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Published in final edited form as: Am J Obstet Gynecol. 2024 Apr 3;231(6):647.e1–647.e12. doi: 10.1016/j.ajog.2024.04.001

Magnesium sulfate and risk of hypoxic ischemic encephalopathy in a high-risk cohort

Kathleen C MINOR 1, Jessica LIU 2,3, Maurice L DRUZIN 1, Yasser Y EL-SAYED 1, Susan R HINTZ 2,3, Sonia L BONIFACIO 2, Stephanie A LEONARD 1, Henry C LEE 2,3,4, Jochen PROFIT 2,3, Scarlett D KARAKASH 1
PMCID: PMC11508778  NIHMSID: NIHMS2028345  PMID: 38580044

Abstract

Background:

Hypoxic ischemic encephalopathy contributes to morbidity and mortality among neonates ≥ 360 weeks’ gestation. Evidence of preventative antenatal treatment is limited. Magnesium sulfate has neuroprotective properties among preterm fetuses. Hypertensive disorders of pregnancy are a risk factor for hypoxic ischemic encephalopathy and magnesium sulfate is recommended for maternal seizure prophylaxis among patients with pre-eclampsia with severe features.

Objectives:

1) Determine trends in incidence of hypertensive disorders of pregnancy, antenatal magnesium sulfate and hypoxic ischemic encephalopathy, 2) evaluate the association between hypertensive disorders of pregnancy and hypoxic ischemic encephalopathy and 3) evaluate if, among patients with hypertensive disorders of pregnancy, the odds of hypoxic ischemic encephalopathy is mitigated by receipt of antenatal magnesium sulfate.

Study Design:

We conducted an analysis of a prospective cohort of live births ≥360 weeks’ gestation between 2012–2018 within the California Perinatal Quality Care Collaborative registry, linked with the California Department of Health Care Access and Information files. We used Cochran-Armitage tests to assess trends in hypertensive disorders, encephalopathy diagnoses, and magnesium sulfate utilization, and compared demographic factors between patients with or without hypertensive disorders of pregnancy or treatment with magnesium sulfate. Hierarchical logistic regression models were built to explore if hypertensive disorders of pregnancy were associated with any severity and moderate/severe hypoxic ischemic encephalopathy. Separate hierarchical logistic regression models were built among those with hypertensive disorders of pregnancy to evaluate the association of magnesium sulfate with hypoxic ischemic encephalopathy.

Results:

Among 44,314 unique infants, the diagnosis of hypoxic ischemic encephalopathy, maternal hypertensive disorders of pregnancy and the use of magnesium sulfate increased over time. Compared to patients with hypertensive disorders of pregnancy alone, patients with hypertensive disorders treated with magnesium sulfate represented a higher risk population. They were more likely to be publicly insured, born 36–38 weeks’ gestation, be small for gestational age, have lower Apgar scores, require a higher level of resuscitation at delivery, have prolonged rupture of membranes, preterm labor, fetal distress, and undergo operative delivery (all p-values <0.002). Hypertensive disorders of pregnancy were associated with hypoxic ischemic encephalopathy (aOR 1.26, 95% CI 1.13–1.40, p-value <.001) and specifically moderate/severe hypoxic ischemic encephalopathy (aOR 1.26, 95% CI 1.11–1.42, p-value <.001). Among patients with hypertensive disorders of pregnancy, treatment with magnesium sulfate was associated with 29% reduction in the odds of neonatal hypoxic ischemic encephalopathy (aOR 0.71, 95% CI 0.52–0.97, p-value= 0.03) and a 37% reduction in the odds of moderate/severe neonatal hypoxic ischemic encephalopathy (aOR 0.63, 95% CI 0.42–0.94, p-value=0.03).

Conclusion:

Hypertensive disorders of pregnancy are associated with hypoxic ischemic encephalopathy and specifically, moderate/severe disease. Among people with hypertensive disorders, receipt of antenatal magnesium sulfate is associated with significant reduction in the odds of hypoxic ischemic encephalopathy and moderate/severe disease in a neonatal cohort admitted to the NICU ≥360 weeks’ gestation. The findings of this observational study cannot prove causality and are intended to be hypothesis generating for future clinical trials on MgSO4 in term infants.

Keywords: fetal neuroprotection, neonatal neuroprotection, seizure prophylaxis, pre-eclampsia with severe features, neonatal morbidity, hypertensive disorders of pregnancy

Tweetable statement:

Hypertensive disorders of pregnancy are associated with neonatal hypoxic ischemic encephalopathy. Antenatal magnesium sulfate is associated with a reduced hypoxic ischemic encephalopathy risk.

Introduction:

The neuroprotective potential of antenatal magnesium sulfate (MgSO4) was initially proposed in a case-controlled study among very low birthweight infants nearly 30 years ago.1 Our understanding of its benefit in preventing cerebral palsy2–9 has grown, and it is now routinely administered to patients at high risk of delivery <32 weeks’ gestation.10,11 However, it is unknown if administration of MgSO4 impacts the risk of hypoxic ischemic encephalopathy (HIE)—a major neurological injury that affects infants born after 36 weeks’ gestation.12–19

HIE develops due to disruption in perfusion to cerebral tissues from either an acute or chronic insult.20–25 The prevailing theory suggests hypertensive disorders of pregnancy (HDP) are associated with an increased risk of HIE26,27 via utero-placental dysfunction, evidenced by placental mal-perfusion.28–30 This likely sensitizes the developing fetal brain, altering gene expression to favor cerebral apoptosis and increases vulnerability to intrapartum insults.25,26,31 In response to hypoxemia in HIE, cerebral arteries preferentially shunt blood to the posterior brain circulation to protect the brainstem, cerebellum and basal ganglia.13 Neurons in watershed areas shift to anaerobic metabolism, developing aberrant glutamate homeostasis.13,32 This leads to excessive stimulation of the post-synaptic NMDA receptor, allowing calcium and sodium accumulation intracellularly and a cascade of excitotoxic events, culminating in cell damage and apoptosis.13,25,32 It is hypothesized that MgSO4 exerts neuroprotective properties through antagonizing the NMDA receptor,32,33 reducing oxidative damage,34 and augmenting anti-inflammation via TNF-alpha, IL-1beta, IL-635–39 and nuclear factor-kB.38,40,41 Thus, biologic plausibility exists for MgSO4 preventing the deleterious effects of HIE. However, there is a gap in the literature regarding efficacy of MgSO4 among fetuses at risk for HIE.14,32,42,43

The objectives of this study are: 1) characterize current trends in incidence of a diagnosis of HDP, neonatal HIE and antenatal MgSO4 administration; 2) determine the association between HDP and severity of HIE; and 3) evaluate if among patients with HDP the odds of HIE are mitigated by receipt of antenatal MgSO4. We hypothesize that antenatal MgSO4 will reduce the risk of HIE among neonates born to patients with HDP.

METHODS

Study Design and Cohort

This is a retrospective cohort study, of the population-based California Perinatal Quality Care Collaborative (CPQCC) database, which is prospectively collected, and linked with the California Department of Health Care Access and Information (HCAI) files. The CPQCC collects data from >90% of neonatal intensive care units (NICUs) in California.44 All infants with a birth weight of 401–1,500 grams or born between 220 weeks and 316 weeks are eligible. Those with a birth weight >1500 grams and born at 320 days gestation or later are eligible for data collection if they are admitted to the NICU within the first 28 days of life and have a qualifying condition (Supplementary table). Suspected neonatal encephalopathy or suspected perinatal asphyxia includes infants with cardiorespiratory depression at birth and one or more of the following: pH less than 7.0 on an umbilical blood sample or blood gas within one hour of life, 5-minute Apgar score less than or equal to 3 or a 10-minute Apgar score less than or equal to 4.45 This study includes all infants ≥ 360 weeks gestational age cared for in a CPQCC member NICU from 2012–2018. This gestational age aligns with prior literature on therapeutic hypothermia.17 We excluded infants who died in the delivery room, those with unknown HIE status, had missing covariates, MgSO4 or HDP data . The exposure of interest was HDP, which included chronic hypertension or pregnancy-associated hypertension, such as gestational hypertension or pre-eclampsia with or without severe features.46–48 The exposure was analyzed with or without the maternal MgSO4. We viewed the use of MgSO4 as a surrogate for gestational hypertension with severe features or pre-eclampsia with severe features.

To examine population-based trends, we identified all infants born 360 to 420 weeks’ gestation by obstetric estimate between 2010–2018 from the California Department of HCAI vital statistics data, which we linked to CPQCC clinical data using a high-fidelity probabilistic approach.49–51 Data were available starting in 2010 for HDP and HIE status, but MgSO4 was not collected until 2012. The trend analysis for HDP and HIE included 2010 and 2011, but these years were excluded from the regression models. This study was approved by the Stanford University Institutional Review Board (IRB #14746).

Outcomes of Interest

The primary outcome was severity of HIE defined by the Vermont Oxford Network.52 HIE severity was based on the most abnormal level of consciousness observed during the first seven days after birth, and was categorized as mild, moderate, or severe. The most severe HIE diagnosis across admissions was used. We examined infant and maternal characteristics that were selected a priori based on prior literature review and obtained from CPQCC (2012–2018) or HCAI (2010–2018).

Statistical Analysis

We calculated yearly population-based incidence of HIE and HDP using the linked CPQCC and state data by dividing the number of infants with HIE and maternal HDP by the number of infants ≥36 weeks’ gestation who were at risk per year within the state database. Rates were expressed per 1,000 infants. Data on MgSO4 usage were unavailable in the state vital statistics data. All analyses of MgSO4 were limited to infants in the CPQCC network between the years of 2012–2018. We calculated average percent changes per year by separately regressing HIE, HDP and MgSO4 administration on birth year. All tests for trend were performed with Cochran-Armitage tests.53–55 We used bootstrapping with 5000 iterations to estimate the standard error for the changes over time in the rates of HIE, HDP and MgSO4.

We compared neonatal, maternal and peripartum characteristics (Table 1) by HDP and MgSO4 treatment status, using chi-squared tests for categorical variables and t-tests for continuous variables. We evaluated the association of all covariates of interest with HDP and any or moderate/severe HIE using unadjusted hierarchical logistic regression with NICU as a random effect. Hierarchical logistic regressions were used account for clustering of patients within hospitals, as well as the clustering of births within an individual.56 Robust standard errors were used to account for multiple gestations. Significant factors were considered potential confounders. Based on causal diagrams and available data, the final multivariable hierarchical logistic regression model included: maternal age, highest level of maternal education attained, payer status, receipt of prenatal care, obesity (BMI ≥30mg/kg2), multiple gestation, and birth year.

Table 1:

Maternal and neonatal characteristics for normotensive patients, patients with hypertensive disorders of pregnancy versus hypertensive disorders of pregnancy treated with magnesium for neonates ≥36 weeks’ gestation in the California Perinatal Quality Care Collaborative Network from 2012–2018

Characteristic Overall
(n=44,314)
n (%)		 Normotensive
(n=39,394)
n (%)		 Hypertensive disorders of pregnancy
(n=3,777)
n (%)		 Hypertensive disorders of pregnancy treated with MgSO4
(n=1,143)
n (%)		 p-value
Neonatal Characteristics
Infant Death 1721 (4) 1536 (4) 137 (4) 48 (4) 0.60
Male Sex 25528 (58) 22641 (57) 2229 (59) 658 (57) 0.19
Gestational Age (weeks)
Mean (sd) 38.4 (1.5) 38.5 (1.5) 37.8 (1.4) 37.5 (1.4) <.001
36–38 12846 (29) 10408 (26) 1770 (47) 668 (58)
38–40 28201 (64) 25876 (66) 1883 (50) 442 (39)
≥ 40 3267 (7) 3110 (8) 124 (3) 33 (3)
Small for Gestational Age 8199 (19) 6967 (18) 884 (23) 4348 (30) <.001
Birthweight (grams)
Mean (sd) 3242 (630) 3255 (615) 3175 (734) 2988 (714) <.001
<2000 1097 (2) 831 (2) 184 (5) 82 (7) <.001
2001–2500 3843 (9) 3166 (8) 478 (13) 199 (17)
2501–3000 10470 (24) 9220 (23) 920 (24) 330 (29)
3001–3500 14639 (33) 13317 (34) 1041 (28) 281 (25)
>3500 14265 (32) 12860 (33) 1154 (31) 251 (22)
Apgar score at 5 minutes *
Mean (sd) 7.8 (1.9) 7.8 (1.9) 7.6 (2.1) 7.3 (2.1) <.001
<5 3649 (8) 3099 (8) 5406 (11) 144 (13) <.001
5–7 7425 (17) 6429 (16) 707 (19) 289 (26)
>7 32152 (73) 28833 (73) 2615 (68) 704 (61)
Apgar score at 10 minutes †
Mean (sd) 6.9 (2.1) 6.9 (2.1) 6.7 (2.1) 6.9 (2.0) 0.06
<5 1308 (3) 1122 (3) 139 (4) 47 (4) 0.12
5–7 4201 (10) 3589 (9) 448 (12) 164 (14)
>7 4887 (11) 4255 (11) 445 (12) 187 (16)
Delivery Room Resuscitation
-Cardiac compression or 2119 (5) 1818 (5) 221 (6) 80 (7) <.001
Epinephrine 4009 (9) 3517 (9) 363 (10) 129 (11)
-Intubation 7836 (18) 6665 (17) 850 (23) 321 (28)
-NIPPV/Bag Mask 4579 (10) 4035 (10) 402 (11) 142 (12)
-CPAP 3446 (8) 3064 (8) 302 (8) 80 (7)
-Oxygen 21972 (50) 19976 (51) 1612 (43) 384 (34)
-None
Maternal Characteristics
Maternal Age
Years, mean (sd) 29.1 (6.4) 28.9 (6.3) 30.5 (6.5) 29.5 (7.0) <.001
Advanced Maternal Age (≥35 years) 9329 (21) 7973 (20) 1058 (28) 298 (26)
Payer Source
Public (Medi-Cal, Other Government) 23377 (53) 20780 (53) 1959 (52) 638 (56) <.001
Private 18145 (41) 16044 (41) 1642 (43) 459 (40)
Other 1817 (4) 1664 (4) 114 (3) 39 (3)
Missing 975 (2) 906 (2) 62 (2) 7 (1)
Maternal Education
High School or GED or 19308 (44) 17131 (43) 1645 (44) 532 (47) 0.15
Less 21745 (49) 19296 (49) 1896 (50) 553 (48)
>High School or GED 2396 (5) 2159 (5) 185 (5) 52 (5)
Unknown
Diabetes 5957 (13) 4587 (12) 1075 (28) 295 (26) <.001
Obesity (BMI ≥30) 24411 (55) 20871 (53) 2752 (73) 788 (69) <.001
Prenatal Care 42687 (96) 37957 (96) 3643 (97) 1087 (95) 0.21
Multiple Gestation 1340 (3) 1118 (3) 176 (5) 46 (4) <.001
Chorioamnionitis 2827 (6) 2511 (6) 241 (6) 75 (7) 0.97
Delivery Characteristics
Bleeding/Previa/Abruption 1961 (4) 1728 (4) 174 (5) 59 (5) 0.39
Malpresentation 2529 (6) 2198 (6) 274 (7) 57 (5) <.001
Prolonged ROM (>18 hours) 3189 (7) 2813 (7) 258 (7) 118 (10) <.001
Preterm Labor 3060 (7) 2656 (7) 285 (8) 119 (10) <.001
Fetal Distress 8332 (19) 7189 (18) 857 (23) 286 (25) <.001
Inborn at CPQCC Center 23292 (53) 20533 (52) 2085 (55) 674 (59) <.001
Operative Vaginal Birth 2527 (5) 1947 (5) 147 (4) 71 (6) .002
Cesarean Birth 21311 (48) 18292 (46) 2315 (61) 704 (62) <.001
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*

1088 records missing

†

33918 records missing

Chi-squared/t-test comparing across hypertension groups

MgSO4: Magnesium sulfate

ROM: Rupture of membranes

CPQCC: California Perinatal Quality Care Collaborative

GED: General Educational Development

SD: Standard deviation

BMI: Body mass index

CPAP: Continuous positive airway pressure

NIPPV: Nasal intermittent positive pressure ventilation

Payer source other: includes self-pay

Additional hierarchical logistic regression models were conducted in a subset of patients with HDP to examine the association of MgSO4 with any or moderate/severe HIE. In addition to the previously mentioned confounders, these models also adjusted for gestational age, small for gestational age, 5-minute Apgar score and maximum level of respiratory support in the delivery room. We performed sensitivity analyses to determine how closely rates of HIE and HDP within CPQCC compared to population level data. All analyses were performed with SAS version 9.4 (SAS Institute, Cary, NC) and SigmaPlot 15.0 (Systat Software, Inc).

RESULTS

Descriptive Analysis:

After exclusions, the final analytic cohort included 3,633,170 infants in the state of California and 44,314 unique infants in the CPQCC network (Figure 1). When comparing characteristics for those with HDP who did not receive MgSO4 versus those who did, those that received MgSO4 had higher risk neonatal and delivery characteristics traditionally associated with HIE (Table 1). Specifically, patients with HDP who received MgSO4 were statistically more likely to have the following high risk characteristics: be 36–38 weeks’ gestation, be small for gestational age, have lower 5-minute Apgar scores, require a higher level of resuscitation in the delivery room, have prolonged rupture of membranes (defined as > 18 hours), preterm labor, fetal distress, undergo operative vaginal delivery, deliver in a CPQCC center and be publicly insured. However, those that received MgSO4 were less likely to be advanced maternal age, obese, or diabetic.

Figure 1:

Figure 1:

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Flow diagram

Temporal Analysis

From 2010 to 2018, CPQCC cases linked with the state database indicated an increase in the incidence of an HIE diagnosis among the California population (Figure 2A, p(trend)<.001). The incidence rates of any severity of HIE increased three-fold from 0.54 (0.46–0.61) per 1,000 in 2010 to 1.67 (1.54–1.81) per 1,000 in 2018. When examining by severity, the largest increase occurred in moderate HIE, which rose from 0.23 per 1,000 to 0.93 per 1,000 during the study period. Similarly, the incidence of HDP in the California population significantly increased from approximately 64.92 (64.12–65.71) patients to 94.86 (93.88–95.84) patients per 1,000 livebirths (Figure 2B, p(trend)<.001). These trends were maintained in a sensitivity analysis examining only the CPQCC network between 2010–2019. Within CPQCC, the unadjusted trend analysis demonstrated a significant rise in the incidence of HIE diagnosis, with moderate HIE contributing the largest average percent change per year (change per year=0.42, p(trend) <.001). In addition, the incidence of a diagnosis with HDP (change per year=0.74, p(trend)<.001) and maternal treatment with MgSO4 (change per year=0.34 p(trend)<.001) increased.

Figure 2:

Figure 2:

Figure 2:

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Trends for neonates ≥36 weeks’ gestation from 2010–2018 within HCAI records for (a) use of magnesium sulfate within CPQCC (MgSO4 available starting in 2012) and the diagnosis of any hypoxic ischemic encephalopathy and moderate or severe hypoxic ischemic encephalopathy within CPQCC linked HCAI records and (b) maternal hypertensive disorders of pregnancy.

Association between Hypertensive Disorders of Pregnancy, Magnesium and HIE

Analyses of associations between HDP, MgSO4 and HIE were limited to the CPQCC network due to data availability. In the unadjusted model, maternal HDP, compared to normotensive patients, were associated with a statistically significant increase odds of neonatal HIE of any severity and moderate/severe HIE (Table 2). Likewise, in the adjusted model, maternal HDP, compared to normotensive patients, had a statistically significant increase in the odds of neonatal HIE with any severity (aOR 1.26, 95% CI 1.13–1.40, p<.001) or moderate/severe HIE (aOR 1.26, 95% CI 1.11–1.42, p<.001) (Table 2). We investigated the association of maternal antenatal exposure to MgSO4 on neonatal HIE among those with maternal HDP. Neonates born to mothers with HDP treated with MgSO4 were associated with lower adjusted odds of any neonatal HIE (aOR 0.71, 95% CI 0.52–0.97, p= 0.03) and moderate/severe HIE (aOR 0.63, 95% CI 0.42–0.94, p=0.03) (Table 3).

Table 2.

Adjusted multivariable analyses of the association between of hypertensive disorders of pregnancy with any severity of hypoxic ischemic encephalopathy or moderate or severe hypoxic ischemic encephalopathy for neonates ≥36 weeks’ gestation in the California Perinatal Quality Care Collaborative network from 2012–2018.

Characteristic Any HIE Moderate or Severe HIE
OR (95% CI) p value aOR (95% CI) p value OR (95% CI) p value aOR (95% CI) p value
Normotensive 1.00 Ref 1.00 Ref 1.00 Ref 1.00 Ref
Hypertensive disorder of pregnancy 1.33 (1.21–1.48) <.001 1.26 (1.13–1.40) <.001 1.35 (1.20–1.53) 0.90 1.26 (1.11–1.42) <.001
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Adjusted for maternal age (<35 years, ≥35 years), education, payer status, receipt of prenatal care (yes/no), obesity (BMI <30 or ≥30), multiple gestation, birth year

HIE: hypoxic ischemic encephalopathy

Table 3:

Adjusted multivariable analyses of the association between magnesium sulfate treatment among patients with hypertensive disorders of pregnancy and any severity of hypoxic ischemic encephalopathy or moderate or severe hypoxic ischemic encephalopathy for neonates ≥36 weeks’ gestation in the California Perinatal Quality Care Collaborative network from 2012–2018.

Characteristic Any HIE Moderate or Severe HIE
OR (95% CI) p value aOR (95% CI) p value OR (95% CI) p value aOR (95% CI) p value
Hypertensive disorder of pregnancy alone 1.00 Ref 1.00 Ref 1.00 Ref 1.00 Ref
Hypertensive disorder of pregnancy with MgSO4 Treatment 0.91 (0.72–1.15) 0.43 0.71 (0.52–0.97) 0.03 0.89 (0.68–1.19) 0.90 0.63 (0.43–0.94) 0.03
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Adjusted for maternal age (<35 years, ≥35 years), education, payer status, receipt of prenatal care (yes/no), obesity (BMI <30 or ≥ 30), multiple gestation, birth year, gestational age, small for gestational age, 5-minute Apgar score and maximum level of respiratory support in the delivery room

HIE: hypoxic ischemic encephalopathy

MgSO4: Magnesium sulfate

Comment:

Principal Findings:

In California, the diagnoses of neonatal HIE and HDP increased between 2010 and 2018. These trends were maintained among an enriched, high-risk neonatal cohort in the CPQCC. From 2012–2018, the use of antenatal MgSO4 within the CPQCC for maternal seizure prophylaxis also increased. Compared to normotensive patients, birthing patients with HDP were associated with an increased crude and adjusted odds of any severity of neonatal HIE and moderate/severe HIE. Among patients with HDP, exposure to MgSO4 was associated with a 29% and 37% lower odds of a diagnosis of any severity of neonatal HIE and moderate/severe HIE respectively.

Results in Context of What is Known:

Hypertensive disorders of pregnancy and HIE

In our analysis, the rate of HDP, including chronic hypertension, gestational hypertension and pre-eclampsia, was 11%, comparable to prior studies.57,58 Recently, a report from the CDC corroborated the trend toward an increasing prevalence of a diagnosis with HDP.46 From 2017–2019, the prevalence of pregnancy associated hypertension among delivery hospitalizations increased from 10.8% to 13% and chronic hypertension from 2% to 2.3%. This was attributed to the increased prevalence of risk factors for hypertension among reproductive aged patients.46 Our ability to examine trends in the use of MgSO4 in the CPQCC database among patients with HDP ≥ 36 weeks gestational age is unique. The increased rate of administration observed likely parallels the trend in the diagnosis of maternal pre-eclampsia with severe features.

The incidence of a diagnosis of HIE has increased in our analysis. Other studies conflict as to if there has been an increase in the incidence of the diagnosis of HIE52,59 or if it has remained unchanged.60,61 Furthermore, the clinical relevance of these changes is challenged.59 These variances likely stem from study design and if subcategories of HIE based on severity were examined. Our observed increase may be attributed, in part, to the implementation of therapeutic hypothermia for patients with moderate to severe HIE, leading to increased ascertainment due to treatment availability.60,62 Although we observed increasing trends in the diagnosis of HIE and HDP, this does not indicate causality.

Similar to our results, a recent population-based study of term infants demonstrated that those with hypertension, compared to normotensive patients, had twice the risk of HIE among offspring (aRR 2.09, 95% CI 1.49–2.92).26 However, prior publications on the relationship between hypertension and HIE have conflicting results. There is a preponderance of evidence pointing towards hypertension increasing the risk of HIE,16,21–23,26,27,59,63 however some studies have demonstrated no association24,64–67 or a protective68 effect of hypertension on development of HIE. The latter was a preclinical study, which speculated that maternal hypertension induces inflammation leading to hypoxic preconditioning68 with upregulation of endogenous neuroprotective factors.69 The heterogeneity may be attributed to the lack of statistical significance among studies with low incidence of the outcome, indicating possible type II error. Another limitation of previous studies is the lack of maternal variables, such as treatment with MgSO4, which may modify the relationship between HDP and a diagnosis of HIE.

Neuroprotection of magnesium

It is well described from RCTs2,4,5 and meta-analyses6–9 that antepartum MgSO4 administered to a person at risk of preterm birth confers neuroprotective benefits against cerebral palsy. Recently, an individual participant data meta-analysis of 5 RCTs illustrated a strong protective effect of MgSO4 against cerebral palsy in a preterm population (RR 0.68, 95% CI 0.54–0.87, NNT 46).8 This conclusion was confirmed by high quality evidence from a Cochrane review.70 Despite a mechanistic explanation for efficacy, safety data, cost effectiveness71 and clinical evidence in a preterm population, MgSO4 use has not been extended in clinical trials to term infants. A Cochrane review from 2013 indicated that there was insufficient evidence to comment on the use of antenatal MgSO4 to prevent neonatal cerebral palsy in a term population with pre-eclampsia.42 Our findings add to this literature a potential neuroprotective effect of MgSO4 in a high risk population at risk for HIE, but this observation requires prospective confirmation.

MgSO4 has also been studied in postnatal populations diagnosed with HIE. Trials in infants ≥35 weeks’ gestation with moderate to severe HIE assessed MgSO4 administration within 24 hours of birth have demonstrated benefit72–74 or no effect on neurologic outcomes.75,76 Adverse events, such as hypotension or infant death, limited some studies.32 There is promise that MgSO4 administration with concomitant therapeutic hypothermia is safe, but long-term outcomes are unknown.76 Maternal antenatal MgSO4 administration may circumvent risk with neonatal administration.

Clinical Implications:

Therapeutic hypothermia is the current treatment for a diagnosis of moderate to severe HIE.77 Despite widespread adoption of cooling protocols, long term morbidity persists, with approximately 15% mortality.78 Elucidating effective adjuvant treatments in this population is of interest. A recent systematic review included preclinical studies investigating perinatal MgSO4 in animal models of perinatal encephalopathy at gestations equivalent to term or near-term human models. It demonstrated heterogeneity in dosing protocols, lack of normothermia maintenance and inconsistency in short and long term outcomes.43 This indicates a need for additional preclinical studies prior to clinical trials.43

Research Implications:

In a population-based trend analysis, we demonstrate an increased incidence in the diagnosis of neonatal HIE and HDP. In a large neonatal network, we have illustrated an increase in MgSO4 use and exposed an association between HDP and HIE, and protection conferred by MgSO4. However, additional preclinical, translational and prospective studies are required to better understand this association.14,43

Strengths and Limitations:

This study must be interpreted within the context of its design and results should be viewed as hypothesis generating. For the association between HDP and neonatal HIE, we utilized a NICU database in which term neonates are not routinely entered, unless they have a qualifying condition. This introduces selection bias as patients with HDP and those that received MgSO4 are only included if the neonate was admitted to the NICU. The association between HDP and HIE in our study may be exaggerated since HIE is one of the main reasons a term neonate would require admission to the NICU. Outcomes for infants not requiring NICU admission cannot be ascertained from this study.

Our observational design and utilization of a neonatal dataset contributes to possible residual confounding from unobserved variables. The nature and spectrum of maternal comorbidities, type of HDP, and management is unknown. For example, the degree of placental disease in chronic hypertension may differ from other HDP and thus confer a different HIE risk profile. In our analysis those treated with MgSO4 were presumed to have pre-eclampsia with severe features. An alternative interpretation could be that worsening HDP may be protective, although biologic plausibility favors neuroprotective properties of MgSO4. The use of MgSO4 for seizure prophylaxis is standard of care for pre-eclampsia with severe features, therefore, it would be unethical to study withhold MgSO4 treatment to further elucidate the relationship.

The populations with HDP and HDP treated with MgSO4 differed with respect to baseline maternal, neonatal and delivery characteristics. Those treated with MgSO4 were higher risk for neonatal and delivery characteristics associated with HIE. However, they were less likely to be of advanced maternal age, have diabetes or be obese. We addressed this potential confounding by adjusting for the variables most strongly associated with HIE.

A strength of our study is the use of population-based data to assess the risk of HIE and HDP in our trend analysis. California is the most populous state in the Union, with sociodemographic diversity and a range of healthcare settings. However, our study may not generalize to other settings. Data within the CPQCC are prospectively collected with clearly defined, standardized terms. At term gestation, from a population perspective, the incidence of HIE is low. This necessitates a database with strong ascertainment of this outcome. There is increased attention to therapeutic hypothermia to treat moderate and severe HIE, and admission to the nursery rather than the NICU is uncommon for those meeting diagnostic criteria. Therefore, the CPQCC is unlikely to misclassify the outcome and uniquely affords the ability to study the rare outcome of HIE and its association with HDP and MgSO4.

Conclusion:

Neonates born to those with HDP treated with MgSO4 had more comorbid baseline neonatal and delivery characteristics. HDP alone are associated with neonatal HIE of any severity and specifically moderate/severe HIE. The odds of any HIE and moderate/severe HIE were significantly reduced among those with HDP treated with MgSO4 despite this population exhibiting high risk propensities. Due to the limitations of an observational study design and neonatal database, prospective trials are needed to test whether antenatal MgSO4 reduces the incidence of HIE or HIE severity in high-risk neonates.

Supplementary Material

1

AJOG at a Glance:

A. Why was this study conducted?

  • Hypoxic ischemic encephalopathy (HIE) affects neonates ≥ 360 weeks’ gestation and contributes to neurologic morbidity and mortality. The effect of antenatal magnesium sulfate (MgSO4) as a neuroprotective agent is well studied, but not at this gestation or for this disease process.

B. Key Findings:

  • The incidence of HIE, hypertensive disorders of pregnancy (HDP), and use of antenatal MgSO4 have increased.

  • Compared to normotensive patients, patients with HDP have increased odds of neonatal HIE. In patients with HDP, antenatal MgSO4 and presumed HDP with severe features were associated with lower odds of HIE and specifically, moderate/severe HIE among neonates admitted to the NICU ≥ 360 weeks’ gestation.

C. What does this add to what is already known?

  • Antenatal MgSO4 may diminish the odds of HIE associated with HDP in neonates admitted to the NICU ≥ 36 weeks’ gestation. Prospective studies are needed to corroborate this finding.

Acknowledgements:

We acknowledge the California Department of Public Health (CDPH) as the original source of data for this study and used technical descriptions of the data consistent with those provided by CDPH. Any analyses, interpretations, or conclusions from this study represent the work of the authors and not of CDPH.

Footnotes

Disclosure Statement: The authors report no conflict of interest.

Findings presented at the 42nd Annual Pregnancy Meeting, SMFM, January 31-February 5, 2022, Virtual Meeting and Stanford Maternal and Child Health Research Institute, October 21, 2022.

Works Cited:

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