Antenatal Corticosteroids and Magnesium Sulfate in Twin Pregnancy for the Prevention of Neonatal Morbidity

Abstract

The use of corticosteroids is one of the most important therapies used in prenatal care to improve the outcomes of the newborn by reducing the rates of respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis and contribute to the survival of extreme preterm infants. In addition to steroids, the use of magnesium sulfate protects the newborn from cerebral palsy in cases of extreme preterm births. All of these conditions increase perinatal morbidity/mortality and are related to potentially serious illness in the newborn requiring care in neonatal intensive units. The use of corticosteroids and magnesium sulfate are measured to prevent unfavorable outcomes of premature newborns admitted to a neonatal intensive care unit. The incidence of twin pregnancy is only 3% of all live births, however, it accounts for 15% of extreme preterm births less than 32 weeks. Women with multiple pregnancies are six times more likely to terminate the pregnancy before term compared to single pregnancies. The determination of the use of corticosteroids in multiple pregnancies remains conflicting due to the scarcity of studies related to this group. Therefore, this chapter aims to evaluate the effectiveness of the use of corticosteroids in twin pregnancies in early and late preterm, evaluating its outcome in respiratory morbidity and metabolic aspects of the newborn.

1. Introduction

Multiple pregnancies occur in 1 to 3% of live births, with special attention in the obstetric sphere due to its peculiarities, as it increases the risk of practically all prenatal pathologies. It represents about 12% of cases of extreme prematurity (less than 32 weeks), 25% of newborns weighing less than 1500 g, and also increases the risk of death before the first year of life by seven times [1].

Prematurity is responsible for unfavorable outcomes of the newborn that can evolve with respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis. All of these conditions increase perinatal morbidity/mortality and are related to potentially serious illness in the newborn requiring care in neonatal intensive units.

Prematurity represents the largest cause of perinatal mortality in the world, being a major focus of attention in the main research in recent years. In a twin pregnancy, it is 3 to 4 times greater, representing 12% of preterm infants. Throughout the literature, it was understood that as the number of fetuses increases, the duration of pregnancy decreases; approximately 50% of twins are born before or at week 36 and 50% of triplets or from pregnancies with more than three fetuses, before 32 weeks; and the mean gestational age at birth for twins is 36 weeks, for triplets 32 to 33, and for quadruplets approximately 31 [2].

The causes that determine preterm labor in multiple pregnancies are multifactorial [1].

Due to these facts, a twin pregnancy is said to be of high risk, therefore, the obstetrician must be fully updated to conduct challenging prenatal care and allow the best possible results for the maternal-fetal binomial to be obtained.

2. Corticosteroids

Even with the improvement in the survival of preterm newborns, mainly resulting from neonatal intensive care. Preterm birth remains an important public health problem and a leading cause of perinatal mortality and severe short- and long-term morbidities (blindness, deafness, developmental delay and/or other neurological impairments).

The use of corticosteroids is one of the most important therapies used in prenatal care to improve the outcomes of mortality and morbidity in the newborn [3].

The use of corticosteroids in a single course is done in situations of risk for premature birth between 24 and 34 weeks, including multiple pregnancies, premature rupture of ovular membranes and can also be used in fetuses with the gestational age of 23 weeks, with eminence for delivery within 7 days [4].

Studies initiated by Liggins in 1969 analyzed the effect of steroids on the lungs of fetuses of sheep and found that there was a discrepancy in the lungs of full-term offspring compared to premature offspring. With this experience, several clinical trials were carried out on its effect [5].

The first structured review addressing the use of this drug in premature fetuses was published by Crowley et al. in 1990. Later, in 1995, the author published a meta-analysis review citing 15 randomized clinical trials carried out between 1972 and 1994 and concluded that corticosteroids reduce in approximately 50% the risk of respiratory distress syndrome in fetuses born prematurely, when birth occurs after 24 hours to 7 days of the first dose of the drug [5, 6].

It is a practice-based on scientific evidence adopted for 20 years, which aims to reduce the incidence of neonatal death, respiratory distress syndrome, intraventricular hemorrhage or necrotizing enterocolitis and contribute to the survival of extremely preterm infants, having effects such as: cardiovascular adaptation, increased blood pressure, improved renal function and improved skin keratinization [7, 8, 9, 10].

Corticosteroids, unlike other forms of steroids, are easily transported across the placenta. They act on the airways in various ways, such as fetal lung maturation through thinning of the alveolar septa and alveolar differentiation with type 2 pneumocyte induction, which stimulates the production of surfactants [11].

In the fetus, cortisol plays an important role in development as it promotes the maturation of major organs in late pregnancy, including the respiratory system, kidney, gastrointestinal tract and brain. Fetal adrenal cortisol levels increase dramatically in the last six weeks before term completion and play a crucial role in later stages of organogenesis [12, 13].

The most important fetal organ in terms of survival at birth is the lung, where glucocorticoids act in the mesenchymal tissue to reduce the distances from blood vessels to the airways to allow for proper gas exchange. Glucocorticoids, in addition to promoting the production of surfactants, mature the pulmonary mechanisms for the elimination of fluid from the lung’s airways at birth [12].

After birth, dexamethasone has important anti-inflammatory effects in the neonatal lung, including direct suppression of proinflammatory cytokine gene expression, inhibition of cytokine production in lymphocytes and macrophages, and leads to apoptotic cell death of lymphocytes to further promote immune suppression [14].

The use of corticosteroids provides benefits by improving short-term respiratory morbidity. Premature newborns, when they require care, usually need to be admitted to an intensive care unit, with good recovery in most cases.

Despite these benefits, the use of corticosteroids can cause harm, including neonatal hypoglycemia. It has been shown that antenatal betamethasone results in elevated betamethasone concentrations and decreased cord blood cortisol concentrations at birth, leading to fetal hypothalamic pituitary adrenal axis suppression, persisting for up to seven days after birth. This practice results in high levels of blood glucose and C-peptide at birth and consequent hypoglycemia in the early neonatal period, which although appearing to be self-limited, has been reported to be associated with poor neurological outcomes [15, 16].

Seckl et al. in experimental work with animals reported that there may be adverse consequences in prenatal exposure to excess corticosteroids, as well as being a trigger for some diseases in adult life, such as cardiovascular diseases (dyslipidemia and hypertension), type 2 diabetes and impaired glucose tolerance [17, 18, 19]. Clark et al. and Edwards et al. reported the same result in their studies. Kari et al. observed delay in neurological development in childhood, but with a small sample size (n = 82) [20, 21, 22, 23].

Based on scientific reviews to date, the use of steroids has become the mainstay of prophylactic treatment in fetuses at risk of premature birth in singletons. However, there are still some outstanding issues regarding the use of medication, such as the increase in the rate of stillbirths in women with hypertensive syndromes. In addition, its use in parturients diagnosed with premature rupture of ovular membranes may increase the risk of neonatal infection [24, 25].

There are still insufficient data on childhood follow-up in fetuses who received corticosteroids during intrauterine life. There are only two studies that have followed steroid-treated fetuses into adulthood and found no differences in intellectual impairment or school performance [22, 26, 27].

Prophylactic corticosteroids use in multiple-dose protocols has not shown benefit in respiratory distress syndrome, in addition to having adverse effects on fetuses. Therefore, betamethasone is administered intramuscularly, in a daily dose of 12 mg, for two consecutive days or dexamethasone intramuscularly four 6 mg doses every 12 hours, in just one cycle and, exceptionally, two cycles [4].

2.1 Corticosteroids in multiple pregnancy

In dichorionic pregnancies the term is 38 weeks, in uncomplicated diamniotic monochorionic pregnancies it is 36 weeks and in monoamniotic it is 32 weeks. As the term in twins is earlier, there is a greater risk of perinatal morbidity and mortality, especially in monochorionic, because the delivery is in late prematurity [28].

Routine use of corticosteroids in the twin is not recommended except in risky conditions for discontinuation before 34 weeks. There is still doubt in the literature regarding the dose, since the pharmacokinetics after administration of corticosteroids in twins is different in single pregnancies, as the recommended dose is the same for both [29]. Because of this, despite the short-term benefit, many questions remain unanswered in this population: such as the long-term effect of the drug, its pharmacokinetics, its real involvement in neurodevelopment and future metabolic consequences.

In the study by Hashimoto et al., evaluated in their retrospective cohort study consisting of 652 premature twins and 1705 premature single fetuses who were born weighing 500 to 1500 g (from 1991 to 1999), they concluded that the effect of corticosteroids in the prevention of neonatal mortality in twin pregnancies is similar to that observed in single pregnancies [30].

Blickstein and colleagues reported that a complete course of corticosteroids significantly reduced the incidence of respiratory distress syndrome in single children as well as in twins and triplets [31].

Melamed et al. administered a complete course of corticosteroids during prenatal care to twin pregnancies with a gestational age between 24 weeks to 33 weeks and 6 days. The outcome was a 58% reduction in neonatal mortality, decreased respiratory morbidity and severe neurological damage. The same results were observed in singleton pregnancies. The study was carried out in a tertiary neonatology center in Canada (Canadian Neonatal Network), from 2010 to 2014, with 9466 participants, consisting of 2516 mothers of twins and 6950 of singletons [32].

2.2 Corticosteroids in late prematurity

The effectiveness of the use of corticosteroids in multiple pregnancy was only approached retrospectively in 1996. Some difficulties were raised regarding its benefit in twin pregnancies with gestational age after 34 weeks in late prematurity [33, 34].

It has recently been biologically proven that administration of corticosteroids after 34 weeks of gestation reduces respiratory morbidity rates up to 72 hours after birth [33].

Three randomized clinical trials were published by Feitosa et al., Kamath et al. and Ramadam et al. confirming the beneficial effect in reducing transient tachypnea in newborns who used the full cycle of steroids during single gestation in late prematurity [35, 36, 37].

In 2016, a large randomized double-blind multicenter trial called Antenatal Betamethasone for Woman at Risk for Late Preterm Delivery (APLS) was published. Seventeen universities from the Eunice National Institute for Child and Human Development (NICHD) Fetal Medicine Units Network in Kennedy Shriver were included. Participants were assigned to receive two injections of betamethasone 12 mg in 24 hours.

A total of 2827 pregnant women with a gestational age of 34 weeks to 36 weeks +5 days were eligible, totaling 1427 women in the betamethasone group and 1400 in the placebo group. It resulted in significantly lower rates of severe respiratory complications in the betamethasone group compared to the placebo group (8.1% and 12.1%) and rates of various disorders were significantly lower in the betamethasone group than in the placebo group, they are: transient newborn tachypnea (6.7% and 9.9%), bronchopulmonary dysplasia (0.1% and 0.6%), transient newborn tachypnea or apnea (13.9% and 17.8%), resuscitation at birth (14.5% and 18.7%) and use of surfactant (1.8% and 3.1%). Apnea and pneumonia rates were similar in both groups [38].

The administration of corticosteroids beyond 34 weeks’ gestation has been the subject of many discussions around the world, as they are also at risk of significant morbidities, with an emphasis on respiratory morbidity.

However, there is no international consensus regarding the use of corticosteroids above 34 weeks due to the scarcity of trials and meta-analyses, as the long-term effects are still unknown.

3. Magnesium sulfate as fetal neuroprotection

Premature birth is increasing in most developed and developing countries. Overall, preterm birth is the leading cause of perinatal mortality and cerebral palsy remains one of the main long-term morbidities associated with preterm birth.

Cerebral palsy (CP) is the most common neurological impairment related to prematurity. The CP rate is closely linked to the prematurity rate; the more premature, the greater the risk of CP. The incidence of cerebral palsy is 14.6% between 22 and 27 weeks’ gestation, 6.2% between 28 and 31 weeks’ gestation, 0.7% between 32 and 36 weeks’ gestation, and 0.1% at the term of pregnancy [39].

Due to its association with preterm birth, multiple pregnancies also contribute to an increased risk of cerebral palsy, which increases 8-fold in double pregnancy and 47-fold in triple pregnancy [40].

It is a complex disease characterized by motor and/or postural dysfunction, has a permanent and non-progressive character, and can be recognized in the early stages of life. The four main types of cerebral palsy are spastic (increased muscle tone), dyskinetic (uncontrolled or slow movements), ataxic (difficulties with balance and depth perception), and mixed. Most cases of cerebral palsy (85–90%) are congenital and the most common type is spastic, which affects approximately 80% of individuals affected by the disease [41].

As there is no cure for cerebral palsy, among the various drugs used in an attempt to protect premature newborns from neurological complications, magnesium sulfate (MgSO4) has been the subject of a growing number of studies over the last decade.

The history of MgSO4 for neuroprotection began with the observation that the CP rate in pre-eclampsia was markedly lower compared to the gestational age in normotensive pregnancies and the subsequent decrease in neonatal neurological morbidity rates was initially suggested by some observational studies of the decade of 1990. The results of these studies supported the publication of systematic reviews and, also, opinion articles and guidelines by respected international scientific entities. Despite several large studies, with mostly positive results, the debate about routine MgSO4 continues, not only about dosage and administration, but also about safety aspects [42].

There are three large studies: ACTOMgSO4 (2003), PREMAG (2007) and BEAM (2008) that agreed that prenatal use of MgSO4 reduces the rate of cerebral palsy in newborns.

In 2003, Crowther et al. published the results of the ACTOMgSO4 study. A total of 1062 Australian and New Zealand women (1255 children) with less than 30 weeks’ gestation and expected to give birth within 24 hours were randomized. The initial dose of MgSO4 was 4 g IV in 20 minutes, followed by 1 g/hour IV for a maximum of 24 hours. As a conclusion of the study, the administration of MgSO4 before preterm delivery improved important pediatric outcomes without causing serious adverse effects [43].

In the work carried out by Marret et al. (PREMAG (2007)), 573 French women (688 children) with less than 33 weeks of pregnancy and with expected or planned delivery within 24 hours were included. A single IV dose of MgSO4 (4 g) or placebo was administered in 30 minutes. The main outcome of the study was to assess the existence of damage to the newborn’s cerebral white matter, whose diagnosis was made by cranial ultrasonography in the neonatal period. Data on the follow-up of surviving children up to two years of corrected age were described. That without statistical significance, there was protection against the combined outcome of cerebral palsy or death with the use of MgSO4 (RR 0.65; 95%CI 0.42–1.03) [44].

No serious maternal complications were observed in the group treated with MgSO4. Finally, the multicenter study BEAM (2008) had as sample number 2241 American pregnant women (2444 children) with imminent risk of delivery between 24 and 31 weeks. Pregnant women were randomly assigned to receive MgSO4 (6 g IV followed by a 2 g/h infusion) or placebo. MgSO4 administration was interrupted in cases where delivery did not occur within 12 hours. The primary outcome was the combination of fetal death or infant death with one year of corrected age or the presence of moderate/severe cerebral palsy with two years or more of corrected age. There was no significant difference between the primary outcomes of the MgSO4 and placebo groups (11.3 versus 11.7%; RR 0.97; 95%CI 0.77–1.23). However, in a pre-specified secondary analysis, the rate of moderate/severe cerebral palsy was significantly lower in the MgSO4 group (1.9 versus 3.5%; RR 0.55; 95% CI 0.32–0.95) [45].

Despite MgSO4’s role in preventing CP, many physicians are still concerned about side effects for both mother and baby. Since this mode of prevention is inexpensive, easy to use, and can reduce the rate of cerebral palsy by up to almost 50% [45].

Most guidelines (RCOG and Australian) recommend the administration of MgSO4 for fetal neuroprotection of viability for less than 30 weeks. Only SOGC has an upper cutoff at 32 weeks [46, 47, 48].

The definitive mechanism of action of the use of magnesium sulfate in fetal neuroprotection remains unclear. Biochemical and histopathological findings have been implicated as a possible mechanism to explain the neuroprotective effects of MgSO4 and these mechanisms include: neuroprotective ability to prevent early apoptosis of abnormal neuronal cells, decreased neuroinflammation to increase the seizure threshold, decreased hemorrhage of the cerebellum, stimulation of local adaptation responses through vasodilation and stimulation of neurogenesis in the premature maturation of brain cells by encouraging the secretion of neurotrophic factors [49, 50].

The developing brain (in preterm fetuses) is unconditionally vulnerable to insult and its response to adapt to a hypoxic condition is much lower compared to the brain in term fetuses. Damage to the fetal brain primarily occurs in the periventricular region, so it is often called periventricular leukomalacia, and lesions in this area can lead to clinical manifestations of cerebral palsy [50, 51, 52].

Until now, most maintenance doses have been advocated at 1 g/h. However, some studies suggest that if the objective were to optimize results, the dose would potentially have to be increased to a maintenance dose of 2 g/h. At this dose, the maximum dose to be administered is 64 g as shown by statistical simulation by Brookfield et al. However, other researchers claim that a maximum dose to avoid harmful effects would be 50 g [44, 53, 54].

Prenatal MgSO4-related maternal adverse events are widely researched. Common minor side effects include flushing, headache, heat and sweating, nausea, vomiting, blurred vision, or intramuscular discomfort at the injection site. Major adverse events can progress to respiratory and cardiac arrest and even death [55].

Several recent publications have confirmed the efficacy and safety (4 g loading dose, 1 g/h maintenance) of prenatal MgSO4 for preventing cerebral palsy, and this is considered an effective dose without compromising safety [56]. Other neuroprotective agents such as melatonin are being actively researched.

4. Conclusion

Twin pregnancy is an important cause of prematurity. To reduce perinatal morbidity/mortality, antenatal corticosteroids are used. Between 24 and 34 weeks the use of betamethasone in a dose of 12 mg intramuscularly two doses with an interval of 24 hours or dexametasone 6 mg intramuscularly 4 doses every 12 hours. It should be restricted to one or at most two cycles of corticosteroids.

The use of steroids in late prematurity in twin pregnancy is still controversial, however, several guidelines have suggested the use of steroids in elective preterm births such as in monochorionic pregnancies.

In addition to steroids, the use of magnesium sulfate protects the newborn from cerebral palsy.

Prenatal care for a twin pregnancy is challenging and the obstetrician must be aware of the use of corticosteroids and magnesium sulfate in cases of prematurity to reduce perinatal morbidity/mortality.