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Effect of intravenous magnesium sulfate on the biophysical profile of the healthy preterm fetus
CLINICAL
SECTION
Clinical
Articles
Effect of intravenous magnesium sulfate on the biophysical healthy fetus the preterm profile of Scott E. Gray, MD, John F. Rodis, MD, Luanna Lettieri, Anthony Vintzileos, MD
MD, James F. X. Egan, MD, and
Farmington, Connecticut OBJECTIVE: The null hypothesis is that intravenous magnesium sulfate does not affect the biophysical profile of the healthy preterm fetus. STUDY DESIGN: Thirty-one fetuses of 25 patients between the gestational ages of 24 and 35 weeks, median 31.4 and mean (_t SD) 30.4 (-t 2.9), who required tocolysis for uterine contractions were prospectively studied. After normal fetal biophysical assessment was documented, intravenous magnesium sulfate was started as a4 or 6 gm loading dose and then infused at 2 to 3.5 gm/hr to achieve tocolysis. Blood was drawn for measurement of maternal serum magnesium levels immediately before intravenous magnesium sulfate was administered and at 2 and 12 hours after the loading dose. Biophysical profiles, consisting of a possible 12 points, were performed at the same time as blood was drawn. Serum magnesium levels were compared with one-way analysis of variance for repeated measures and biophysical profile scores with Friedman's test. Statistical significance was considered p<0.05. RESULTS. Mean (.t: SD) serum magnesium levels were 1.7 (: tO. 1) mg/dl before infusion, 4.3 (: tO.6) mg/dl at 2 hours, and 5.2 (±0.7) mg/dl at 12 hours (p < 0.001). Six fetuses did not have a 12-hour biophysical profile; three were delivered for severe variable decelerations, two progressed in labor, and in one tocolysis was discontinued. The median biophysical profile score was 11 before intravenous magnesium sulfate, at 2 hours, and at 12 hours after the loading dose. The biophysical parameters present and the percentage of fetuses with each parameter were as follows: breathing (> 30 seconds), 88% (22/25) before magnesium sulfate, 84% (21/25) at 2 hours, and 92% (23/25) at 12 hours; nonstress test (reactive),84% (21/25) before magnesium sulfate, 68% (17/25) at 2 hours, and 80% (20/25) at 12 hours; movement (normal), 100% (25/25) before magnesium sulfate, 100% (25/25), at 2 hours, and 96% (24/25) at 12 hours; tone (normal), 100% (25/25) before magnesium sulfate, 100% (25/25) at 2 hours, and 96% (24/25) at 12 hours. Intravenous magnesium sulfate did not significantly after the biophysical profile in the 25 fetuses evaluated by three biophysical profiles in spite of the significant increase in maternal serum 1994; 170: 1131-5. ) magnesium levels. (Am J OesTETGYNECOL CONCLUSION:
Key words: Magnesium sulfate, biophysical profile, preterm fetus, tocolytic therapy Intravenous magnesium sulfate has been widely used as a tocolytic for more than two decades.' The biophysical profile has been used to assess fetal status in '' been has It shown that fetal evaluation with the utero. biophysical profile can predict neonatal outcome by detection of fetal or intrauterine environment deterioFrom the Division of Maternal-FetalMedicine,Departmentof ObUniversityof ConnecticutHealth Center. sletncsand Gynecology, ReceivedforpublicationMay 6,1993; revisedSeptember 15,1993; November1,199j. accepted Reprintsnot available. CopyrightC) 1994 b-vMosbv-YearBook,Inc. 0002-9378194$3.60 +6 611152765
intraveindicated have " Previous that studies ration. -5 ' breathing'fetal decreases nous magnesium sulfate and fetal heart rate reactivity," thereby significantly decreasing the total biophysical profile score b, ' Howfetuses, term these studies who of evaluated ever, most may respond differently to intravenous magnesium sulfate than do preterm fetuses." '- ' Becauseintravenous magnesium sulfate is frequently used to arrest preterm labor, it is essential to understand the effect of such therapy on the biophysical assessmentof the healthy preterm, fetus. The purpose of this prospective study was to determine the effect, if any, of magnesium sulfate on indi1131
April 1994 Am j Obstet Gyýiecol
1132 Grayetal.
vidual fetal biophysical profile components and the total biophysical score of the healthy preterm fetus during the first 12 hours of therapy. Our null hypothesis was that intravenous magnesium sulfate administered for tocolysisdoes not affect the biophysical profile of the healthy preterm fetus. Material and methods This was a prospective study of 31 fetuses of 25 patients who were between 24 and 35 weeks' gestation admitted to the University of Connecticut Health Center, Farmington, from ]an. I through Aug. 1,1992. All patients required tocolysisfor preterm labor, which was defined as uterine contractions associatedwith documented cervical change or persistent uterine contractions (three or more contractions in a 10-minute interval) for at least 30 minutes after adequatehydration. An ultrasonographic examination for biometry, calculation of estimated fetal weight, and identification of fetal anomalieswas performed in all caseson admissionwith a 3.5 MHz transducer (General Electric RT 2600, Milwaukee). Fetuseswith growth abnormalities or anomalies were excluded. Gestational age was calculated on the basisof a second-trimesterultrasonographic examination, which agreed with the last menstrual period ± 10 days. Biophysical profile scoring, consisting of a maximum of 12 points, was performed as described by Vintzileos et al. " Fetuseswere included if their initial biophysical profile score was 2-8 (including a reactive nonstress test [NSTJ or fetal breathing movements), indicating a healthy fetus. The fetal heart rate tracing for 30 minutes before each biophysical profile wasused to determine fetal heart pte reactivity (AdvancedMedical Systems,IM76, Hamden, Conn.). Zero, one, or two points were assignedfor the NST, fetal movement, fetal tone, fetal breathing movements,amniotic fluid volume, and placental grading. A biophysical profile was performed before and at 2 and 12 hours after the loading dose was administered. No tocolytics or medications were received by any patient for at least I hour before the initial biophysical profile. No narcotic or other analgesic medication was administered to any patient before or during the study period. Intravenous magnesium sulfate was administered as a4 or 6 gm loading dose over 20 to 30 minutes. A magnesium sulfate solution (20 gm in IL 5% dextrose in water) was infused as maintenance at 2 to 3.5 grn/hr to achieve tocolysis. The patient's intravenous mainline fluid was 5% dextrose in Ringer's lactate solution. No other medications for tocolysisor sedation were administered during the study. All patients were on continuous bed rest in a lateral recumbent position with external monitoring of fetal heart rate and uterine contractions throughout the study. A complete blood cell count, serum magnesium level, serum glucose, urinalysis,
urine toxicology screen, and cervical and vaginal culloading before the patients tures were obtained on all dose was administered. Serum magnesium levels were biophysical 212-hour drawn profiles. the and with also The presence of intraamniotic infection was evaluated by transabdominal amniocentesis, maternal laboratory studies, cervical examination with cultures, neonatal examination, and postpartum placental pathologic examination. An amniocentesis was performed on patients with premature rupture of membranes when intact labor in with preterm and on all patients possible fluid The sample was evaluated amniotic membranes. by Gram stain, culture, and glucose concentration. When the gestational age was > 32 weeks, pulmonary maturity studies were also performed on the amniotic fluid. Twenty-four patients received betamethasone, 12 mg, intramuscularly after the magnesium sulfate loading dose. Serum magnesium levelswere compared with one-wayanalysisof variance for repeated measures,and the biophysical profile scores were compared with Friedman's test. Statistical significance was considered at P values < 0.05. Assuming aP error of 0.20, a power calculation estimated that evaluation of 21 fetusescould detect a statistically significant difference in the NST or breathing components. The power calculation was based on results of a comparable study." Results Twenty-five fetuses (15 singletons and 10 twins) of the original 31 fetuses received all three biophysical profiles (before the magnesium sulfate loading dose and 2 and 12 hours after the loading dose). Six singleton fetuses did not receive the 12-hour biophysical profile. Three of these six fetuses were delivered because of persistent severe variable decelerations caused by cord compression and oligohydramnios after premature rupture of the membranes. Two were delivered because of labor progression, and in one tocolysis was discontinued after 10 hours. Regular and frequent (more than two in 30 minutes) uterine contractions had stopped in all patients before the 12-hour biophysical profile. The admitting diagnoses for the 20 patients (25 fetuses) who had all three biophysical profile examinations were preterm premature rupture of membranes (six with singletons and three with twins), premature labor with intact membranes (six with singletons and two with twins), and placenta previa with bleeding (three with singletons). The mean (: t SD) maternal age was 26.6 (: t6.3) years (range 16 to 39). On admission the median gestational age was 31.4 weeks and the mean (±SD) gestational age was 30.4 (±2.9) weeks (range 24 to 34.3). Mean (±SD) admission serum glucose value was 96.5 (±21.4) mg/dl (range 65 to 164). The mean (±SD) serum magnesium levels were
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Table 1. Percentageof fetuseswith biophysical parameter present Biophysical parameter Breathing (> 30 sec) (%) Reactive NST (%)* Movement (%)t Tone (%)+'
Before magnesium sulfate
2 hr
12 hr
88 (22/25)
84 (21/25)
92 (23/25)
84 (21/25) 100 (25/25) 100 (25/25)
68 (17/25) 100 (25/25) 100 (25/25)
80 (20/25) 96 (24/25) 96 (24/25)
*Two or more accelerationsof a 15 beats/min in amplitude and ýt 15 seconds'duration in a 30-minute period. tAt least three gross (trunk and limbs) episodesof fetal movementswithin 30 minutes. TAt least one episode of extension of extremities with return to position of flexion and one episode of extension of spine with return to position of flexion.
1.7 (.tO. I) mg/dI before the loading dose, 4.3 (±0.6) mg/dI at 2 hours, and 5.2 (.± 0.7) mg/dl at 12 hours. The difference between serum magnesium levels was statistically significant, p<0.001. The median biophysical profile score was II before the intravenous magnesium sulfate loading dose and at 2 hours and 12 hours after the loading dose.There was in for difference the points assigned amniotic fluid no between the three biophysical prograde placental or files for any fetus. The mean and median score was 2 fetal breathing for movements, tone, and movepoints ment for each. For NST the mean scoreswere 2,1.8, and 2, whereas the median scoreswere 1,1, and 2 for the three biophysical profiles. The difference in the fetuses with a nonreactive NST was not of number statistically significant between the three biophysical profiles (Friedman's Xr20.54). The exact percentage of fetuses with breathing movements, reactive NSTs, movement, and tone at each biophysical profile is presented in Table 1. Ten patients (12 fetuses) were discharged undelivered. These 12 fetuseswere all normal neonates delivered between 35 and 41 weeks' gestation at outlying hospitals. Of the 13 fetuses delivered at our hospital one was acidemic at birth, with an arterial cord blood 7.19. This fetus was delivered 24 hours after of PH admission and had an uncomplicated neonatal course. Three other fetuses in this delivered group had low 5-minute Apgar scores becauseof Prematurity. These three fetuseswere delivered > 48 hours after admission. None of the 13 neonates delivered at our hospital were septic on evaluation in the neonatal intensive care unit. No evidence of infection or significant findings were identified in the 13 placentas available for pathologic diagnosis.There were no maternal complications attributed to magnesium sulfate.
Comment Any attempt to monitor in utero fetal activities is complicated by the dynamic interaction of maternal and fetal physiologic states. Factors affecting fetal bio-
physical activities include normal periodicity, infection, drugs, gestational age, hypoxia, acidemia, labor, fetal malformation, sound, and maternal glucose level. `" "" Our study concluded that the administration of intravenous magnesium sulfate for tocolysis did not significantly affect the individual components of the fetal biophysical profile or the total score in healthy preterm fetuses. Previous studies have described different conclusions in regard to fetal breathing movements, NST reactivity, and the total biophysical score. Carlan and O'Brien' used the biophysical profile to evaluate normal term (>37 weeks) fetuses. In their for fasting sulfate magnesium mothers study received contraction prophylaxis before external cephalic version. Patients received a4 to 6 gm loading dose of magnesium sulfate and a continuous infusion of magnesium sulfate at 2 to 4 gm/hr for I to 2 hours. The initial biophysical profile was performed immediately before the loading dose of magnesium sulfate, and the 2 I biophysical to at performed profile was second hours after the loading dose. A serum magnesium level was drawn as the second biophysical profile was started. The external cephalic version was then attempted. They found a statistically significant decrease in the biophysical profile score after magnesium sulfate adbreathing in fetal decrease "due activto a ministration ity. " They concluded that "loss of any component (of the biophysical profile) other than respiration cannot be attributed to magnesium. " Our study identified no in breathing fetal difference in movements significant the preloading and postloading dose biophysical profiles. It is not clear whether this difference in breathing be attributed to the gestational age can movements difference between the two study groups. Other studies have found a normal decrease in the incidence of fetal breathing movements in later gestation, especially after Fox et al. " found the amount of time the 36 weeks. `" fetus spent making breathing movements increased decrease A in fetal increasing gestational age. with breathing movements also has been shown in the pres" 12 labor. infection"We believe, on and with ence of
1134 Grayetal.
the basis of the results of our study, that the preterm fetus exposed to intravenous magnesium sulfate therapy for tocolysis must be evaluated carefully before attributing the loss of breathing movements or an abnormal biophysical assessment to any pharmacologic effect of magnesium. Peaceman et al. "' studied 16 patients (22 fetuses) in preterm labor who received magnesium sulfate for tocolysis as an intravenous loading dose of 4 to 6 gm and a continuous infusion at 1.5 to 3.5 gm/hr. Fetuses underwent an initial biophysical profile before the loading dose. A second biophysical profile was performed (at 14.1 t 5.4 hours) once a "therapeutic" serum level of magnesium (6.6 ± 0.6 mg/dl) was documented. The authors do not state whether patients with premature rupture of membranes were included in their study population. They found a significant reduction in the total biophysical profile score because of an increased number of nonreactive NSTs and decreased fetal breathing movements in fetuses exposed to magnesium sulfate. Our study also identified fewer reactive NSTs at 2 hours after the loading dose (68%, 17/25) than with the initial biophysical profile (94%, 21/25). However, in our study this difference was not statistically significant. Moreover, the frequency of a reactive NST at 12 hours (80%, 20/25) was found to be very similar to the frequency of a reactive NST before the loading dose of magnesium sulfate (84%, 21/25). Peaceman et aU did not attempt to rule out intraamniotic infection by amniocentesis or neonatal examination. In fact, they excluded patients with any "significant abnormalities of the fetal heart tracing" from their study. Fetal infection has been implicated in the loss of fetal breathing movements, heart rate reactivity, and a decrease in the total biophysical score. ", " Inclusion of infected fetuses in the study of Peaceman et al. may have confounded the results and could explain differences in the biophysical profiles. An interesting finding in our study was the trend toward "reappearance" of a reactive NST when evaluated at 12 hours (80%, 20/25) compared with the reactivity at 12 hours (68%, 17/25) after the loading dose. This may represent fetal adaption to environmental changes. In the presence of significantly increased magnesium concentrations, the fetus may in time revert to a "normal" physiologic state. This has been shown to occur with fetal breathing movements in fetuses after preterm, premature rupture of membranes. 20This "adaptation" capability may exist in fetuses when they are exposed to different therapeutic agents (e. g., magnesium sulfate) for sufficient periods of time. It is also possible that the level of magnesium to which a fetus is exposed may affect the presence or absence of NST reactivity and breathing movements. The maternal serum levels reported at the time of the
April 1994 Am j Obstet Gynecol
0.6 6.6 biophysical t mg/dl profile were posttreatment 5.1 ±: 1.0 mg/dl (Carlan and (Peaceman et al .7), O'Brien') and 4.3 t 0.6 mg/dI (at 2 hours) and 5.2 t 0.7 mg/dI (at 12 hours) in our study. The "therapeutic" level required for tocolysis in our study patients was below or in the lower range of magnesium concentration proposed for seizure prevention (4.8 to 8.4 mg/dl)2 ' and below the serum level suggested by Elliott22 for inhibition of uterine contractions (5.5 to 7.5 mg/dl). Our inability to demonstrate a statistically significant difference in the biophysical profile score could be related to our lower mean magnesium concentrations. Maternal serum magnesium levels are known to correlate significantly with neonatal serum magnesium levels. ' In utero or amniotic fluid magnesium levels have been shown to be higher than maternal serum levels when magnesium sulfate is administered for an extended period of time .2' The effect of sustained magnesium levels on fetal biophysical activities over an extended period of time, such as 24 or 48 hours, has not been reported. This longer duration of therapy is usually recommended for tocolysis and should be addressed by future studies. REFERENCES 1. Petrie RH. Tocolysis using magnesium Perinatol 1981; 5: 266-73.
sulfate. Semin
2. Manning
FA, Platt LD, Sipos L. Anteparturn fetal development evaluation: of a fetal biophysical profile. Am j OBsTrr GYNECOL 1980; 136: 787-95.
3. Vintzileos AM, Tsapanos V. Biophysical assessment of the fetus. Ultrasound Obstet Gynecol 1992; 2: 133-43. 4. Manning FA, Morrison I, Unge CR, ChamIR, Harman berlain PF. Fetal assessment based on fetal biophysical high-risk in 12,620 referred profile scoring: experience 1. Perinatal mortality by frequency and etiolpregnancies. ogy. Am j OBsTE-r GYNECOL 1985; 151: 343-50.
5. Vintzileos AM, Campbell WA, Nochimson Dj, Connolly ME, Fuenfer MM, Hoehn Gj. The fetal biophysical profile in patients with premature rupture of the membranes -an early predictor of fetal infection. Am j OBsm GYNECOL 1985; 152: 510-6. 6. Carlan Sj, O'Brien WF. Ile effect of magnesium sulfate on the biophysical profile of normal term fetuses. Obstet Gynecol 1991; 77: 681-4. 7. Peaceman AM, Meyer BA, Thorp JA, Parisi VM, Creasy RK. The effect of magnesium sulfate tocolysis on the fetal biophysical profile. Am j OBs-ryr GYNECOL1989; 161: 771-4. 8. Petrikovsky BM, Vintzileos AM. Magnesium sulfate and intraparturn fetal behavior. Am j Perinatol 1990-,7: 154-6. 9. Canez MS, Reed KL, Shenker L. Effect of maternal magnesium sulfate treatment on fetal heart rate variability. Am ] Perinatol 1987; 4: 167-70. 10. Vintzileos AM, Campbell WA, Ingardia Cj, Nochimson Dj. Me fetal biophysical profile and its predictive value. Obstet Gynecol 1983; 62: 271-8. 11. Baskett ment.
IFF. Gestational age and fetal biophysical Am j OB= GYNECOL 1988; 158: 332-4.
assess-
12. Sassoon DA, Castro CL, Davis JL, Bear M, Hobel Cj'ne biophysical profile in labor. Obstet Gynecol 1990; 76: 360-5. 13. Gagnon R, Hunse C, Carmichael L, Fellows F, Patrick J. Effects of vibratory acoustic stimulation on human fetal breathing and gross fetal body movements near term. Am j Oasm GYNEcoi. 1986; 155: 1227-30.
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14. Patrick J, Campbell K, Carmichael L, Natale R, Richardson B. Patterns of human fetal breathing during the last 10 weeks of pregnancy. Obstet Gynecol 1980; 56: 24-30. 15. Pillai M, James D. Development of human fetal behavior: a review. Fetal Diagn Ther 1990; 5: 15-32.
16. Fox HE, Inglis J, Steinbrecher M. Fetal breathing move1. Relationship to ments in uncomplicated pregnancies. age. Am J OBSFET GYNECOL 1979; 134: 544-6. gestational
17. Vintzileos AM, Campbell WA, Nochimson Dj, Weinbaum Pj. Fetal breathing as a predictor of infection in premature rupture of the membranes. Obstet Gynecol 1986; 67: 813-7. RL, Glass C, Boehm detection of membranes: rupture premature Am J OBSFEF GYNECOL 199 1; 165: 1099-104.
18. Roussis
P, Rosemond
FH.
Preterm of infection.
S, et al. Fetal body and 19. Goldstein 1, Romero R, Merrill infecbreathing of intraamniotic movements as predictors Am j tion in preterm rupture of membranes. premature OBSTF. 'r GYNECOI. 1988; 159: 363-8. R, Hobbins J. Fetal 20. Roberts AB, Goldstein 1, Romero breathing rupture of movements after preterin premature Am j OBSTET GYNECOL 199 1; 164: 821-5. membranes.
21. Sibai BM, Lipshitz J, Anderson GD, Dilts PV. Reassessment of intravenous MgSO4 therapy in preeclampsiaeclampsia. Obstet Gynecol 1981; 57: 199-202. 22. Elliott JP. Magnesium sulfate as a tocolytic agent, Contemp Obstet Gynecol 1985; 25: 49-61. 23. Hankins GDV, Hammond TL, Yeomans ER. Amniotic cavity accumulation of magnesium with prolonged magnesium sulfate tocolysis. j Reprod Med 1991; 36: 446-9.
Elevated serum human chorionic gonadotropin as evidence in of secretory response severe preeclampsia Chaur-Dong Hsu, MD, MPH, ' Daniel W. Chan, PhD, ' Brian Iriye, MD, ' Timothy R. B. Johnson, MD, ' Shih-Fen Hong, MPH, * and John T. Repke, MD' Baltimore, Ma?yland OBJECTIVE: Because preeciampsia is a trophoblastic disorder and human chorionic gonadotropin is secreted from trophoblast, we sought to determine whether measurement of serum human chorionic gonadotropin might reflect a different trophoblastic secretory response of preeclampsia. STUDY DESIGN: Twenty patients with mild preeclampsia and 12 with severe preeclampsia were matched with 32 healthy normotensive women in the third trimester with singleton pregnancies. Serum total human chorionic gonadotropin and total human chorionic gonadotropin-0 were measured by a two-site immunoenzymometric assay, and total hCG-txwas determined by a double-antibody radioimmunoassay. Wilcoxon signed-rank and Mann-Whitney rank-sum tests were used for statistical analysis. RESULTS: Serum total human chorionic gonadotropin, total human chorionic gonadotropin-a, and total human chorionic gonadotropin-P levels were significantly higher in severely preeclamptic women (p < 0.05), but not in those with mild preeclampsia, compared with those in their matched controls. CONCLUSION: Elevated serum human chorionic gonadotropin levels in severely preeclamptic women might reflect a significantly pathologic change and secretory reaction of the placenta. (Am J OBSTET 1994; 170: 1135-8. ) GYNECOL
Key words: Human chorionic gonadotropin, preeclampsia, trophoblast Preeclampsia.is one of the most common and least understood disorders of pregnancy, affecting 5% to 7% of pregnancies. Associatedwith hypertension, proteinFrom the Division of Maternal-Fetal Medicine, Department of Gynecology and ObstetnCS'a and the Division of Chncial Chemistr% DePartment ofPatholoob Johns Hopkins University School ofMedicine. Receivedfor publication November 1,1993; acceptedNovember 1, 1993. Reprint requests: Chaur-Dong Hsu, MD, MPH, Department of Gynecologyand Obstetrics,Yale University, P. O. Box 208063, New Haven, CT 06520. Copyright C 1994 by Mosby--YearBook, Inc. 0002-9378194 $3.00 +0 611152565
uria, and edema, it is a disorder that has been studied extensively,and yet the causeremains largely unknown. Becausepreeclampsiais likely a trophoblastic disorder, ' investigating pathologic changesand secretory reaction of the placenta may be essentialfor understanding this disease. Human chorionic gonadotropin (hCG), a glycoprotein hormone, is produced by normal and neoplastic trophoblastic tissues.' Twin pregnancies' and molar hCG levels higher of and are pregnancies' produce higher incidence of preeclampsia than a with associated Serum bCG singleton pregnancies. are uncomplicated 1135
SECTION
Clinical
Articles
Effect of intravenous magnesium sulfate on the biophysical healthy fetus the preterm profile of Scott E. Gray, MD, John F. Rodis, MD, Luanna Lettieri, Anthony Vintzileos, MD
MD, James F. X. Egan, MD, and
Farmington, Connecticut OBJECTIVE: The null hypothesis is that intravenous magnesium sulfate does not affect the biophysical profile of the healthy preterm fetus. STUDY DESIGN: Thirty-one fetuses of 25 patients between the gestational ages of 24 and 35 weeks, median 31.4 and mean (_t SD) 30.4 (-t 2.9), who required tocolysis for uterine contractions were prospectively studied. After normal fetal biophysical assessment was documented, intravenous magnesium sulfate was started as a4 or 6 gm loading dose and then infused at 2 to 3.5 gm/hr to achieve tocolysis. Blood was drawn for measurement of maternal serum magnesium levels immediately before intravenous magnesium sulfate was administered and at 2 and 12 hours after the loading dose. Biophysical profiles, consisting of a possible 12 points, were performed at the same time as blood was drawn. Serum magnesium levels were compared with one-way analysis of variance for repeated measures and biophysical profile scores with Friedman's test. Statistical significance was considered p<0.05. RESULTS. Mean (.t: SD) serum magnesium levels were 1.7 (: tO. 1) mg/dl before infusion, 4.3 (: tO.6) mg/dl at 2 hours, and 5.2 (±0.7) mg/dl at 12 hours (p < 0.001). Six fetuses did not have a 12-hour biophysical profile; three were delivered for severe variable decelerations, two progressed in labor, and in one tocolysis was discontinued. The median biophysical profile score was 11 before intravenous magnesium sulfate, at 2 hours, and at 12 hours after the loading dose. The biophysical parameters present and the percentage of fetuses with each parameter were as follows: breathing (> 30 seconds), 88% (22/25) before magnesium sulfate, 84% (21/25) at 2 hours, and 92% (23/25) at 12 hours; nonstress test (reactive),84% (21/25) before magnesium sulfate, 68% (17/25) at 2 hours, and 80% (20/25) at 12 hours; movement (normal), 100% (25/25) before magnesium sulfate, 100% (25/25), at 2 hours, and 96% (24/25) at 12 hours; tone (normal), 100% (25/25) before magnesium sulfate, 100% (25/25) at 2 hours, and 96% (24/25) at 12 hours. Intravenous magnesium sulfate did not significantly after the biophysical profile in the 25 fetuses evaluated by three biophysical profiles in spite of the significant increase in maternal serum 1994; 170: 1131-5. ) magnesium levels. (Am J OesTETGYNECOL CONCLUSION:
Key words: Magnesium sulfate, biophysical profile, preterm fetus, tocolytic therapy Intravenous magnesium sulfate has been widely used as a tocolytic for more than two decades.' The biophysical profile has been used to assess fetal status in '' been has It shown that fetal evaluation with the utero. biophysical profile can predict neonatal outcome by detection of fetal or intrauterine environment deterioFrom the Division of Maternal-FetalMedicine,Departmentof ObUniversityof ConnecticutHealth Center. sletncsand Gynecology, ReceivedforpublicationMay 6,1993; revisedSeptember 15,1993; November1,199j. accepted Reprintsnot available. CopyrightC) 1994 b-vMosbv-YearBook,Inc. 0002-9378194$3.60 +6 611152765
intraveindicated have " Previous that studies ration. -5 ' breathing'fetal decreases nous magnesium sulfate and fetal heart rate reactivity," thereby significantly decreasing the total biophysical profile score b, ' Howfetuses, term these studies who of evaluated ever, most may respond differently to intravenous magnesium sulfate than do preterm fetuses." '- ' Becauseintravenous magnesium sulfate is frequently used to arrest preterm labor, it is essential to understand the effect of such therapy on the biophysical assessmentof the healthy preterm, fetus. The purpose of this prospective study was to determine the effect, if any, of magnesium sulfate on indi1131
April 1994 Am j Obstet Gyýiecol
1132 Grayetal.
vidual fetal biophysical profile components and the total biophysical score of the healthy preterm fetus during the first 12 hours of therapy. Our null hypothesis was that intravenous magnesium sulfate administered for tocolysisdoes not affect the biophysical profile of the healthy preterm fetus. Material and methods This was a prospective study of 31 fetuses of 25 patients who were between 24 and 35 weeks' gestation admitted to the University of Connecticut Health Center, Farmington, from ]an. I through Aug. 1,1992. All patients required tocolysisfor preterm labor, which was defined as uterine contractions associatedwith documented cervical change or persistent uterine contractions (three or more contractions in a 10-minute interval) for at least 30 minutes after adequatehydration. An ultrasonographic examination for biometry, calculation of estimated fetal weight, and identification of fetal anomalieswas performed in all caseson admissionwith a 3.5 MHz transducer (General Electric RT 2600, Milwaukee). Fetuseswith growth abnormalities or anomalies were excluded. Gestational age was calculated on the basisof a second-trimesterultrasonographic examination, which agreed with the last menstrual period ± 10 days. Biophysical profile scoring, consisting of a maximum of 12 points, was performed as described by Vintzileos et al. " Fetuseswere included if their initial biophysical profile score was 2-8 (including a reactive nonstress test [NSTJ or fetal breathing movements), indicating a healthy fetus. The fetal heart rate tracing for 30 minutes before each biophysical profile wasused to determine fetal heart pte reactivity (AdvancedMedical Systems,IM76, Hamden, Conn.). Zero, one, or two points were assignedfor the NST, fetal movement, fetal tone, fetal breathing movements,amniotic fluid volume, and placental grading. A biophysical profile was performed before and at 2 and 12 hours after the loading dose was administered. No tocolytics or medications were received by any patient for at least I hour before the initial biophysical profile. No narcotic or other analgesic medication was administered to any patient before or during the study period. Intravenous magnesium sulfate was administered as a4 or 6 gm loading dose over 20 to 30 minutes. A magnesium sulfate solution (20 gm in IL 5% dextrose in water) was infused as maintenance at 2 to 3.5 grn/hr to achieve tocolysis. The patient's intravenous mainline fluid was 5% dextrose in Ringer's lactate solution. No other medications for tocolysisor sedation were administered during the study. All patients were on continuous bed rest in a lateral recumbent position with external monitoring of fetal heart rate and uterine contractions throughout the study. A complete blood cell count, serum magnesium level, serum glucose, urinalysis,
urine toxicology screen, and cervical and vaginal culloading before the patients tures were obtained on all dose was administered. Serum magnesium levels were biophysical 212-hour drawn profiles. the and with also The presence of intraamniotic infection was evaluated by transabdominal amniocentesis, maternal laboratory studies, cervical examination with cultures, neonatal examination, and postpartum placental pathologic examination. An amniocentesis was performed on patients with premature rupture of membranes when intact labor in with preterm and on all patients possible fluid The sample was evaluated amniotic membranes. by Gram stain, culture, and glucose concentration. When the gestational age was > 32 weeks, pulmonary maturity studies were also performed on the amniotic fluid. Twenty-four patients received betamethasone, 12 mg, intramuscularly after the magnesium sulfate loading dose. Serum magnesium levelswere compared with one-wayanalysisof variance for repeated measures,and the biophysical profile scores were compared with Friedman's test. Statistical significance was considered at P values < 0.05. Assuming aP error of 0.20, a power calculation estimated that evaluation of 21 fetusescould detect a statistically significant difference in the NST or breathing components. The power calculation was based on results of a comparable study." Results Twenty-five fetuses (15 singletons and 10 twins) of the original 31 fetuses received all three biophysical profiles (before the magnesium sulfate loading dose and 2 and 12 hours after the loading dose). Six singleton fetuses did not receive the 12-hour biophysical profile. Three of these six fetuses were delivered because of persistent severe variable decelerations caused by cord compression and oligohydramnios after premature rupture of the membranes. Two were delivered because of labor progression, and in one tocolysis was discontinued after 10 hours. Regular and frequent (more than two in 30 minutes) uterine contractions had stopped in all patients before the 12-hour biophysical profile. The admitting diagnoses for the 20 patients (25 fetuses) who had all three biophysical profile examinations were preterm premature rupture of membranes (six with singletons and three with twins), premature labor with intact membranes (six with singletons and two with twins), and placenta previa with bleeding (three with singletons). The mean (: t SD) maternal age was 26.6 (: t6.3) years (range 16 to 39). On admission the median gestational age was 31.4 weeks and the mean (±SD) gestational age was 30.4 (±2.9) weeks (range 24 to 34.3). Mean (±SD) admission serum glucose value was 96.5 (±21.4) mg/dl (range 65 to 164). The mean (±SD) serum magnesium levels were
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Table 1. Percentageof fetuseswith biophysical parameter present Biophysical parameter Breathing (> 30 sec) (%) Reactive NST (%)* Movement (%)t Tone (%)+'
Before magnesium sulfate
2 hr
12 hr
88 (22/25)
84 (21/25)
92 (23/25)
84 (21/25) 100 (25/25) 100 (25/25)
68 (17/25) 100 (25/25) 100 (25/25)
80 (20/25) 96 (24/25) 96 (24/25)
*Two or more accelerationsof a 15 beats/min in amplitude and ýt 15 seconds'duration in a 30-minute period. tAt least three gross (trunk and limbs) episodesof fetal movementswithin 30 minutes. TAt least one episode of extension of extremities with return to position of flexion and one episode of extension of spine with return to position of flexion.
1.7 (.tO. I) mg/dI before the loading dose, 4.3 (±0.6) mg/dI at 2 hours, and 5.2 (.± 0.7) mg/dl at 12 hours. The difference between serum magnesium levels was statistically significant, p<0.001. The median biophysical profile score was II before the intravenous magnesium sulfate loading dose and at 2 hours and 12 hours after the loading dose.There was in for difference the points assigned amniotic fluid no between the three biophysical prograde placental or files for any fetus. The mean and median score was 2 fetal breathing for movements, tone, and movepoints ment for each. For NST the mean scoreswere 2,1.8, and 2, whereas the median scoreswere 1,1, and 2 for the three biophysical profiles. The difference in the fetuses with a nonreactive NST was not of number statistically significant between the three biophysical profiles (Friedman's Xr20.54). The exact percentage of fetuses with breathing movements, reactive NSTs, movement, and tone at each biophysical profile is presented in Table 1. Ten patients (12 fetuses) were discharged undelivered. These 12 fetuseswere all normal neonates delivered between 35 and 41 weeks' gestation at outlying hospitals. Of the 13 fetuses delivered at our hospital one was acidemic at birth, with an arterial cord blood 7.19. This fetus was delivered 24 hours after of PH admission and had an uncomplicated neonatal course. Three other fetuses in this delivered group had low 5-minute Apgar scores becauseof Prematurity. These three fetuseswere delivered > 48 hours after admission. None of the 13 neonates delivered at our hospital were septic on evaluation in the neonatal intensive care unit. No evidence of infection or significant findings were identified in the 13 placentas available for pathologic diagnosis.There were no maternal complications attributed to magnesium sulfate.
Comment Any attempt to monitor in utero fetal activities is complicated by the dynamic interaction of maternal and fetal physiologic states. Factors affecting fetal bio-
physical activities include normal periodicity, infection, drugs, gestational age, hypoxia, acidemia, labor, fetal malformation, sound, and maternal glucose level. `" "" Our study concluded that the administration of intravenous magnesium sulfate for tocolysis did not significantly affect the individual components of the fetal biophysical profile or the total score in healthy preterm fetuses. Previous studies have described different conclusions in regard to fetal breathing movements, NST reactivity, and the total biophysical score. Carlan and O'Brien' used the biophysical profile to evaluate normal term (>37 weeks) fetuses. In their for fasting sulfate magnesium mothers study received contraction prophylaxis before external cephalic version. Patients received a4 to 6 gm loading dose of magnesium sulfate and a continuous infusion of magnesium sulfate at 2 to 4 gm/hr for I to 2 hours. The initial biophysical profile was performed immediately before the loading dose of magnesium sulfate, and the 2 I biophysical to at performed profile was second hours after the loading dose. A serum magnesium level was drawn as the second biophysical profile was started. The external cephalic version was then attempted. They found a statistically significant decrease in the biophysical profile score after magnesium sulfate adbreathing in fetal decrease "due activto a ministration ity. " They concluded that "loss of any component (of the biophysical profile) other than respiration cannot be attributed to magnesium. " Our study identified no in breathing fetal difference in movements significant the preloading and postloading dose biophysical profiles. It is not clear whether this difference in breathing be attributed to the gestational age can movements difference between the two study groups. Other studies have found a normal decrease in the incidence of fetal breathing movements in later gestation, especially after Fox et al. " found the amount of time the 36 weeks. `" fetus spent making breathing movements increased decrease A in fetal increasing gestational age. with breathing movements also has been shown in the pres" 12 labor. infection"We believe, on and with ence of
1134 Grayetal.
the basis of the results of our study, that the preterm fetus exposed to intravenous magnesium sulfate therapy for tocolysis must be evaluated carefully before attributing the loss of breathing movements or an abnormal biophysical assessment to any pharmacologic effect of magnesium. Peaceman et al. "' studied 16 patients (22 fetuses) in preterm labor who received magnesium sulfate for tocolysis as an intravenous loading dose of 4 to 6 gm and a continuous infusion at 1.5 to 3.5 gm/hr. Fetuses underwent an initial biophysical profile before the loading dose. A second biophysical profile was performed (at 14.1 t 5.4 hours) once a "therapeutic" serum level of magnesium (6.6 ± 0.6 mg/dl) was documented. The authors do not state whether patients with premature rupture of membranes were included in their study population. They found a significant reduction in the total biophysical profile score because of an increased number of nonreactive NSTs and decreased fetal breathing movements in fetuses exposed to magnesium sulfate. Our study also identified fewer reactive NSTs at 2 hours after the loading dose (68%, 17/25) than with the initial biophysical profile (94%, 21/25). However, in our study this difference was not statistically significant. Moreover, the frequency of a reactive NST at 12 hours (80%, 20/25) was found to be very similar to the frequency of a reactive NST before the loading dose of magnesium sulfate (84%, 21/25). Peaceman et aU did not attempt to rule out intraamniotic infection by amniocentesis or neonatal examination. In fact, they excluded patients with any "significant abnormalities of the fetal heart tracing" from their study. Fetal infection has been implicated in the loss of fetal breathing movements, heart rate reactivity, and a decrease in the total biophysical score. ", " Inclusion of infected fetuses in the study of Peaceman et al. may have confounded the results and could explain differences in the biophysical profiles. An interesting finding in our study was the trend toward "reappearance" of a reactive NST when evaluated at 12 hours (80%, 20/25) compared with the reactivity at 12 hours (68%, 17/25) after the loading dose. This may represent fetal adaption to environmental changes. In the presence of significantly increased magnesium concentrations, the fetus may in time revert to a "normal" physiologic state. This has been shown to occur with fetal breathing movements in fetuses after preterm, premature rupture of membranes. 20This "adaptation" capability may exist in fetuses when they are exposed to different therapeutic agents (e. g., magnesium sulfate) for sufficient periods of time. It is also possible that the level of magnesium to which a fetus is exposed may affect the presence or absence of NST reactivity and breathing movements. The maternal serum levels reported at the time of the
April 1994 Am j Obstet Gynecol
0.6 6.6 biophysical t mg/dl profile were posttreatment 5.1 ±: 1.0 mg/dl (Carlan and (Peaceman et al .7), O'Brien') and 4.3 t 0.6 mg/dI (at 2 hours) and 5.2 t 0.7 mg/dI (at 12 hours) in our study. The "therapeutic" level required for tocolysis in our study patients was below or in the lower range of magnesium concentration proposed for seizure prevention (4.8 to 8.4 mg/dl)2 ' and below the serum level suggested by Elliott22 for inhibition of uterine contractions (5.5 to 7.5 mg/dl). Our inability to demonstrate a statistically significant difference in the biophysical profile score could be related to our lower mean magnesium concentrations. Maternal serum magnesium levels are known to correlate significantly with neonatal serum magnesium levels. ' In utero or amniotic fluid magnesium levels have been shown to be higher than maternal serum levels when magnesium sulfate is administered for an extended period of time .2' The effect of sustained magnesium levels on fetal biophysical activities over an extended period of time, such as 24 or 48 hours, has not been reported. This longer duration of therapy is usually recommended for tocolysis and should be addressed by future studies. REFERENCES 1. Petrie RH. Tocolysis using magnesium Perinatol 1981; 5: 266-73.
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2. Manning
FA, Platt LD, Sipos L. Anteparturn fetal development evaluation: of a fetal biophysical profile. Am j OBsTrr GYNECOL 1980; 136: 787-95.
3. Vintzileos AM, Tsapanos V. Biophysical assessment of the fetus. Ultrasound Obstet Gynecol 1992; 2: 133-43. 4. Manning FA, Morrison I, Unge CR, ChamIR, Harman berlain PF. Fetal assessment based on fetal biophysical high-risk in 12,620 referred profile scoring: experience 1. Perinatal mortality by frequency and etiolpregnancies. ogy. Am j OBsTE-r GYNECOL 1985; 151: 343-50.
5. Vintzileos AM, Campbell WA, Nochimson Dj, Connolly ME, Fuenfer MM, Hoehn Gj. The fetal biophysical profile in patients with premature rupture of the membranes -an early predictor of fetal infection. Am j OBsm GYNECOL 1985; 152: 510-6. 6. Carlan Sj, O'Brien WF. Ile effect of magnesium sulfate on the biophysical profile of normal term fetuses. Obstet Gynecol 1991; 77: 681-4. 7. Peaceman AM, Meyer BA, Thorp JA, Parisi VM, Creasy RK. The effect of magnesium sulfate tocolysis on the fetal biophysical profile. Am j OBs-ryr GYNECOL1989; 161: 771-4. 8. Petrikovsky BM, Vintzileos AM. Magnesium sulfate and intraparturn fetal behavior. Am j Perinatol 1990-,7: 154-6. 9. Canez MS, Reed KL, Shenker L. Effect of maternal magnesium sulfate treatment on fetal heart rate variability. Am ] Perinatol 1987; 4: 167-70. 10. Vintzileos AM, Campbell WA, Ingardia Cj, Nochimson Dj. Me fetal biophysical profile and its predictive value. Obstet Gynecol 1983; 62: 271-8. 11. Baskett ment.
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12. Sassoon DA, Castro CL, Davis JL, Bear M, Hobel Cj'ne biophysical profile in labor. Obstet Gynecol 1990; 76: 360-5. 13. Gagnon R, Hunse C, Carmichael L, Fellows F, Patrick J. Effects of vibratory acoustic stimulation on human fetal breathing and gross fetal body movements near term. Am j Oasm GYNEcoi. 1986; 155: 1227-30.
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14. Patrick J, Campbell K, Carmichael L, Natale R, Richardson B. Patterns of human fetal breathing during the last 10 weeks of pregnancy. Obstet Gynecol 1980; 56: 24-30. 15. Pillai M, James D. Development of human fetal behavior: a review. Fetal Diagn Ther 1990; 5: 15-32.
16. Fox HE, Inglis J, Steinbrecher M. Fetal breathing move1. Relationship to ments in uncomplicated pregnancies. age. Am J OBSFET GYNECOL 1979; 134: 544-6. gestational
17. Vintzileos AM, Campbell WA, Nochimson Dj, Weinbaum Pj. Fetal breathing as a predictor of infection in premature rupture of the membranes. Obstet Gynecol 1986; 67: 813-7. RL, Glass C, Boehm detection of membranes: rupture premature Am J OBSFEF GYNECOL 199 1; 165: 1099-104.
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S, et al. Fetal body and 19. Goldstein 1, Romero R, Merrill infecbreathing of intraamniotic movements as predictors Am j tion in preterm rupture of membranes. premature OBSTF. 'r GYNECOI. 1988; 159: 363-8. R, Hobbins J. Fetal 20. Roberts AB, Goldstein 1, Romero breathing rupture of movements after preterin premature Am j OBSTET GYNECOL 199 1; 164: 821-5. membranes.
21. Sibai BM, Lipshitz J, Anderson GD, Dilts PV. Reassessment of intravenous MgSO4 therapy in preeclampsiaeclampsia. Obstet Gynecol 1981; 57: 199-202. 22. Elliott JP. Magnesium sulfate as a tocolytic agent, Contemp Obstet Gynecol 1985; 25: 49-61. 23. Hankins GDV, Hammond TL, Yeomans ER. Amniotic cavity accumulation of magnesium with prolonged magnesium sulfate tocolysis. j Reprod Med 1991; 36: 446-9.
Elevated serum human chorionic gonadotropin as evidence in of secretory response severe preeclampsia Chaur-Dong Hsu, MD, MPH, ' Daniel W. Chan, PhD, ' Brian Iriye, MD, ' Timothy R. B. Johnson, MD, ' Shih-Fen Hong, MPH, * and John T. Repke, MD' Baltimore, Ma?yland OBJECTIVE: Because preeciampsia is a trophoblastic disorder and human chorionic gonadotropin is secreted from trophoblast, we sought to determine whether measurement of serum human chorionic gonadotropin might reflect a different trophoblastic secretory response of preeclampsia. STUDY DESIGN: Twenty patients with mild preeclampsia and 12 with severe preeclampsia were matched with 32 healthy normotensive women in the third trimester with singleton pregnancies. Serum total human chorionic gonadotropin and total human chorionic gonadotropin-0 were measured by a two-site immunoenzymometric assay, and total hCG-txwas determined by a double-antibody radioimmunoassay. Wilcoxon signed-rank and Mann-Whitney rank-sum tests were used for statistical analysis. RESULTS: Serum total human chorionic gonadotropin, total human chorionic gonadotropin-a, and total human chorionic gonadotropin-P levels were significantly higher in severely preeclamptic women (p < 0.05), but not in those with mild preeclampsia, compared with those in their matched controls. CONCLUSION: Elevated serum human chorionic gonadotropin levels in severely preeclamptic women might reflect a significantly pathologic change and secretory reaction of the placenta. (Am J OBSTET 1994; 170: 1135-8. ) GYNECOL
Key words: Human chorionic gonadotropin, preeclampsia, trophoblast Preeclampsia.is one of the most common and least understood disorders of pregnancy, affecting 5% to 7% of pregnancies. Associatedwith hypertension, proteinFrom the Division of Maternal-Fetal Medicine, Department of Gynecology and ObstetnCS'a and the Division of Chncial Chemistr% DePartment ofPatholoob Johns Hopkins University School ofMedicine. Receivedfor publication November 1,1993; acceptedNovember 1, 1993. Reprint requests: Chaur-Dong Hsu, MD, MPH, Department of Gynecologyand Obstetrics,Yale University, P. O. Box 208063, New Haven, CT 06520. Copyright C 1994 by Mosby--YearBook, Inc. 0002-9378194 $3.00 +0 611152565
uria, and edema, it is a disorder that has been studied extensively,and yet the causeremains largely unknown. Becausepreeclampsiais likely a trophoblastic disorder, ' investigating pathologic changesand secretory reaction of the placenta may be essentialfor understanding this disease. Human chorionic gonadotropin (hCG), a glycoprotein hormone, is produced by normal and neoplastic trophoblastic tissues.' Twin pregnancies' and molar hCG levels higher of and are pregnancies' produce higher incidence of preeclampsia than a with associated Serum bCG singleton pregnancies. are uncomplicated 1135