Antenatal magnesium sulfate (MgSO₄) regimens for neuroprotection in preterm neonates

Introduction / Введение

Cerebral palsy (CP) is considered one of the most hazar­dous neurodevelopmental disorders affects approximately 2/1,000 live births. Prematurity is one of the most impor­tant causes of CP (about 30 % of CP cases). The need of neuroprotection for premature baby was a necessary step for decreasing the neonatal morbidity and mortality especially with the high incidence of preterm birth (7.5 % of live birth), and it was suggested the use of for that purpose upon the observation of its use as a tocolytic drug and for eclampsia prevention [1].

The mechanism of MgSO₄ action is still obscured, it is believed that it protects the preterm brain against cytokine and excitatory amino acid damage, decrease vascular instability, and avoid hypoxic damage. The safety of use of magnesium poisoning, MgSO₄ is guarded by the use of intravenous calcium gluconate as antidote [2].

MgSO₄ as a tocolytic drug, used in a regimen of 4–6 g loading dose over 15–30 minutes is followed by a conti­nuous infusion of 2 g per hour, and this infusion may be raised up to 4–5 g per hour as needed in the absence of clinical side effects or oliguria [3].

Despite MgSO₄ has been used in obstetrics for decades, without any reports or concerns regarding fetal or neonatal problems, Food and Drug Administration (FDA) has revised the medication categorization of MgSO₄ from Category A to D as there is a concern for fetal and neonatal bone demi­neralization and fractures related (9.6 weeks exposure, with an average total dose of 3,700 g). But it is worthy to inform that the dose used and the time of exposure is less than the dangerous total doses [4].

MgSO₄ use for the purpose of neuroprotection has its debate as regard the proper dose of its use. But it is approved that the total adult daily dose should not exceed 30 to 40 g of MgSO₄. No more than 8 g of MgSO₄ should be supplied over 1 hour. It should continue for up to 24 hours or until birth, whichever comes first [5].

MgSO₄ should be administered when preterm birth is planned or expected within 24 hours. MgSO₄ should be star­ted as close as possible to 4 hours in case of planned preterm birth. Even if delivery is planned or expected to occur in time less than 4 hours MgSO₄ should be admi­nistered [6].

The controversy of MgSO₄ dose in studies include the loading doses which varies between 4 g and 6  g, or even not supplied. MgSO₄ toxicity is uncommon, so routine serum magnesium monitoring is not advised [7], but many adverse maternal effects were noted including flushing, sweating, a sense of warmth due to its peripheral vasodilation effects when given intravenous, vomiting, nausea, headaches, palpitations, and, in rare cases, pulmonary edema. There is no evidence of any unintended adverse outcomes in the neonate [8].

The use of MgSO₄ injection to prevent preterm labor should not exceed 5–7 days. FDA stated that if it is given for longer period the baby or fetus may experience low calcium levels, bone abnormalities, including osteopenia and fractures, and low calcium levels [4].

Table 1 is showing the different MgSO₄ regimens as neuroprotection against cerebral palsy [9–12].

Table 2 show the rest of different MgSO₄ regimens as neuroprotector [13–15].

Aim: to assess the comparative effectiveness and adverse effects of different magnesium sulfate (MgSO₄) regi­mens for fetus neuroprotection in women who are consi­dered at risk of preterm birth.

Materials and Methods / Материалы и методы

Study design / Дизайн исследования

This randomized controlled clinical single-center study was taken place from august 2023 at the Obstetrics and Gynecology Department of Tanta University Hospital, a tertiary care referral center and neonatology department. The duration of the study was about 9 months.

Inclusion and exclusion criteria / Критерии включения и исключения

Inclusion criteria: pregnant female with gestational age 24–34 weeks with established preterm labor.

Exclusion criteria: patients with insufficient medical records who have severe congenital anomalies or intraute­rine fetal deaths. If the cervix is more than 8 cm dilated, an urgent delivery may be necessary for reasons related to the mother or the fetus, such as electrolyte disorders, renal fai­lure, and maternal cardiac arrhythmia during this pregnancy, myasthenia, or ingestion of calcium channel blockers in the previous two hours.

All patients who participated in the trial gave written consent after being informed of its objectives, benefits, and risks. All their files were kept in confidential way with no discrimination as regard the races or the social standard.

Sample size calculation / Расчет размера выборки

The sample size was calculated using Epi-Info 7 specific program (Center for Disease Control and Prevention, USA). H0 was postulated as the prevalence of preterm labor was about 13.6 % in Egypt. The power was adjusted to be 80 %.

Randomization, grouping, and intervention / Рандомизация, стратификация по группам, вмешательство

All patients had their histories thoroughly recorded. The patients were sorted into four groups at random, and they were assigned to one of the four groups using a computer-­based program. Number of cases in each group was 20 cases.

Group I: the patients had received MgSO₄ infusion by the following protocol:

1. loading dose 6 g over 20–30 min;
2. maintenance dose 2 g per hour till birth or for 12 hours;
3. treatment was repeated if more than 6 hours since last dose had passed, so additional loading dose was given followed by maintenance.

Group 2: the patients had received MgSO₄ infusion by the following protocol:

1. loading dose 4 g over 20 min;
2. maintenance dose 1 g per hour till birth or for 24 hours;
3. no repeated treatment.

Group 3: the patients had received MgSO₄ infusion by the following protocol.

1. loading dose 4 g over 30 min,
2. no maintenance dose;
3. no repeated treatment.

Group 4 (control group): the patients had not received MgSO₄ infusion at all.

All groups of women had received care in accordance with accepted clinical standards. Throughout the infusion, the protocol required that the mother's heart rate, blood pressure, breathing rate, tendon reflexes, and any negative effects be recorded. Throughout labor, the fetal heart rate had been checked. If any of the following symptoms were present, treatment had to be stopped: respiration rate 10/min, hypotension, areflexia, disturbances of consciousness, or oliguria/anuria. Mothers and their newborns were monitored until they were released from the hospital.

The following results were found after an examination of neonatal medical records:

1. 1-minute and 5-minute Apgar score < 7;
2. the need for incubator or neonatal intensive care unit;
3. the occurrence of any neonatal complications like int­racerebral hemorrhage, necrotizing enterocolitis or hypoxic encephalopathy.

The outcomes / Исходы

Primary outcomes: the effect of MgSO₄ in neuroprotection which could be assessed clinically by assessing the neonatal condition for the presence of the signs of ence­phalopathy including seizure, conscious level, intact refle­xes, muscle tone, or could be assessed by trans cranial ultrasound for assessing the signs of encephalopathy even the neonates were clinically normal.

Secondary outcomes included other measures of effectiveness and safety.

For the infant / Исходы для младенца

Apgar score (less than 7 at 5 minutes): use of respiratory support (mechanical ventilation or continuous positive airways pressure, or both) or the occurrence of intrapartum fetal complications including non-reassuring cardiotoco­graphy (CTG), meconium-stained amniotic fluid.

For the woman / Исходы для матери

The occurrence of maternal complications related to MgSO₄ use including oliguria, hypotension, respiratory problems, are flexia and disturbed conscious level – deli­very related complications including postpartum hemor­rhage and prolonged labor – or discontinuation of the MgSO₄ infusion regimen.

Use of health services / Использование медицинских услуг

• Admission to intensive care unit for the mother.
• Length of postnatal hospitalization for the women.
• Admission to neonatal intensive care for the infant.
• Length of stay in neonatal intensive care unit for the infant.
• Length of neonatal hospitalization for the infant.

Methods of statistical analysis / Методы статистического анализа

Statistical analysis was performed with computerized SPSS (SPSS Inc., USA) version 16 for Windows. Qualitative data were expressed as numbers (N) and percentages, while quantitative data were expressed as mean (M) ± standard deviation (SD). Quantitative variables were analyzed for line­arity using the One-Sample Kolmogorov–Smirnov Test and all variables were normally distributed. Student t-test was used to compare between means body mass index (BMI), P-test to measure the strength of evidence against a  null hypothesis, ANOVA test to analyze the ratio of variance bet­ween groups to variance within groups and other quantitative variables between four groups according to MgSO₄ dose. Further, the paired sample t-test was used for analysis of quantitative variables before and after treatment.

Results / Результаты

Table 3 shows distribution of cases according demographic data, and the value of the APGAR score after 1 and 5 minutes.

In our study, 80 cases were enrolled, and they were divided into 4 groups at random. As shown in Table 3, there were no significant differences between the four groups in terms of age, gravidity, parity, gestational age at delivery, or length of labor.

Four cases in group 1 (20 %) had developed maternal complications in the form of hypotension , and only one case had hypotension accompanied with oliguria , while 3 cases in group 2 had developed hypotension (15 %) and only one case in group 3 (5 %) had developed hypotension, and no cases developed maternal complications related to MgSO₄ in group 4 (control group), but there was no significant difference between all the groups as regard the maternal complications with P value 0.364 (Table 4).

Seven cases in group 1 (35 %) had developed fetal complications (5 cases non reassurance CTG and 2 ca­ses developed meconium-stained amniotic fluid), while 8 cases in group 2 (40 %) had developed fetal complications (6 cases non reassurance CTG and 2 cases developed meconium-stained amniotic fluid), and 5 cases in group 3 (25 %) had developed fetal complications (5 cases non reassurance CTG and 1 case developed meconium-­stained amniotic fluid) and 2 cases (10 %) developed fetal complications in group 4 (2 cases non reassurance CTG), but there was no significant difference between all the groups as regard the fetal complications with P value 0.153 (Table 4).

Seven cases in group 1 (35 %) had developed deli­very related complications (6 cases prolonged labor and 3 cases developed postpartum hemorrhage), and 8 cases in group 2 (40 %) had developed delivery related complications (7 cases prolonged labor and 2 cases developed postpartum hemorrhage), and 3 cases in group 3 (15 %) had developed delivery related complications (3 cases prolonged labor), and 3 cases (15 %) developed deli­very related complications in group 4 (3 cases prolonged labor and 1 case developed postpartum hemorrhage), but there was no significant difference between all the groups as regard the fetal complications with P value 0.147 (Table 4).

There was no significant difference between the 3 study groups as regard the completion of the MgSO₄ infusion (15, 17, 19 cases in group 1, 2, 3 respectively) with P value 0.208 (Table 4).

There was also no significant difference between all the groups as regard the Apgar score evaluation of the neonate after 1 minutes and 5 minutes with P value 0.833 and 0.733 respectively. While by evaluation of the neonatal condition as regard the presence of clinical signs like seizure, loss of consciousness, abnormal tone, abnormal reflexes and the need of ventilator there was non-significant diffe­rence between all the groups, despite the number of cases which had abnormal clinical signs were lower in the study groups as compared by the control group (Table 5).

Also, there was non-significant differences between four groups as regard the number of neonates diagnosed with intraventricular hemorrhage (P = 0.701), and non-significant difference as regard the number of cases with early neonatal mortality (P = 0.774) (Table 5).

While there was a significant difference between the groups as regard the ultrasound findings suggesting encephalopathy with P value 0.009, as the number of cases which had abnormal ultrasound findings in group 1, 2 ,3 and 4 were 6, 7, 5 and 15 cases respectively (Table 3).

Discussion / Обсуждение

Many animal studies have investigated the neuroprotective role of MgSO₄. In 1984, F.X. Vacanti and A. Ames demonstrated neuroprotective effects of MgSO₄ in an adult rabbit spinal cord ischemia model [16]. In 1987, MgSO₄ administration to rat hippocampal slices reduced the effect of hypoxia [17]. T.K. McIntosh et al. demonstrated in 1989 that post-traumatic MgSO₄ injection decreased neurological disorders in a dose-dependent manner [18].

Many countries have developed national clinical guidelines that support the use of prenatal MgSO₄ at impen­ding preterm delivery, but the majority of European nations haven’t. As there is no global agreement, due to the lack of the agreement on the ideal gestational age for MgSO₄ thera­py that provides neuroprotection. For example, the natio­nal guidelines of both England and Canada advised the use of prenatal MgSO₄ for neuroprotection prior to 34 weeks of gestation, but not by those of Belgium, France, Ireland, or the WHO administration. In Australia, MgSO₄ is recommended before 30 weeks of gestation [19].

The dosage of MgSO₄ varied between studies, with loa­ding dosages range between 4 g and 6 g and inconsistent administration of a maintenance dose. The positive effects of MgSO₄ maintained even in studies with lower overall dosages, according to a meta-analysis, although there insufficient data to establish a minimal effective dose or the best course of treatment [1].

E. Shepherd et al., studied MgSO₄adverse effect inclu­ding flushing, sweating, sensation of warmth and, in rare cases, pulmonary edema which is linked to dosage, infusion rate and mode of administration (intravenous). This side effect is due to the peripheral vasodilator effect. But they found no evidence of neonatal adverse effect. Our fin­dings corroborated their findings about the absence of fetal side effects, but also we found no maternal side effects with various MgSO₄dosages which may attributed to the single dose of infusion with long infusion time [19].

As regard the dose-related perinatal adverse outcomes, no clear differences between different dose regimens of MgSO₄ were seen for the outcome of perinatal death (relative risk (RR) = 1.01; 95 % confidence interval (CI) = 0.75–1.36; 6 trials, 543 babies; analysis 2.1), nor for stillbirth or neonatal death [19].

As there are several different dosing regimens were used in the randomized controlled trial (RCTs). The data of a meta-analysis concluded that MgSO₄ should be administered at the smallest effective dose (4 g with or without 1 g per hour maintenance dose until birth) [20]. Our results corrobo­rated this recommendation. Another meta-analysis (2017), studied the effect of neuroprotection of MgSO₄, which comprised 5 RCTs, and it was found that it was decreased in the subgroup of children exposed to antenatal MgSO₄ at 28 weeks of gestation. This finding is consistent with our own. Children exposed between 28 and 31 weeks of pregnancy showed a comparable reduced risk [21].

Our study agreed with The BEAM trial who studied by randomized controlled trial 2241 women in preterm labor before 32 gestational weeks at 20 centers with regard to the fetal outcome, the effect of MgSO₄ with a dose of a 6-g bolus followed by a 12-hour 2 g per hour maintenance dosage (1,096 women and 1,188 fetuses) versus as a placebo (1,145 women and 1,256 fetuses). They found that although major outcomes – stillbirth, death at one year, or cerebral palsy at two years – in both groups were identical, the MgSO₄ group saw a markedly lower rate of moderate or severe cerebral palsy (1.9 % versus 3.5 %; RR = 0.55; 95 % CI = 0.32–0.95) [12].

The MAGPIE was a multinational trial had studied the effectiveness of antenatal MgSO₄ treatment in the prevention of eclampsia over 10,141 women, as they gave them MgSO₄ (4 g bolus followed by 1 g per hour maintenance dosage for 24 hours) or a placebo was given to the women, one of the secondary outcomes of the study was the neonatal outcome, they found that 1,593 fetuses were born before 37 weeks of gestation. A pediatric follow-up study with 4,483 children (2,254 in the MgSO₄ group and 2,229 in the placebo group, respectively) found no differences in mortality or neurological outcomes at 18 months (as measured by the Ages and Stages questionnaire). There result was different from ours and this may be attributed to that their study was focusing in the prevention of preeclampsia, and neglect the effect of preeclampsia of the neonates, also the dose of MgSO₄ was different as the goal was not neuroprotection [22].

Our study agreed with 4 meta-analyses that have been conducted on data from 5 RCTs that studied prenatal MgSO₄ administered to mothers at risk of preterm deli­very and linking to the risk of cerebral palsy in children; all produced consistent findings and conclusions. With an RR ranging from 0.61 to 0.70 and no effect on mortality, minor side effects for the mother (such as flushing, nausea or vomiting, sweating, and soreness at the injection site) were more common in the MgSO₄ groups. But these studies did not evaluate the dose and the regimen. They concluded the positive effect of MgSO₄ whatever the dose is [6][23].

The MAGNET trial had studied the effect of the highest neuroprotective dose of MgSO₄ and they found that the high dose of MgSO₄ may lead to the vasculopathy and high mortality due to cerebral hypoperfusion, whereas the lowest dose did not. These data agreed with our study, as MgSO₄ treatment had no effect on neonatal morbidity or pediatric mortality in any RCTs or meta-analyses performed to date. Similarly, there were no significant adverse effects on the mother from MgSO₄ therapy. The benefit remained constant whatever the gestational age, the reason for prematurity, the dose, or if the maintenance dose was admi­nistered after the loading dose. These findings support the use of low doses MgSO₄ [24].

In agreement with the meta-analysis done by X. Zeng et al. (2016), they have shown that antenatal MgSO₄ exposure does not improve 5-minute Apgar scores that are < 7 [23]. Also, in second analysis of the BEAM cohort did not show any difference in rates of intubation, chest compressions, hypotension, or mechanical ventilation between the MgSO₄ and placebo groups [25]. These findings support the safety of antenatal MgSO₄ exposure on short-term neonatal outcomes.

The authors did not observe any significant difference in the Apgar score according to the use or not of MgSO₄ when it was greater than or equal to 7. They also did not find significant differences in the resuscitation of neonates at birth. Indeed, newborns were resuscitated in 21.8 % of the exposed and 21.2 % of the unexposed [25]. Our results corroborated that issue.

Our results are in line with the meta-analysis of 4 neuroprotection trials which stated that maternal exposure to MgSO₄ did not affect neonatal resuscitation in the short term with no significant effect on Apgar score, need for assisted ventilation at birth [26].

Conclusion / Заключение

In conclusion there are different regimens for use of MgSO₄ for neuroprotection for preterm baby, and there was no difference between all the regimens in its effect for neuroprotection either clinically or radiologically or in its safety, so we recommend the use of the least dose (loading dose 4 g over 30 minutes) to decrease the risk of side effects. It is recommended to use MgSO₄ for neuroprotection as it is a safe feasible effective and efficient method as well as it can prevent the trans cranial ultrasound positive findings for encephalopathy.