Demographics and characteristics of the study cohort
Between 2012 and 2015, 345 neonates were born alive before 32 weeks’ gestation and admitted to the neonatal intensive care unit. One hundred and three neonates (29.9%) were part of a twin and five of a triplet (1.4%). Two hundred and ninety six mothers were included.
There are 218 neonates in the control group (63.2%), 68 in the neuroprotection group (19.7%), and 59 in the preeclampsia group (17.1%). Demographics and characteristics are summarised in Table 1. In the preeclampsia group, maternal body mass index (BMI) is, on average, higher compared to the other groups (+3.1 kg/m2 [95% confidence interval (CI) 1.3, 4.9] versus the control group, and + 2.7 kg/m2 [95%CI 0.5, 4.8] versus the neuroprotection group) and neonatal birth weight is, on average, lower (-283.0 g [95%CI -390.0, -176.0] versus the control group and -210.7 g [95%CI -348.0, -73.2] versus the neuroprotection group). There is a difference in number of multiple pregnancies, with less multiple pregnancies in the preeclampsia group (-22.7% [95%CI -36.5, -0.9] versus the control group, and -17.3% [95%CI -35.2, 0.5] versus the neuroprotection group). There are no other significant differences between groups found in our sample.
Table 1
Demographics and characteristics of the study cohort
| No MgSO4 (N=218) | Neuroprotection (N=68) | Preeclampsia (N=59) | Overall (N=345) |
Maternal age (years) | | | | |
Mean (SD) | 30.5 (5.1) | 30.2 (5.8) | 30.4 (4.8) | 30.4 (5.2) |
Median [Min, Max] | 30.0 [16.0, 42.0] | 30.0 [16.0, 43.0] | 30.0 [17.0, 44.0] | 30.0 [16.0, 44.0] |
Pre-pregnancy BMI (kg/m2) | | | | |
Mean (SD) | 23.9 (4.3) | 24.4 (5.1) | 27.0 (7.3) | 24.5 (5.2) |
Median [Min, Max] | 23.3 [15.2, 37.2] | 23.4 [16.5, 42.8] | 26.0 [16.2, 64.5] | 23.6 [15.2, 64.5] |
Parity | | | | |
Nulliparous | 129 (59.2%) | 46 (67.6%) | 37 (62.7%) | 212 (61.4%) |
Primiparous | 53 (24.3%) | 11 (16.2%) | 13 (22.0%) | 77 (22.3%) |
Multiparous | 36 (16.5%) | 11 (16.2%) | 9 (15.3%) | 56 (16.2%) |
Conception | | | | |
Spontaneous | 156 (71.6%) | 49 (72.1%) | 47 (79.7%) | 252 (73.0%) |
Assisted | 62 (28.4%) | 19 (27.9%) | 12 (20.3%) | 93 (27.0%) |
Antenatal corticosteroids | | | | |
No | 17 (7.8%) | 2 (2.9%) | 4 (6.8%) | 23 (6.7%) |
Yes | 201 (92.2%) | 66 (97.1%) | 55 (93.2%) | 322 (93.3%) |
Number of fetuses | | | | |
Singleton | 139 (63.8%) | 47 (69.1%) | 51(86.4%) | 237 (68.7%) |
Twin | 74 (33.9%) | 21 (30.9%) | 8 (13.6%) | 103 (29.9%) |
Triplet | 5 (2.3%) | 0 (0.0%) | 0 (0.0%) | 5 (1.4%) |
Sex | | | | |
Male | 120 (55.0%) | 32 (47.1%) | 27 (45.8%) | 179 (51.9%) |
Female | 98 (45.0%) | 36 (52.9%) | 32 (54.2%) | 166 (48.1%) |
Gestational age at birth (weeks) | | | | |
24-27+6w | 43 (19.7%) | 21 (30.9%) | 12 (20.3%) | 76 (22.0%) |
28-31+6w | 175 (80.3%) | 47 (69.1%) | 47 (79.7%) | 269 (78.0%) |
Birth weight (grams) | | | | |
Mean (SD) | 1340 (356) | 1260 (396) | 1050 (356) | 1270 (378) |
Median [Min, Max] | 1360 [565, 2200] | 1280 [620, 2120] | 980 [538, 2500] | 1290 [538, 2500] |
There is a moderately positive correlation between the total maternal dose of MgSO4 and the maternal magnesemia in the whole population (pearson = 0.64) and in the preeclampsia group (pearson = 0.60). The neonatal magnesemia is, for all days and in all groups, correlated with the neonatal magnesemia of the subsequent day. Table 2 provides a summary of the observed maternal and neonatal magnesium values.
Table 2
Observed maternal and neonatal (day of birth - neonatal day 7) magnesium values
| No MgSO4 (N=218) | Neuroprotection (N=68) | Preeclampsia (N=59) | Overall (N=345) |
Maternal magnesemia (mmol/l) | | | | |
Mean (SD) | 1.00 (0.59) | 1.23 (0.37) | 1.91 (0.64) | 1.49 (0.75) |
Median [Min, Max] | 0.75 [0.63, 2.97] | 1.24 [0.76, 1.64] | 1.85 [0.74, 3.08] | 1.52 [0.63, 3.08] |
Missing | 177 (81.2%) | 62 (91.2%) | 8 (13.6%) | 247 (71.6%) |
Maternal total Mg dose (grams) | | | | |
Mean (SD) | - | 2610 (5250) | 9190 (12200) | 5640 (9640) |
Median [Min, Max] | - | 838 [4, 33600] | 3570 [4, 52300] | 1480 [4, 52300] |
Missing | - | 1 (1.5%) | 2 (3.4%) | 221 (64.1%) |
Duration MgSO4 infusion (minutes) | | | | |
Mean (SD) | - | 688 (722) | 6240 (6820) | 3240 (5400) |
Median [Min, Max] | - | 336 [39, 3020] | 3600 [15, 31200] | 1020 [15, 31200] |
Missing | - | 1 (1.5%) | 2 (3.4%) | 221 (64.1%) |
Neonatal magnesemia, day of birth (mmol/l) | | | | |
Mean (SD) | 0.82 (0.25) | 1.12 (0.20) | 1.65 (0.51) | 1.02 (0.43) |
Median [Min, Max] | 0.77 [0.55, 2.86] | 1.12 [0.73, 1.81] | 1.61 [0.79, 3.17] | 0.84 [0.55, 3.17] |
Missing | 28 (12.8%) | 10 (14.7%) | 8 (13.6%) | 46 (13.3%) |
Neonatal magnesemia, day 1 (mmol/l) | | | | |
Mean (SD) | 0.92 (0.20) | 1.13 (0.17) | 1.51 (0.45) | 1.06 (0.33) |
Median [Min, Max] | 0.89 [0.53, 2.55] | 1.12 [0.77, 1.63] | 1.52 [0.76, 2.78] | 0.95 [0.53, 2.78] |
Missing | 21 (9.6%) | 6 (8.8%) | 8 (13.6%) | 35 (10.1%) |
Neonatal magnesemia, day 2 (mmol/l) | | | | |
Mean (SD) | 1.04 (0.15) | 1.17 (0.14) | 1.39 (0.31) | 1.13 (0.23) |
Median [Min, Max] | 1.02 [0.73, 2.00] | 1.17 [0.87, 1.58] | 1.34 [0.89, 2.26] | 1.07 [0.73, 2.26] |
Missing | 16 (7.3%) | 4 (5.9%) | 5 (8.5%) | 25 (7.2%) |
Neonatal magnesemia, day 3 (mmol/l) | | | | |
Mean (SD) | 1.10 (0.13) | 1.16 (0.14) | 1.28 (0.24) | 1.15 (0.17) |
Median [Min, Max] | 1.09 [0.77, 1.88] | 1.15 [0.88, 1.47] | 1.23 [0.92, 1.77] | 1.11 [0.77, 1.88] |
Missing | 24 (11.0%) | 5 (7.4%) | 5 (8.5%) | 34 (9.9%) |
Neonatal magnesemia, day 4 (mmol/l) | | | | |
Mean (SD) | 1.09 (0.12) | 1.13 (0.11) | 1.17 (0.21) | 1.11 (0.14) |
Median [Min, Max] | 1.09 [0.62, 1.59] | 1.12 [0.92, 1.47] | 1.15 [0.76, 1.60] | 1.10 [0.62, 1.60] |
Missing | 34 (15.6%) | 8 (11.8%) | 10 (16.9%) | 52 (15.1%) |
Neonatal magnesemia, day 5 (mmol/l) | | | | |
Mean (SD) | 1.04 (0.12) | 1.06 (0.09) | 1.06 (0.17) | 1.05 (0.13) |
Median [Min, Max] | 1.04 [0.38, 1.46] | 1.05 [0.91, 1.26] | 1.04 [0.79, 1.48] | 1.04 [0.38, 1.48] |
Missing | 47 (21.6%) | 16 (23.5%) | 6 (10.2%) | 69 (20.0%) |
Neonatal magnesemia, day 6 (mmol/l) | | | | |
Mean (SD) | 1.00 (0.10) | 1.02 (0.09) | 1.00 (0.16) | 1.00 (0.11) |
Median [Min, Max] | 0.98 [0.72, 1.39] | 1.02 [0.81, 1.27] | 0.98 [0.79, 1.41] | 0.99 [0.72, 1.41] |
Missing | 68 (31.2%) | 14 (20.6%) | 11 (18.6%) | 93 (27.0%) |
Neonatal magnesemia, day 7 (mmol/l) | | | | |
Mean (SD) | 0.96 (0.09) | 0.96 (0.08) | 0.93 (0.13) | 0.95 (0.10) |
Median [Min, Max] | 0.95 [0.71, 1.28] | 0.96 [0.80, 1.10] | 0.91 [0.72, 1.27] | 0.95 [0.71, 1.28] |
Missing | 72 (33.0%) | 30 (44.1%) | 22 (37.3%) | 124 (35.9%) |
Primary aim (Online Resource S1)
The distribution of neonatal magnesemia according to neonatal day of life (day 0-14) and indication for MgSO4 administration is visualised in Figure 1.
There is a significant difference in geometric mean neonatal magnesemia between the three groups from the day of birth up to the fourth day of life (day 0-3). No significant differences in neonatal magnesemia between the three exposure groups beyond day four of neonatal life could be found in our sample. The estimated geometric mean neonatal magnesemia (with 95% CI) per neonatal day of life and group is depicted in Figure 2a and numerically summarised in Online Resource Table S1.
In all three groups, there is no indication of an association of maternal BMI and neonatal birth weight with neonatal magnesemia.
Maternal magnesemia (Online Resource S1)
In our cohort, there is a significant association between maternal magnesemia and neonatal magnesemia during the first four days of life (day 0-3) in both the control and the preeclampsia group. The association remains significant until the eight day of life (day 0-7) in the preeclampsia group (Online Resource Table S3).
Maternal magnesemia is, on average, higher in the preeclampsia group versus the control group (+0.70 mmol/L [95%CI 0.50, 0.89])(Online Resource Figure S1a).
The estimated geometric mean neonatal magnesemia per neonatal day of life per exposure group for a maternal magnesemia corresponding to the overall geometric mean of 1.30 mmol/l is depicted in Figure 2b and numerically summarised in Online Resource Table S2. Only on the first day of neonatal life (day 0), independent of the maternal magnesemia, neonatal magnesemia is significantly higher in the preeclampsia group compared to the control group.
Total maternal dose of MgSO4 (Online Resource S1)
Most women in the neuroprotection group received MgSO4 for less than 24 hours; only 12 out of 68 women in the neuroprotective group received the maximum dose of 28 grams.
There is a significant association between total maternal dose and neonatal magnesemia during the first four days of life (day 0-3) in both the neuroprotection and the preeclampsia group. The association is significant until the seventh day of life (day 0-6) in the preeclampsia group (Online Resource Table S3).
The geometric mean maternal total dose is, on average, 4.62 times higher in the preeclampsia group versus the neuroprotection group (x4.62 [95% CI x3.13, x6.82])(Online Resource Figure S1b).
The estimated geometric mean neonatal magnesemia per neonatal day of life per exposure group for a total maternal dose of MgSO4 corresponding the overall geometric mean in these two exposure groups of 23.82 grams, is depicted in Figure 2c and numerically summarised in Online Resource Table S2. In our cohort, on the two first days of neonatal life (day 0-1) neonatal magnesemia is significantly higher in the preeclampsia group compared to the neuroprotection group, independent of the total maternal MgSO4 dose.
Duration of MgSO4 exposure (Online Resource S1)
There is a significant association between the duration of MgSO4 administration and the neonatal magnesemia during the first three days of life (day 0-2) in both the neuroprotection and the preeclampsia group. The association remains significant until the seventh day of life (day 0-6) in the preeclampsia group (Online Resource Table S3).
The duration of maternal MgSO4 administration is, on average, 6.96 times higher in the preeclampsia group versus the neuroprotection group (x6.96 [95% CI x3.97, x12.18])(Online Resource Figure S1c).
The estimated geometric mean neonatal magnesemia per neonatal day of life per exposure group for a duration of MgSO4 administration corresponding to the overall geometric mean of 850 minutes in these two exposure groups is depicted in Figure 2d and numerically summarised in Online Resource Table S2. In our cohort, on the two first days of neonatal life (day 0-1) neonatal magnesemia is significantly higher in the preeclampsia group compared to the neuroprotection group, independent of the duration of MgSO4 administration.
Short-term outcome (Online Resource S1)
Ninety three neonates (27.0%) experienced the composite short-term neonatal outcome (mortality, IVH and/or PVL). No significant differences in short-term neonatal outcome between the three exposure groups were identified in our cohort.