Antenatal Low Dose Magnesium Sulphate for Foetal Neuroprotection in Preterm Birth Versus Control: A Comparative Prospective Cohort Study in Tertiary Care Centre in India

Abstract

Introduction

Preterm infants are at great risk of neurological impairments. This study aimed to evaluate what is the difference in short- and long-term neonatal outcome comparing magnesium sulphate in small dose (4 g) versus controls.

Methods

Prospective cohort study was conducted in the Department of Obstetrics and Gynaecology over a period of 4 years. Group A comprised of the study group (intravenous 4 g magnesium sulphate was given over 20 min). Group B consisted of control group who did not receive magnesium sulphate.

Results

The study population comprised of 116 pregnant women who received intravenous bolus of 4 grams MgSO4 while the control group comprised of 95 pregnant women who did not receive MgSO4. Fewer neonates in the MgSO4 group required intubation at birth (32% vs. 52%) or chest compression (4% vs. 6%); however, the difference was not statistically significantly (p = 0.175 and p = 0.329). Neonatal brain ultrasound done in first month showed a significant reduction intraventricular haemorrhage of severe grade 3–4 IVH in the MgSO4 group (p = 0.016). MgSO4 administration was associated with a decrease in neonatal mortality before discharge (p = 0.039). Follow-up at 3 years showed a significant reduction in delayed milestones, visual impairment, Bayley score < 85 (p = 0.015). MgSO4 treatment antenatally was associated with lower risk of Cerebral Palsy (2.6% vs. 23.2%, p < 0.001).

Conclusion

The benefits from single smaller dose magnesium sulphate 4 gram prove its potential to be used for foetal neuroprotection in any healthcare setting without any maternal concerns.

Introduction

Preterm infants before 34 weeks are at great risk of neurological impairments such as cerebral palsy (CP), gross motor dysfunction, deafness, blindness, developmental delay, and intellectual impairment. [1] Manuck et al. reported approximately 1 in 4 preterm children born before 34 weeks had some neurodevelopmental impairment at age 2 years. [2] Among these, CP is the leading cause of neurologic impairment. The incidence of cerebral palsy increases significantly with decreasing gestational age ranging from 0.1% in term infants to 6.2% at 28–31 weeks and 14.6% at 22–27 weeks of gestation. [3] CP is a nonprogressive neurological disorder affecting motor function and may have various morbid conditions that can arise at any time during brain development and may affect motor function that is permanent but may change over time [4]. As suggested in literature, magnesium sulphate probably blocks N-methyl -D-aspartate receptors and reduces calcium influx into the cells and acts as a vasodilator by inhibiting ischaemic cell death during and after cerebral ischaemic events [5]. The role of magnesium sulphate (MgSO4) first emerged when studies showed a reduced incidence of germinal matrix haemorrhage was seen amongst women treated with magnesium sulphate for preeclampsia or as a tocolytic agent in preterm labour [6, 7]. Since then, there have many trials supporting that antenatal exposure to magnesium sulphate could significantly decrease the risk of CP for preterm infants [8, 9]. Xianling Zeng et al. did a meta-analysis to study effect and safety of magnesium sulphate and found that the risk of CP was reduced in preterm infants exposed to MgSO₄ which was significant for moderate to severe CP [10].

There have been several doses of magnesium sulphate recommended by World Health Organization for use of magnesium sulphate in women at risk of imminent preterm birth before 32 weeks of gestation for prevention of cerebral palsy in the child. Three dosing regimens have been studied intravenous 4 g over 20 min, then 1 g/hour until delivery or for 24 h, whichever came first, intravenous 4 g over 30 min (single dose) and intravenous 6 g over 20 to 30 min followed by intravenous maintenance of 2 g/hour for 12 h [11]. Most studies have evaluated the 24 h intravenous regimen given between 24 and 33 weeks 6 days of pregnancy for women who are in established preterm labour or having a planned preterm birth within 24 h. The use of magnesium sulphate as a neuroprotective agent had been a very appreciable development in obstetrics; however, still its use is not universal in all heath care settings especially in developing countries owing to the fear of side effects to the mother [12, 13]. Administration of 24 h intravenous dose is difficult in small settings; hence, there is a need to evaluate benefit of lower dose magnesium so that we can escape from side effects and gain neuroprotective benefits. Efficacy of lower dose can of great help to encourage its use in all low resource heath care settings which do encounter the problem preterm deliveries but do not have enough resources or expertise to monitor while giving a high dose of magnesium given to mother. Hence, the study was planned to evaluate what is the difference in neonatal outcome comparing magnesium sulphate in small dose (4 gram intravenous infusion over 20 min) in established preterm labour versus those who did not receive magnesium sulphate (controls).

Methodology

This prospective cohort study was conducted in the Department of Obstetrics and Gynaecology along with the Department of Paediatrics, Paediatrics’ Surgery and Radiology at King George Medical University, Lucknow, India. The pregnant patients admitted in the labour ward fulfilling the inclusion and exclusion criteria were enrolled in the study after a written informed consent. The study was carried over a period of one year (from May 2019 to May 2020) along with a follow-up of children up to 3 years of age. Inclusion criteria were women with established preterm labour (regular uterine contraction with cervical dilatation of ≥ 4 cm) at gestational age of less than 32 weeks and women requiring iatrogenic preterm labour/caesarean at gestational age less than 32 weeks. Exclusion criteria were myasthenia gravis, acute renal failure, false preterm labour, congenital malformation, congenital infection, gestational age more than 32 weeks and drug delivery interval of less than 4 h. Recruited patient were divided in two groups. Group A comprised of the study group (intravenous 4 g magnesium sulphate was given over 20 min). Group B consisted of control group who did not receive magnesium sulphate. Recruitment flowchart is shown in Fig. 1. Both the groups were given antenatal corticosteroids. Maternal and foetal outcomes were documented. Apgar score and type of resuscitation required were noted. All newborns underwent neonatal cranial ultrasound within 4 weeks of birth to look for intraventricular haemorrhage. Once after discharge these newborns were followed at 3 years of age and were checked to document milestones [14] and neurodevelopmental performance [15].

Fig. 1.

Study flowchart

This study was approved by Institutional Ethics Committee, King George’s Medical University (Ref code 87th ECM IIA/P1). The study was registered under Clinical Trial Registry of India (CTRI/2019/05/019293).

Results

There was a total of 211 preterm infants admitted during the study period, out of which 116 preterm neonates received antenatal MgSO4 for neuroprotection. The flow diagram depicts the enrolment and follow-up as shown in Fig. 1. The study population (group A) comprised of 116 pregnant women who recieved intravenous bolus of 4 g MgSO4 while the control group (group B) comprised of 95 pregnant women who did not receive MgSO4. Statistical analysis was done applying chi square test/Fisher exact test as appropriate for qualitative analysis and unpaired t test for quantitative analysis. The study population was comparable in maternal characteristics and comorbidities as shown in Table 1.

Table 1.

Maternal characteristics

Characteristics	Antenatal MgSO4 (n = 116)	Control (n = 95)	P value
Maternal age	27.06 ± 5.27(27)	27.51 ± 4.43(27)	0.513
Multipara	69 (59.4%)	57(60%)	0.380
BMI Mean ± SD	23.96 ± 2.17	24.47 ± 2.16	0.230
Gestational diabetes	7 (6%)	6(6.3%)	0.933
Non-severe preeclampsia	12(10.3%)	10(10.5%)	0.966
Preterm rupture of membranes	19(16.4%)	24(25.3%)	0.111
Chronic hypertension	1(0.9%)	2(2.1%)	0.589
Chorioamnionitis	2(1.7%)	2(2.1%)	1.0
Antenatal steroids	88 (75.8%)	70 (73.6%)	0.530
In vitro fertilization	5(4.3%)	3(3.2%)	0.732
Autoimmune diseases	3(2.6%)	1(1.1%)	0.629
Hypothyroidism	16(13.7%)	9 (6.2%)	0.334
Antepartum haemorrhage	4 (6%)	5(5.2%)	0.734
Foetal growth restriction	7(6%)	5(5.3%)	0.810

The mean gestational age at delivery in women receiving MgSO4 was 30.32 ± 1.62 weeks while the mean gestational age at delivery in control group was 30.31 ± 2.11 weeks. Incidence of twin pregnancy and male child was comparable in both groups. There were no differences between the rates of caesarean section and 5-min Apgar score as shown in Table 2.

Table 2.

Comparison between mode of delivery and neonate immediately after birth

	Antenatal MgSO4 (n = 116)	Control (n = 96)	P value
Median Gestational age (weeks)	30.32 ± 1.62	30.31 ± 2.11	0.988
Birth weight, median	1267.51 ± 296.25	1290 ± 308.63	0.452
Twin birth	5 (4.3%)	5 (5.3)	0.757
Caesarean section, N (%	57 (49.6)	39 (41.1)	0.241
Male, N (%)	66 (56.8)	53 (55.7)	0.204
Median 5 min Apgar score	6 (5–7)	6 (5–8)	0.351

Maternal side effects were also documented. Three out of 116 (2.5%) women in magnesium group while two in control group (2.1%) had postpartum haemorrhage which was managed medically, the difference was not statistically significant. None of the women given 4 g dose in an infusion in an hour had any hypotension, respiratory distress, or oliguria. Five women (4.3%) had feeling of warmth while three (2.5%) had sweating.

The type of neonatal resuscitation required is shown in Table 3. Although fewer neonates in the MgSO4 group required intubation at birth (32% vs. 52%) or chest compression (4% vs. 6%), the difference was not statistically significantly (p = 0.175 and p = 0.329). There was a lower incidence of early hypotension in the MgSO4 group compared to those in the control group (4.2% vs. 13%; p = 0.111) but the difference was not statistically significant. There were no differences in the incidence of early onset sepsis and necrotising enterocolitis (NEC) between the two groups (Table 3). The need for surfactant was also comparable in both the groups.

Table 3.

Neonatal resuscitation

	Antenatal MgSO4 (n = 116)%	Control (n = 95)%	P value
5-Minute Apgar score < 7	53 (45.7)	43 (45.3)	0.951
Bag and mask only	36 (31)	34 (35.8)	0.465
Tracheal intubation	36 (31)	38 (40)	0.175
Chest compression	4 (3.4)	6 (6.3)	0.329
Hypotension	11 (9.5)	16 (16.8)	0.111
Early onset sepsis	36 (31.3)	39(41)	0.130
NEC stage > 2	2(1.7)	4 (4.2)	0.412
Surfactant	80 (68.9)	67 (70.5)	0.806

Neonatal brain ultrasound done in first month showed a significant reduction intraventricular haemorrhage of severe grade 3–4 IVH in the MgSO4 group (p = 0.016). MgSO4 administration was associated with a decrease in neonatal mortality before discharge (8 [6.9%] vs. 15 [15.8%] p = 0.039) as shown in Table 4. Figure 2 shows an image of neonatal brain USG done in shows intraventricular haemorrhage and layering of blood and fluid in ventricles in a 15-day-old infant in control group.

Table 4.

Comparison of neonatal outcomes

Neonatal ultrasound in one month	Antenatal MgSO4 (N = 116)%	Control (N = 95)%	P value
Normal	93 (80)	59 (62)	0.003
Grade 1–2 IVH	6 (5.2)	7 (7.4)	0.509
Grade 3–4 IVH	9 (7.7)	14 (14.7)	0.016
Mortality before discharge (%)	8 (6.8)	15 (15.8)	0.039

Fig. 2.

Neonatal ultrasound showing intraventricular haemorrhage

Two neonates had pneumothorax after tracheal intubation while one had bowel perforation which was managed in the Department of Paediatric Surgery.

Follow-up of neurodevelopmental outcomes at 3 years were completed in 94 children [magnesium sulphate (study group) 81% of the survived and control group 89% of the survived]. Delayed milestones were seen in 18 (15.5%) in magnesium sulphate group while 24 (25.3%) in control group. The number of children with any visual impairment were 10 (8.6%) in MgS04 group and 25 (26.3%) in control group. Children with Bayley score < 85 were significantly higher in the neonates not antenatally treated with MgSO4 (p = 0.015). MgSO4 treatment antenatally was associated with lower risk of Cerebral Palsy (2.6% vs. 23.2%, p < 0.001) Table 5.

Table 5.

Analysis of neurodevelopmental outcome at 3 years

Neurodevelopmental outcome	Antenatal MgSO4 (n = 94)%	Control (n = 85)%	P value
Delayed milestones	18(15.5)	24(25.3)	0.018
Visual impairment	10(8.6)	25 (26.3)	0.001
Mental development Index < 85 on Bayley Scales of infant development	9 (7.8)	18 (18.9)	0.015
Cerebral palsy	3 (2.6)	22(23.2)	< 0.001

Discussion

Premature births bring with itself a series of complication turning future neonatal course into a turbulent journey; however, its long-term impact on mental development of the baby is further devastating. Identification of magnesium sulphate having neuroprotective role was a breakthrough research as far as preterm birth is considered. Most guidelines recommend the use of MgSO4 in women with risk of imminent early preterm birth up to 30 weeks of gestation and to consider its use in pregnancies below 33 weeks 6 days of gestation regardless of the cause for preterm labour whenever preterm birth is planned or expected within 24 h. Best effects have been seen when MgSO4 is given at least 4 h before birth.

The optimal regimen of MgSO4 for foetal neuroprotection is an intravenous loading dose of 4 g (administered slowly over 20–30 min), followed by a maintenance dose of 1 g per hour for maximum of 24 h and minimum for 4 h. This regimen should continue until birth but should be stopped after 24 h if undelivered [16]. However, there has been several regimes recommended in existing literature. Magee AL et al. in Canadian foetal neuroprotection guidelines recommended to consider 4 g dose with discontinuation of concurrent tocolysis [17]. One of the largest randomized trial, the BEAM trial [18] used a loading dose of 6 g followed by a maintenance dose of 2 g/hour for 24 h, giving a total dose over 52 g. Various studies done in past have expressed concerns about the risk of serious side effects for both mother and neonate. Systematic review by Bachnas M et al. [19] showed that the most commonly used dosage, 4 g bolus continued by 1 g/hour maintenance, did not increase neonatal mortality and other suspected neonatal complication such as neonatal asphyxia, necrotizing enterocolitis or feeding intolerance; however, giving a single bolus injection of 4 g MgSO4 for stimulating brain-derived neurotrophic factor production in cases of suspected preterm labour and repeating 4 g again when preterm birth become inevitable may be best regime from a safety perspective with a stronger rationale. This is also highlighted by another large randomized control trial where 573 pregnant women were randomly assigned to receive a single 40-ml infusion of 0.1 g/ml of MgSO4 (4 g) solution or isotonic 0.9% saline (placebo) over 30 min. On comparing total mortality (9.4 versus 10.4%; OR: 0.79, 95% CI 0.44–1.44), severe white matter injury (10.0 versus 11.7%; OR: 0.78, 95% CI 0.47–1.31) and their combined outcomes (16.5 versus 17.9%; OR: 0.86, 95% CI 0.55–1.34) were less frequent in the MgSO4 group, but these differences were not statistically significant. They did not report any major maternal adverse effects in MgSO4 group. They also concluded that results were inconclusive but improvements of neonatal outcome obtained with 4 g MgSO4 were of potential clinical significance and the need of further research.

When MgSO4 is administered, women might have severe side effects and ideally should be monitored for clinical signs of magnesium toxicity at least every 4 h by measuring pulse, blood pressure, respiratory rate, deep tendon patellar reflexes and urine output [20]. The side effects of MgSO4 are a hindrance to its rampant use in small low resource health care settings who are otherwise have huge incidence of preterm deliveries and are unable to refer women to a higher tertiary care centre due to various issues. This study was planned to evaluate the potential of lower and much safer but effective dose of MgSO4 which can be easily delivered in any health care settings. The identified patterns of central nervous system injury which underlie the development of CP in the preterm infant include intraventricular haemorrhage typically starting in the germinal matrix and white matter injury also known as periventricular leukomalacia (PVL). Severe intraventricular haemorrhage (grades 3 and 4) is reliably detected by ultrasound, while PVL is best detected with MRI. We found a significant reduction in intraventricular haemorrhage in neonates within 4 weeks of birth in neonates who received MgSO4 in utero. Neurodevelopment follow-up was done at 3 years after birth which showed a significant improvement in the motor and cognition score. Benefits of MgSO4 have been documented in landmark trials done before [18]; however, we found that benefits exist even with smaller dose of 4 g. More recent evidences suggest that lower doses of magnesium sulphate may help in neuronal survival while higher doses may promote cell apoptosis. Study done by Ginsberg Y et [21] on rat model suggested that lower dose 150 mg/kg as compared to higher dose 150 mg/kg along with maintenance 15 mg/kg for 2 h found that lower dose is as effective as higher dose in reducing inflammatory markers.

We also found a significant reduction in the incidence of intraventricular haemorrhage on ultrasound. This result is consistent with the recent meta analysis of seven pooled studies, which showed a trend toward lower intraventricular haemorrhage relative risk 0.80 (95% CI: 0.63–1.03), though they used a higher dose [22]. Neurodevelopment follow-up showed a better Bayley scale of infant development score at 3 completed years in MgSO4 exposed neonates. There was reduction in CP as reported in previous studies [23, 24]. In our study, we did not find any significant increase in the need of bag and mask, tracheal intubation, chest compression and need of vasopressor for hypotension contrary to few non-randomized studies in meta analysis by Shepherd E et al. [25]. Apgar score at birth did not different in both groups, emphasizing the minimal effect of smaller dose on respiratory depression of newborn.

There was no neonatal complication noted differently in any group. There was no significant difference in incidence of foetal growth restriction, necrotizing Enterocolitis and early onset sepsis between both the groups contrary to that reported in a study done by Mittendorf R et al. [26]. In a prospective study on Indian population done by Bansal V, only 4 g intravenous loading dose MgSO4 was given in one group compared to controls preferably 4 h prior to preterm birth. They did not find any significant difference maternal morbidity or mortality while noticed a reduced risk for need for mechanical ventilation, intraventricular haemorrhage, neonatal hypotension, hypothermia, and length of NICU stay in the magnesium sulphate group. Although they did report a longer follow-up of newborns, IVH was less frequent and less severe in babies exposed to antenatal MgSO4 [27].

Larger scale randomized trials are needed to compare low dose MgSO4 with a higher dose in various ethnic population with a long-term follow-up.

The strength of our study includes studying the novel concept of using smaller dose of drug in south Asian population, prospective nature of study along with long-term neurodevelopmental follow-up at 36 months. Limitations include a relatively smaller sample size pilot study, selection bias and lack of MRI in evaluation of brain lesion. There was a lost to follow-up rate of 19% in magnesium group and 11% in the control group at 36 months.

Conclusion

The benefits from single smaller dose magnesium sulphate 4 gram prove its potential to be used for foetal neuroprotection in any healthcare setting without any maternal concerns. While the lower dose did not prove any significant difference in mild brain lesion, however there was significant difference in severe brain lesion, cerebral palsy, delayed milestones, and mental development index. Large-scale studies are still required to compare smaller doses of magnesium sulphate with current standard one in order to ascertain the effective dose of drug required for neuroprotection.

Author Contributions

NK conceptualized the study, collected, and analysed the data and drafted the manuscript. PT helped in neonatal management and follow-up. SK carried neonatal ultrasound and PK did paediatric surgical intervention and helped in literature review.

Funding

No funding sources have been used.

Declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical Statement

Written informed consent was taken from each parent. This study was approved by Institutional Ethics Committee, King George Medical University (Ref code 87^th ECM IIA/P1).

Patient Consent

Informed consent was taken from all the study participants.