor antagonists**

acceptance and compliance to treatment [39].

tor antagonist (as atosiban), as exposed in **Table 3**.

**Table 3.** Principal drugs used nowadays in tocolysis, with recommended regimen dose and important characteristics of them.

to approve it as a tocolytic due to the results of one trial, which questioned safety of this drug in pregnancies before 28 weeks. Perhaps, these findings can be explained by the concentration of oxytocin receptors that increases as more advanced the pregnancy is [41].

In UNIFESP, as in Europe, this tocolytic class is considered an interesting choice, and its administration begins with a bolus of 6.75 mg followed by a 300 mcg/min infusion for 3 hours and then 100 mcg/min for up to 45 hours [40].

## **3.3. Beta-agonists**

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. 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

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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

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

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

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

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%

the incidence of necrotizing enterocolitis, as shown in **Table 4** [2].

mortality among infants less than the 5th percentile for birthweight.

attention [49].

CA1, as a compensatory reaction.

neuronal apoptosis in the hippocampus.

(215/2062) in control clusters (p < 0·0001).

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

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 more 12 hours [40].
