Magnesium diethyl dicarbonate

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment Case studies from clinical observations after infusion not relevant for industrial exposures

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1978

Reference 2

Reference Type:

publication

Title:

The effect of magnesium sulfate tocolysis on the fetal biophysical profile

Author:

Peaceman, A. M., Meyer, B. A., Thorp, J. A., Parisi, V. M. and Creasy, R. K.

Year:

1989

Bibliographic source:

American Journal of Obstetrics and Gynecology 1989; 160: 771-774

Reference 3

Reference Type:

publication

Title:

Effect of maternally administered magnesium sulfate on the neonate

Author:

Stone, S. R. and Pritchard, J. A.

Year:

1970

Bibliographic source:

Obstetrics and Gynecology 1970; 35: 574-577

Reference 4

Reference Type:

publication

Title:

Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3-5 years

Author:

Schendel, D.E., Berg, C.J., Yeargin-Allsopp, M., Boyle, C.A., Decoufle, P.

Year:

1996

Bibliographic source:

Journal of the American Medical Association, December 11, 1996, Vol 276, No. 22

Reference 5

Reference Type:

publication

Title:

Clinical perinatal/neonatal case presentation

Author:

Herschel, M and Mittendorf, R

Year:

2001

Bibliographic source:

Journal of Perinatology 2001; 12:261-262

Reference 6

Reference Type:

publication

Title:

Unnamed

Year:

1973

Reference 7

Reference Type:

publication

Title:

Unnamed

Year:

2000

Materials and methods

Study type:

clinical case study

Endpoint addressed:

developmental toxicity / teratogenicity

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Magnesium sulphate

EC Number:

231-298-2

EC Name:

Magnesium sulphate

Cas Number:

7487-88-9

Molecular formula:

MgO4S

IUPAC Name:

magnesium sulfate

Applicant's summary and conclusion

Conclusions:

These studies show that intravenously administered magnesium sulphate during pregnancy can cause inhibition of foetal heart rate (Babaknia et al, 1978) can affect foetal heart rate, breathing and overall biophysical profile scores (Peaceman et al, 1989), reduce the risk of cerebral palsy and possibly mental retardation among very low birth weight children (Schendel et al, 1996), may cause death in neonates if magnesium toxicity in the mother is reported (Herschel and Mittendorf, 2001), is well tolerated and beneficial in the treatment of eclampsia for both mother and infant (Lu, J.F. and Nightingale, C.H., 2000) and may lead to infant death if a magnesium sulfate enema is administered for the therapy of hyaline membrane disease. However, magnesium sulphate does not have an effect on the foetal mortality rate (Stone et al, 1970 and Schendel et al, 1996), and according to this study does not negatively affect the foetus.

Side effects mostly of transient nature on the fetus during therapeutic use of magnesium sulphate intravenous infusions as tocolytic agent (mostly in combination with other medicines) in the management of preterm labour have been reported at dose levels that exceeded the therapeutic doses. The majority of the studies did not observe any adverse effects on the newborns. Babaknia et al, 1978 reported two cases a reversible reduced variability of fetal heart rate during infusions of magnesium sulphate to pregnant women suffering from hypertension and also receiving other medical drugs. Peaceman et al, 1989 studied effects on fetal stress reactions of magnesium sulphate infusions to 16 pregnant women (6 pregnant with twins) with preterm labour. The authors report a decrease in fetal heart rate in 16 of 22 fetuses and a reduction in fetal breathing movements in 18 of 22 fetuses while all fetuses revealed normal tone and gross movements and amniotic fluid volumes. No effects on the newborn after delivery were reported. The fact that newborns are not adversely affected by treatment of mothers with tocolytic doses of magnesium sulphate was corroborated by an epidemiological study of Schendel et al., 1996 who examined the risk of cerebral palsy or mental retardation in a cohort of very low birth weight children whose mothers were treated with magnesium sulphate during pregnancy. The children were followed up to one year of age including a subcohort followed up until 3 to 5 years of age. The study included all very low birth weight infants born during a 2-year period in Atlanta and 24 counties in Eastern Georgia. The authors report a 90% lower prevalence of cerebral palsy and a 70% lower prevalence of mental retardation in children whose mothers were treated with magnesium sulphate during pregnancy compared to the cohort that did not receive magnesium sulphate. Herschel and Mittendorf, 2001 report one case of a women pregnant with twins that received magnesium sulphate infusions, antibiotics and betametasone following a spontaneous rupture of the membranes and contractions. The women received an overdose of magnesium sulphate with Mg2+ blood levels of 9 mg/dl. After cessation of the infusion and a caesarian delivery one of the twin infants died. The authors report that this was probably related to the magnesium sulphate overdose, but a clear causal relationship cannot be deduced from this case report. Intravenously administered sulphate was reported to be well tolerated and beneficial in the treatment of eclampsia for both mother and infant at therapeutic magnesium serum concentrations of about 2 to 3.5 mmol/L (Lu, J. F. and Nightingale, C. H., 2000). Magnesium sulphate administered by deep intramuscular injection at does levels of 30 to 40g per day to pregnant women that were monitored for the absence of effects on the knee jerc reflex, urine flow and respiratory rate, was reported to have no effects on the neonatal mortality rate (Stone et al, 1970)

Executive summary:

Babaknia et al:

Two black females (16 and 14) were administered magnesium sulphate intravenously, which resulted in inhibition of the foetal heart rate variability (a sign of foetal distress). This effect had also been observed in four other patients but this was not recorded as there may have been other interfering factors to consider. In each case, the loss of variability was observed within four minutes of injection. Since foetal outcome was good in all cases, this suggests that the decreased baseline variability was drug-induced.

Peaceman et al:

A total of 16 patients (mean age 23.4 ± 4.5 years) were recruited for the study, 6 of whom were pregnant with twin gestations (mean gestational age 30.7 ± 2.2 weeks). A biophysical profile was performed before the initiation of tocolytic therapy. The foetuses were continually monitored and each patient was administered magnesium sulphate intravenously. The doses used were determined to attain serum magnesium concentrations in the therapeutic range 6 -8 mg/dl, and serum magnesium concentrations were measured every 4-6 hours. After a therapeutic level was documented, a repeat biophysical profile was performed. Foetal heart rate activity was measured in the 60 minute interval after the magnesium level reached the therapeutic range. Foetal heart rate baselines were then compared.

All 22 foetuses were found to have reactive foetal heart rate patterns on admission, but only 11 of 22 were found to be reactive during therapeutic magnesium tocolysis. All but one foetus sustained breathing movements at the time of the initial biophysical profile. However, after a therapeutic magnesium level was achieved, only four foetuses demonstrated sustained breathing movements. Magnesium sulphate tocolysis resulted in statistically significant decreases in overall biophysical profile scores.

In conclusion, when magnesium sulphate is used as a tocolytic agent, it can reduce foetal heart rate, can affect foetal breathing movements and results in a decrease in overall biophysical profile scores.

Stone et al:

Magnesium sulphate has been used for 14 years to treat severe toxemia of pregnancy where the mother receives magnesium sulphate parenterally. Blood collected from the recently severed cords of 118 infants, and blood obtained from 42 mothers about the time of delivery were examined. The neonatal mortality rate was determined for all patients with antepartum and intrapartum eclampsia cared for during the past 14 years. The neonatal mortality rate was determined for all patients treated prior to delivery with magnesium sulphate during the past two years due to antepartum and intrapartum maternal hypertension.

Magnesium concentration: The magnesium concentration of cord serum and maternal blood samples showed that there was not a positive correlation between cord serum magnesium concentration and Apgar score. Of the 118 infants, only 8 had Apgar scores of 5 or less and all 8 survived.

Neonatal mortality in eclampsia treated with magnesium sulphate: 80 infants had been delivered from mothers treated with magnesium sulphate for eclampsia since 1955. Every foetus in whom a heart beat was identified at the time that eclampsia was diagnosed and treated was delivered alive.

Neonatal mortality between 1967 and 1968: In this period 1248 infants were born of mothers who had received magnesium sulphate sulphate parenterally due to hypertension complicating the pregnancy. 24 of these succumbed during the newborn period (neonatal death rate of 1.9 %). The neonatal death rate of all infants delivered in this time was 301 out of 11897 (neonatal death rate of 2.5 %). Therefore the neonatal death rate for the total newborn population is greater by nearly one third than that of infants whose mothers received magnesium sulphate.

Parenterally administered magnesium sulphate is used extensively in the treatment of toxemia of pregnancy. In the hospital concerned in this report, during a 14 -year period, 7000 infants were born of mothers who had received magnesium sulphate parenerally because of preeclampsia or eclampsia. This study disproves that magnesium sulphate has a negative effect on the foetus, and it was found that the neonatal mortality rate was less for infants whose mothers were treated, than for the total neonatal population at the hospital.

Schendel et al., 1996:

The relationship between prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low birth weight (<1500g) children was examined. The effect of prenatal magnesium sulfate exposure on very low birth weight children's mortality was also examined. The study was conducted in 29 Georgia counties including the 5 -county Atlanta metropolitan area, on 1097 very low birth weight children born over a two year period (1986 -1988) and 519 metropolitan Atlanta very low birth weight neonates who survived infancy.

Main outcomes were measured via infant mortality as determined from vital statistics records. The development of cerebral palsy or mental retardation by 3 -5 years of age among metropolital Atlanta very low birth weight survivors was determined from the Metropolitan Atlanta Developmental Disabilities Surveillance Program.

There was no association between prenatal magnesium sulfate exposure and infant mortality. Among Atlanta-born survivors, those exposed to magnesium sulfate had a lower prevalance of cerebral palsy and mental retardation than those not exposed.

A reduced risk for cerebral palsy and possibly mental retardation among very low birth weight children is associated with prenatal magnesium sulfate exposure. The reduced risk for childhood cerebral palsy or mental retardation does not appear to be due to selective mortality of magnesium-sulfate exposed infants.

Herschel and Mittendorf, 2001:

A 31 -year-old primigravida with twins had spontaneous rupture of the membranes at 32 weeks' gestation. On admission, because of contractions, the mother was started on tocolytic magnesium sulfate (MgSO4) along with betamethasone and prophylactic antibiotics. About a day later, she was found to have magnesium toxicity. Her serum total magnesium levels was 9.0 mg/dl. Tocolysis was immediately discontinued. At cesarean delivery the following day, twin A, a female, died at 30 minutes of age despite a vigorous resuscitation. Although the preceeding fetal heart rate patterns had been reassuring and the umbilical blood gases were normal, quite unexpectedly the Apgar scores were 1/1/0. An autopsy revealed no anatomic abnormalities. Twin B, a female who survived, was also intubated at delivery. During her stay in teh Neonatal Intensive Care Unit she was found to have modestly elevated levels of serum cardiotroponin T. In our opinion, it is probably that the death of twin A can be directly attributed to magnesium sulfate toxicity. Neonatologists who attend deliveries should be aware that unexpected death may occur in babies who were exposed to high doses of tocolytic MgSO4.

Outerbridge et al. 1973:

Fatal systemic magnesium intoxication followed the administration of a magnesium sulfate enema for the therapy of presumed hyaline membrane disease in a newborn infnat. Despite antemortem recognition of its occurrence and attempted therapy with an exchange transfusion, the infant died. Coupled with a lack of any demonstrable efficacy of this therapy for hyaline membrane disease, the toxicity is such as to prohibit its further use.

Lu and Nightingale, 2000:

Magnesium sulfate is the agent most commonly used for treatment of eclampsia and prophylaxis of eclampsia in patients with severe pre-eclampsia. It is usually given by either the intramuscular or intravenous routes. The intramuscular regimen is most commonly a 4g intravenous loading dose, immediately followed by 10g intramuscularly and then by 5g intramuscularly every 4 hours in alternating buttocks. The intravenous regimen is given as a 4g dose followed by a maintenance infusion of 1 to 2 g/h by controlled infusion pump.

After administration, about 40% of plasmas magnesium is protein bound. The unbound magnesium ion diffuses into the extravascular-extracellular space, into bone, and across the placenta and fetal membranes and into the fetus and amniotic fluid. In pregnant women, apparent volumes of distribution usually reach constant values between the third and fourth hours after administration, and range from 0.250 to 0.442 L/kg. Magnesium is almost exclusively excreted in the urine, with 90% of the dose excreted during the first 24 hours after and intravenous infusion of MgSO4. The pharmacokinetic profile of MgSO4 after intravenous administration can be described by a 2 -compartment model with a rapid distribution phase followed by a relative slow phase of elimination.

The clinical effect and toxicity of MgSO4 can be linked to its concentration in plasma. A concentration of 1.8 to 3.0 mmol/L has been suggested for treatment of eclamptic convulsions. The actual magnesium dose and concentration needed for prophylaxis has never been estimated. Maternal toxicity is rare when MgSO4 is carefully administered and monitored. The first warning of impending toxicity in the mother is loss of the patellar reflex at plasma concentrations between 3.5 and 5 mmol/L. Respiratory paralysis occurs at 5 to 6.5 mmol/L. Cardiac conduction is altered at greater than 7.5 mmol/L, and cardiac arrest can be expected when concentrations of magnesium exceed 12.5 mmol/L. Careful attention to the monitoring guidelines can prevent toxicity. Deep tendon reflexes, respiratory rate, urine output and serum concentrations are the most commonly followed variables.