- Email: [email protected]
A randomized prospective comparison of nifedipine and bedrest versus bed rest alone in the management of preeclampsia remote from term
Volume 167 Number 4, Part 1
Neonatal intraventricular hemorrhage after maternal !3-sympathomimetic tocolysis
RC. Effects of terbutaline sulfate on fetal cardiac function. A~J OBSTET GYNECOL 1989;161:509-12. 21. Papile L-A, Rudolph AM, Heymann MA. Autoregulation of cerebral blood flow in the preterm fetal Iamb. Pediatr Res 1985; 19: 159-61. 22. Tweed WA, Cote J, Pash M, Lou H. Arterial oxygenation determines autoregulation of cerebral blood flow in the fetal Iamb. Pediatr Res 1983; 17:246-9. 23. Pasternak JF, Groothius DR. Autoregulation of cerebral
blood flow in the newborn beagle puppy. Bioi Neonate 1985;48: 100-9. 24. PasternakJF, Groothius DR, Fischer JM, Fischer DP. Regional cerebral blood flow in the beagle model of neonatal ventricular hemorrhage: studies during systemic hypertension. Neurology 1983;33:559-66. 25. van de Bor M, Walther FJ. Cerebral blood velocity regulation in preterm infants. Bioi Neonate 1991;59:329-35.
A randomized prospective comparison of nifedipine and bed rest versus bed rest alone in the management of preeclampsia remote from term Baha M. Sibai, MD, John R. Barton, MD, Sherif Ald, MD, Cern Sarinoglu, MD, and Brian M. Mercer, MD Memphis, Tennessee OBJECTIVE: The objective of our study was to test the hypothesis that treatment with nifedipine for mild preeclampsia remote from term reduces the number of days of maternal hospitalization and improves pregnancy outcome. STUDY DESIGN: A total of 200 patients at 26 to 36 weeks' gestation were randomly allocated to treatment with either bed rest alone (n = 100) or bed rest in combination with nifedipine (n = 100). RESULTS: Patients receiving nifedipine had significantly lower systolic (p < 0.0001) and diastolic (p < 0.0001) blood pressures during therapy. Severe hypertension as an indication for delivery was significantly (p < 0.05) more frequent in the bed-rest-alone group. The two study groups had similar average days of maternal hospitalization (12.6 ± 7.9 vs 12.3 ± 10.3) and pregnancy prolongation (22.3 ± 13.5 vs 22.5 ± 15.7). There were no differences between groups with respect to birth weight, incidences of small-for-gestational-age infants and preterm birth, number of days spent in special care unit, or cord blood gas measurement. CONCLUSION: Nifedipine therapy for preeclampsia reduces maternal blood pressure but does not reduce number of days of maternal hospitalization or improve perinatal outcome. (AM J OBSTET GYNECOL 1992;167:879-84.)
Key words: Mild preeclampsia, nifedipine, bed rest, pregnancy outcome The optimal management of patients with mild preeclampsia remote from term «36 weeks' gestation) is controversial. Indeed, there is disagreement regarding the need for hospitalization versus ambulatory management with bed rest at home and the potential benefits of using antihypertensive drugs.! Some authors'" have suggested that management in these cases should From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee, Memphis. Presented at the Twelfth Annual Meeting of the Society of Perinatal Obstetricians, Orlando, Florida, February 3-8, 1992. Reprint requests: Baha M. Sibai, MD, 853 jefferson Ave., Memphis, TN 38103. 6/6/39686
involve bed rest in the hospital for the duration of pregnancy. These authors reported that early and prolonged hospitalization for such patients improved perinatal outcome, reduced maternal morbidity, and was cost-effective." 3 In addition, one study found that treatment of blood pressure with labetalol in patients with mild preeclampsia was associated with a high frequency of fetal growth retardation.' In contrast, other authors" 5 believe that management can be safely carried out for some of these patients on an ambulatory basis with bed rest at home, while others recommend that patients with mild preeclampsia should be treated with antihypertensive drugs. 6 . 7 These latter authors reported that this management reduced the number of
879
880
Sibai et al.
October 1992 Am J Obstet Gynecol
Table I. Clinical findings at randomization
Table II. Laboratory findings at
(mean ± SD)
randomization (mean ± SD) No therapy* (n = 100)
Maternal age (yr) Gestational age (wk) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)
No therapy* (n = 100)
Nifedipine* (n = 100)
20.3 ± 4.0
20.5 ± 4.2
33.4 ± 2.7
32.8 ± 2.8
143.5 ± 5.8
143.8 ± 5.6
94.2 ± 4.4
93.9 ± 4.1
*No significant difference for any categories studied.
days of antepartum maternal hospitalization and improved perinatal outcome. Nifedipine, a calcium channel blocker, is a potent oral antihypertensive agent. Several investigatorss. 11 have used nifedipine as a second-line antihypertensive drug in the management of cases of severe preeclampsia. In addition, some authors have found nifedipine to be superior to hydralazine for control of severe maternal hypertension during pregnancy or post partum. 1~~14 Control of maternal blood pressure with nifedipine was reportedly associated with improved maternal and perinatal outcome. The use of this drug led to significant prolongation of pregnancy, lower incidence of fetal distress, improved maternal platelet count, and improved renal outpUt.8~14 Studies have also shown that in women with mild preeclampsia the administration of nifedipine lowers maternal blood pressure without affecting the resistance indexes in fetal or uteroplacental vessels. 15~17 In spite of these favorable results there are no prospective randomized studies comparing nifedipine to no therapy in the management of patients with mild preeclampsia before 37 weeks' gestation. The aim of the prospective study was to test the hypothesis that treatment of maternal blood pressure with nifedipine in patients with mild preeclampsia remote from term reduces antepartum maternal hospital stay, prolongs gestation, and improves perinatal outcome. Material and methods
The study population included 200 primigravid women with mild preeclampsia at 26 to 36 weeks' gestation. All had persistent elevations of blood pressure (systolic between 140 and 160 mm Hg and/or diastolic between 90 and 110 mm Hg) 24 hours after hospitalization. All had proteinuria (>300 mg per 24 hours) and/or elevated uric acid levels (2:6 mg/dl) at the time of entry to the study. Patients with associated medical and obstetric complications (other than preeclampsia) were excluded. In addition, patients with fetal compromise (suspected abnormal fetal growth by ultraso-
Platelets (x 10'1 mm') Creatinine (mg/dl) Uric acid (mg/dl) Creatinine clearance (mil min) Proteinuria (mg/24 hr)
254 0.81 6.1 109
± 53
± 0.16
± 0.9
± 29
639 ± 636
Nifedipine* (n = 100)
248 0.80 6.1 114
± 72 ± 0.19
± l.l ± 34
683 ± 795
*No significant difference for any categories studied.
nography and/or abnormal fetal testing) were excluded. After signing the consent form (previously approved by the investigation review board of this institution) patients were allocated randomly to one of two groups, on the basis of a computer-generated list of random numbers. The physician was asked to draw a sealed envelope containing the method of assignment for each patient. Patients in one group were managed with bed rest alone, whereas the other group received nifedipine, starting at 40 mg/day, that was then increased every 2 to 3 days as needed to a maximum of 120 mg/day, to keep systolic pressure below 140 mm Hg and diastolic pressure below 90 mm Hg. Laboratory evaluation included serial determinations of hematocrit, platelet count, liver function tests, uric acid, creatinine clearance, and 24-hour urinary protein excretion. Fetal evaluation included serial ultrasonography for fetal growth, nonstress test, and/ or biophysical profile at least twice a week and cord blood gas measurements. During the initial hospitalization, clinical management included measurement of blood pressure four times daily, urine by dipstick twice daily, and maternal weight every other day. Patients were given a regular hospital diet, and no other medications were used except for prenatal vitamins and iron supplements. In addition, patients were instructed to report the development of persistent headaches, visual disturbances, epigastric and/or right upper-quadrant pain, uterine contractions, or vaginal bleeding. All blood pressure recordings were performed by two experienced nurses who were assigned to the antepartum ward where the patients were hospitalized. Blood pressures were recorded with the patient in a semirecumbent position with the cuff positioned at heart level. The results of all blood pressure measurements were pooled, and an average was calculated for each patient. Reliable patients with stable maternal and fetal conditions who did not have proteinuria (protein <300 mg per 24 hours) and had average blood pressures persistently < 140 mm Hg systolic and <90 mm Hg diastolic
Nifedipine vs no therapy in preeclampsia 881
Volume 167 Number 4, Part 1
then managed on an ambulatory basis. These patients were instructed to have relative bed rest at home, and then they were evaluated in the antepartum testing area for maternal and fetal well-being at least twice a week. During ambulatory management the patient was hospitalized again if there was any evidence of disease progression and/ or if acute hypertension or significant proteinuria developed. All clinical decisions regarding management and timing of delivery were left to the attending faculty and house staff. No efforts were made to arrest spontaneous onset of labor before the thirtyseventh week. Analysis of data included comparisons of maternal blood pressure, laboratory findings, days of antepartum maternal hospitalization, days gained during management, and perinatal outcome. Perinatal outcome included gestational age at delivery, birth weight, placental weight, cord blood gas measurements, incidence of preterm birth, and incidence of small-for-gestationalage (SGA) infants. Gestational age was determined on the basis of obstetric criteria including early examinations and ultrasonography before 24 weeks' gestation. The diagnosis of SGA was made if the birth weight was below the 10th percentile according to the growth curves of Brenner et al. l " Results were expressed as mean ± SD. Statistical analysis used Student's t test, X2, and Fisher's exact test when applicable. Serial changes in blood pressures and laboratory values between the groups and within each treatment group were examined by analysis of variance for repeated measurements. A value of p < 0.05 was considered significant. Results
The study groups were very similar at the time of randomization with respect to various clinical findings (Table I) and laboratory findings (Table II). Eighty-five patients (85%) in the no-therapy group had proteinuria >300 mg per 24 hours (range 304 to 3600 mg), and the remaining 15 patients had proteinuria of <300 mg per 24 hours (range 96 to 299 mg). On the other hand, eighty-three patients (83%) in the nifedipine group had proteinuria >300 mg per 24 hours (range 302 to 3700 mg), and the remaining 17 patients had proteinuria of <300 mg per 24 hours (range 64 to 287 mg). All patients who had proteinuria <300 mg per 24 hours at the time of randomization had proteinuria of at least 2 + on dipstick on two occasions 6 hours apart. Three patients were lost to follow-up after randomization (one in the no-therapy group and two in the nifedipine group) and therefore were not included in the follow-up analyses. Two patients in the no-therapy group and three in the nifedipine group were noncompliant with the study protocol. Nonetheless, all were included in the blood pressure analyses up to the time
-
160
-
130
C)
::I:
E E
C. £Xl
en
(,) .-
0
tn
>-
o •
Notherapy Nifedipine
150 140
120 110
-
C)
::I:
E E
-
C. £Xl
-
(,) .-
o
tn
as .C
Fig. 1. Blood pressure (mean ± SD) in patients with no therapy (white bars) or treated with nifedipine (black bars). Asterisk, p < 0.0001 for systolic and diastolic blood pressures. In addition, within nifedipine group p < 0.0001 for systolic and diastolic pressures by analysis of variance for repeated measurements.
they became noncompliant, and all were included in the outcome data. Thus a total of 99 women in the notherapy group and 98 in the nifedipine group were included in the final analyses. Fig. 1 compares the systolic and diastolic blood pressures at time of entry and during treatment between the two groups. There were no differences in blood pressure at entry. However, during treatment, the nifedipine group had significantly lower average systolic blood pressure «p < 0.0001), and diastolic blood pressure (p < 0.0001). In addition, the nifedipine group demonstrated a significant drop in blood pressure during treatment (p < 0.0001), whereas the no-therapy group exhibited no change. Table III compares the mean laboratory tests at delivery between the two groups. There were no signifi-
882
Sibai et al.
October 1992 Am J Obstet Gyneco1
Table III. Indications for delivery
Term gestation Severe hypertension Pre term labor or rupture of membranes Suspected SGA Abnormal FHR testing Low platelets or HELLP syndrome Other
Table V. Pregnancy outcome
No therapy (n = 99)
Nifedipine (n = 98)
54 18* 13
50 9* 12
4 5 3
8 8 5
2
5
No therapy*
Antepartum hospitalization (days) Pregnancy prolongation (days) Cesarean section (No. and %) Abruptio placentae (No. and %) HELLP syndrome (No. and %)
Nifedipine*
12.6 ± 7.9
12.3 ± 10.3
22.3 ± 13.5
22.5 ± 15.7
35 (35%)
42 (43%)
2 (2%)
3 (3%)
2 (2%)
4 (4%)
FHR, Fetal heart rate; HELLP, hemolysis, elevated liver enzymes, and low platelets. *p < 0.05.
HELLP, Hemolysis, elevated liver enzymes, and low platelets. *No significant difference for any categories studied.
Table IV. Laboratory findings at delivery
pine group received such management. The number of days of antepartum maternal hospitalization ranged from 3 to 48 in the no-therapy group, and it ranged from 3 to 63 in the nifedipine group. However, the average number of days was similar between the two groups. In addition, there were no differences between the groups with respect to pregnancy prolongation, incidence of cesarean section, or incidence of abruptio placentae. Pregnancy outcome was subsequently analyzed after exclusion of patients in both groups who had proteinuria of <300 mg per 24 hours at the time of randomization. The mean number of days of antepartum hospitalization and the number of days of pregnancy prolongation were similar in both groups. There were 101 births (two twins) in the no-therapy group and 99 births (one set of twins) in the nifedipine group. No fetal or neonatal deaths occurred in either group. There were no differences between the groups in average placental weight (605 ± 176 gm for no therapy vs 588 ± 183 gm for nifedipine). Table VI summarizes the neonatal outcome in the two study groups. There were no differences with respect to gestational age at delivery, birth weight, or number of days spent in the special care nursery. In addition, the two groups had similar frequencies of preterm infants and infants considered to be SGA. Table VII compares the neonatal cord blood values in the two groups. There were no differences with respect to any of the measurements studied. In addition, the two groups had similar frequencies of cord pH values <7.20.
(mean ± SD) No therapy*
Platelets (x 103 I mm') Creatinine (mg/dl) Uric acid (mg/dl) Creatinine clearance (mil min) Proteinuria >5 gm/24 hr
250 0.86 6.2 104
±
66
±
28
± 0.16 ± 1.3
10
Nifedipine*
232 ± 82 0.87 ± 0.21 6.3 ± 1.5 110 ± 39 16
*No significant difference for any categories studied.
cant differences between the two groups with respect to either platelet count or renal function tests. During treatment, 10 patients (10%) in the no-therapy group demonstrated nephrotic range proteinuria (>5 gm per 24 hours) as compared with 16 (16%) in the nifedipine group having such a finding. This difference was not statistically significant. Table IV compares the indications for delivery in the two groups. Severe hypertension as an indication was significantly more frequent (p < 0.05) in the no-therapy group. On the other hand, fetal compromise (suspected SGA and/ or abnormal testing) as an indication was more frequent in the nifedipine group (16% vs 9%, P < 0.09, odds ratio 2: 1). Interestingly, 12 patients (12%) in the nifedipine group were delivered preterm «37 weeks' gestation) after the onset of spontaneous labor and/or rupture of membranes while receiving nifedipine at 100 to 120 mg per day. Two patients in the no-therapy group were delivered because of cerebral manifestations (headaches, visual symptoms), whereas three patients in the nifedipine group were delivered because of severe ascites and two because of severe epigastric pain. Table V compares the pregnancy outcomes in the two groups. Thirty-eight patients in the no-therapy group received ambulatory management after the initial hospitalization, whereas 45 patients in the nifedi-
Comment
This study is the largest and first prospective, randomized trial comparing no therapy to the use of nifedipine in the management of mild preeclampsia remote from term. All patients studied were youn~ and primigravid with documented evidence of "pure" preeclampsia (persistent hypertension on bed rest with
Nifedipine vs no therapy in preeclampsia 883
Volume 167 Number 4, Part 1
substantial proteinuria). In addition, no other antihypertensive medications were used in either study group. In contrast, almost all previous studies describing the use of nifedipine to treat hypertension in pregnancy have included patients with various parities and various forms of hypertension (with and without proteinuria).81" In addition, nifedipine was used in association with other antihypertensive drugs S- ll or it was compared with hydralazine. '211 We found that nifedipine was effective in reducing maternal systolic and diastolic blood pressures in women with mild preeclampsia. However, this reduction in maternal blood pressure was not associated with a reduced number of antepartum hospital days in the nifedipine group. In addition, the use of nifedipine led to a lower incidence of delivery for severe hypertension (9%) as compared with the no-therapy group (18%). However, such reduction in incidence of severe hypertension in the nifedipine group was not associated with a concomitant improved pregnancy prolongation when compared with the no-therapy group. This was due to the fact that a larger percentage of patients in the nifedipine group (16%) were delivered for fetal reasons (abnormal antepartum testing and fetal growth retardation), as compared with the no-therapy group (9%). Consequently, the two groups had similar gestational ages at the time of delivery and similar birth weights. In addition, the incidence of preterm births, SGA infants, and infants admitted to the special care nursery were similar in the two groups. Nifedipine has potent activity against uterine contractions, and it has been recommended as a tocolytic for patients with spontaneous pre term labor. '9 . 2o Our findings reveal that nifedipine is not suitable for the prevention or treatment of premature labor in women with preeclampsia. Indeed, 12% of the patients in the nifedipine group had spontaneous preterm labor and/or rupture of the membranes while receiving tocolytic doses (100 to 120 mg per day). Interestingly, this incidence was similar to the respective incidence found in the no-therapy group. These findings argue against any potential benefits from using nifedipine for this purpose. We also found that the use of nifedipine had no beneficial effects on renal function tests. It is interesting to note that the serial changes in proteinuria were similar in both groups. This finding is in agreement with those of Rubin et al. lo and Fenakel et al. li In addition, nifedipine had no beneficial effects on platelet count. In fact, the serial changes in platelet counts, as well as the mean platelet counts at delivery, were similar in both groups. Moreover, the incidence of thrombocytopenia (platelet count < 100 X 10 3 / mm') was similar in both groups. This finding is in disagreement with the conclusions of previous investigators. 10. II. 14
Table VI. Neonatal outcome No therapy* (n = 101)
Nifedipine* (n = 99)
Gestational age at delivery
36.7 ± 2.5
36.1 ± 2.8
<37 wk (No. and %) Birth weight (gm) <10th (No. and %) Admitted to special care nursery (No. and %) Days in special care nursery
41 (41 %) 2509 ± 728 13 (13%) 21 (21%)
49 (49%) 2403 ± 769 15 (15%) 30 (30%)
22.5 ± 15.3
22.9 ± 20.1
(wk)
*No significant difference for any categories studied.
Table VII. Neonatal cord blood values
Blood pH <7.20 (No. and %) Blood Peo 2 Blood P02 Base deficit
No therapy (n = 85)
Nifedipine (n = 87)
7.27 ± 0.07 11 (13%) 51 ± 9.5 24 ± 7.8 -1.8 ± 2.9
7.27 ± 0.07 9 (10%) 52 ± 10 24 ± 8.5 -1.7 ± 3.4
The use of calcium channel blockers in the pregnant animal model was reportedly associated with a reduction in placental blood flow and in the development of fetal hypoxemia and acidosis when reviewed by Moretti et al. 17 However, their use in human pregnancy was not associated with any reported adverse perinatal outcome. 8-12.1420 The use of nifedipine in preeclamptic gestations in this study had no adverse effects on either utero placental blood flow or fetal hypoxemia. It is important to note that the neonatal birth weights and the incidence of SGA infants were similar in both groups. In addition, neonatal cord blood gas findings and the incidence of cord blood acidosis (pH <7.20) were similar in both groups. The goals of therapy for preeclampsia must always be safety of the mother first and then delivery of a live infant that will not require intensive and prolonged neonatal care. Previous randomized studies of antihypertensive drugs for mild preeclampsia have noted a reduction in the incidence of delivery for severe maternal hypertension. I However, the use of these drugs has not been associated with improved perinatal outcome when compared with results in well-matched control groups. I Similarly, it appears that nifedipine therapy for mild preeclampsia remote from term does not reduce the number of days of maternal hospitalization and does not improve perinatal outcome when compared to bed rest alone. REFERENCES I. Sibai BM. Management of preeclampsia. Clin Perinatol 1991; 18:793-808.
884
Sibai et al.
2. Gilstrap LC, Cunningham GF, Whalley PJ. Management of pregnancy induced hypertension in the nulliparous patient remote from term. Semin PerinatoI1978;2:73-81. 3. Sibai BM, Gonzalez AR, Mabie WC, Moretti M. A comparison of labetalol plus hospitalization versus hospitalization alone in the management of preeclampsia remote from term. Obstet GynecoI1987;70:323-7. 4. Mathews DD. A randomized controlled trial of bed rest and sedation or normal activity and non-sedation in the management of non-albuminuric hypertension in late pregnancy. Br] Obstet Gynaecol 1977;84:108-14. 5. Feeney]G. Hypertension in pregnancy managed at home by community midwives. BM] 1984;2888:1046-7. 6. Rubin PC, Butters L, Clark DM, et al. Placebo controlled trial of atenolol in treatment of pregnancy associated hypertension. Lancet 1983;1:431-4. 7. Pickles Cj, Symonds EM, Broughton-Pipkin F. The fetal outcome in a randomized double-blind controlled trial of labetalol versus placebo in pregnancy-induced hypertension. Br] Obstet Gynaecol 1989;96:38-43. 8. Walters BN], Redman CWG. Treatment of severe pregnancy-associated hypertension with the calcium antagonist nifedipine. Br] Obstet Gynaecol 1984;91 :330-6. 9. Constantine G, Beevers DG, Reynolds AL, Luesley DM. Nifedipine as a second line antihypertensive drug in pregnancy. Br] Obstet GynaecoI1987;94:1136-42. 10. Rubin PC, Butters L, McCake R. Nifedipine and platelets in preeclampsia. Am] Hypertens 1988;1:175-7. 11. Greer lA, Walker ]], Bjornsson S, Calder AA. Second line therapy with nifedipine in severe pregnancy-induced hypertension. Clin Exp Hypertens [B] 1989;B8:277-92.
October 1992 Am J Obstet Gynecol
12. Seabie S], Moodley], Becker P. Nifedipine in acute hypertension emergencies in pregnancy. S Afr Med ] 1989; 76:248-50. 13. Barton]R, Hiett AK, Conover WB. The use ofnifedipine during the postpartum period in patients with severe preeclampsia. AM] OBSTET GYNECOL 1990;162:788-92. 14. Fenakel K, Fenakel G, Appelman Z, et al. Nifedipine in the treatment of severe preeclampsia. Obstet Gynecol 1991;77:331-7. 15. Lindow SW, Davies N, Davey DA, Smith ]A. The effect of sublingual nifedipine on utero placental blood flow in hypertensive pregnancy. Br ] Obstet Gynaecol 1988; 95:1276-81. 16. Pirhonen ]P, Erkkola RU, Ekblad UU. Uterine and fetal flow velocity waveforms in hypertensive pregnancy: the effect of single dose of nifedipine. Obstet Gynecol 1990;76:37-41. 17. Moretti MM, Fairlie FM, Akl S, Khoury AD, Sibai BM. The effect of nifedipine therapy on fetal and placental Doppler waveforms in preeclampsia remote from term. AM] OBSTET GYNECOL 1990;163:1844-8. 18. Brenner WE, Edelman DA, Hendricks CH. A standard of fetal growth for the United States of America. AM] OBSTET GYNECOL 1976;126:575-82. 19. Reed WD, Welby DE. The use of calcium antagonist (nifedipine) to suppress preterm labour. Br] Obstet Gynaecol 1986;93:933-7. 20. Mari G, Kirshon B, Moise K, et al. Doppler assessment of the fetal and uteroplacental circulation during nifedipine therapy for preterm labor. AM ] OBSTET GYNECOL 1989; 161: 1514-8.
Bound volumes available to subscribers Bound volumes of the AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY are available to subscribers (only) for the 1992 issues from the Publisher, at a cost of $68.00 for domestic, $95.76 for Canada, and $91.00 for international for Vol. 166 (January-June) and Vol. 167 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the JOURNAL name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby- Year Book, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis, MO 63146-3318, USA; phone (800) 325-4177, ext. 4351, or (314) 453-4351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular JOURNAL subscription.
Neonatal intraventricular hemorrhage after maternal !3-sympathomimetic tocolysis
RC. Effects of terbutaline sulfate on fetal cardiac function. A~J OBSTET GYNECOL 1989;161:509-12. 21. Papile L-A, Rudolph AM, Heymann MA. Autoregulation of cerebral blood flow in the preterm fetal Iamb. Pediatr Res 1985; 19: 159-61. 22. Tweed WA, Cote J, Pash M, Lou H. Arterial oxygenation determines autoregulation of cerebral blood flow in the fetal Iamb. Pediatr Res 1983; 17:246-9. 23. Pasternak JF, Groothius DR. Autoregulation of cerebral
blood flow in the newborn beagle puppy. Bioi Neonate 1985;48: 100-9. 24. PasternakJF, Groothius DR, Fischer JM, Fischer DP. Regional cerebral blood flow in the beagle model of neonatal ventricular hemorrhage: studies during systemic hypertension. Neurology 1983;33:559-66. 25. van de Bor M, Walther FJ. Cerebral blood velocity regulation in preterm infants. Bioi Neonate 1991;59:329-35.
A randomized prospective comparison of nifedipine and bed rest versus bed rest alone in the management of preeclampsia remote from term Baha M. Sibai, MD, John R. Barton, MD, Sherif Ald, MD, Cern Sarinoglu, MD, and Brian M. Mercer, MD Memphis, Tennessee OBJECTIVE: The objective of our study was to test the hypothesis that treatment with nifedipine for mild preeclampsia remote from term reduces the number of days of maternal hospitalization and improves pregnancy outcome. STUDY DESIGN: A total of 200 patients at 26 to 36 weeks' gestation were randomly allocated to treatment with either bed rest alone (n = 100) or bed rest in combination with nifedipine (n = 100). RESULTS: Patients receiving nifedipine had significantly lower systolic (p < 0.0001) and diastolic (p < 0.0001) blood pressures during therapy. Severe hypertension as an indication for delivery was significantly (p < 0.05) more frequent in the bed-rest-alone group. The two study groups had similar average days of maternal hospitalization (12.6 ± 7.9 vs 12.3 ± 10.3) and pregnancy prolongation (22.3 ± 13.5 vs 22.5 ± 15.7). There were no differences between groups with respect to birth weight, incidences of small-for-gestational-age infants and preterm birth, number of days spent in special care unit, or cord blood gas measurement. CONCLUSION: Nifedipine therapy for preeclampsia reduces maternal blood pressure but does not reduce number of days of maternal hospitalization or improve perinatal outcome. (AM J OBSTET GYNECOL 1992;167:879-84.)
Key words: Mild preeclampsia, nifedipine, bed rest, pregnancy outcome The optimal management of patients with mild preeclampsia remote from term «36 weeks' gestation) is controversial. Indeed, there is disagreement regarding the need for hospitalization versus ambulatory management with bed rest at home and the potential benefits of using antihypertensive drugs.! Some authors'" have suggested that management in these cases should From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee, Memphis. Presented at the Twelfth Annual Meeting of the Society of Perinatal Obstetricians, Orlando, Florida, February 3-8, 1992. Reprint requests: Baha M. Sibai, MD, 853 jefferson Ave., Memphis, TN 38103. 6/6/39686
involve bed rest in the hospital for the duration of pregnancy. These authors reported that early and prolonged hospitalization for such patients improved perinatal outcome, reduced maternal morbidity, and was cost-effective." 3 In addition, one study found that treatment of blood pressure with labetalol in patients with mild preeclampsia was associated with a high frequency of fetal growth retardation.' In contrast, other authors" 5 believe that management can be safely carried out for some of these patients on an ambulatory basis with bed rest at home, while others recommend that patients with mild preeclampsia should be treated with antihypertensive drugs. 6 . 7 These latter authors reported that this management reduced the number of
879
880
Sibai et al.
October 1992 Am J Obstet Gynecol
Table I. Clinical findings at randomization
Table II. Laboratory findings at
(mean ± SD)
randomization (mean ± SD) No therapy* (n = 100)
Maternal age (yr) Gestational age (wk) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)
No therapy* (n = 100)
Nifedipine* (n = 100)
20.3 ± 4.0
20.5 ± 4.2
33.4 ± 2.7
32.8 ± 2.8
143.5 ± 5.8
143.8 ± 5.6
94.2 ± 4.4
93.9 ± 4.1
*No significant difference for any categories studied.
days of antepartum maternal hospitalization and improved perinatal outcome. Nifedipine, a calcium channel blocker, is a potent oral antihypertensive agent. Several investigatorss. 11 have used nifedipine as a second-line antihypertensive drug in the management of cases of severe preeclampsia. In addition, some authors have found nifedipine to be superior to hydralazine for control of severe maternal hypertension during pregnancy or post partum. 1~~14 Control of maternal blood pressure with nifedipine was reportedly associated with improved maternal and perinatal outcome. The use of this drug led to significant prolongation of pregnancy, lower incidence of fetal distress, improved maternal platelet count, and improved renal outpUt.8~14 Studies have also shown that in women with mild preeclampsia the administration of nifedipine lowers maternal blood pressure without affecting the resistance indexes in fetal or uteroplacental vessels. 15~17 In spite of these favorable results there are no prospective randomized studies comparing nifedipine to no therapy in the management of patients with mild preeclampsia before 37 weeks' gestation. The aim of the prospective study was to test the hypothesis that treatment of maternal blood pressure with nifedipine in patients with mild preeclampsia remote from term reduces antepartum maternal hospital stay, prolongs gestation, and improves perinatal outcome. Material and methods
The study population included 200 primigravid women with mild preeclampsia at 26 to 36 weeks' gestation. All had persistent elevations of blood pressure (systolic between 140 and 160 mm Hg and/or diastolic between 90 and 110 mm Hg) 24 hours after hospitalization. All had proteinuria (>300 mg per 24 hours) and/or elevated uric acid levels (2:6 mg/dl) at the time of entry to the study. Patients with associated medical and obstetric complications (other than preeclampsia) were excluded. In addition, patients with fetal compromise (suspected abnormal fetal growth by ultraso-
Platelets (x 10'1 mm') Creatinine (mg/dl) Uric acid (mg/dl) Creatinine clearance (mil min) Proteinuria (mg/24 hr)
254 0.81 6.1 109
± 53
± 0.16
± 0.9
± 29
639 ± 636
Nifedipine* (n = 100)
248 0.80 6.1 114
± 72 ± 0.19
± l.l ± 34
683 ± 795
*No significant difference for any categories studied.
nography and/or abnormal fetal testing) were excluded. After signing the consent form (previously approved by the investigation review board of this institution) patients were allocated randomly to one of two groups, on the basis of a computer-generated list of random numbers. The physician was asked to draw a sealed envelope containing the method of assignment for each patient. Patients in one group were managed with bed rest alone, whereas the other group received nifedipine, starting at 40 mg/day, that was then increased every 2 to 3 days as needed to a maximum of 120 mg/day, to keep systolic pressure below 140 mm Hg and diastolic pressure below 90 mm Hg. Laboratory evaluation included serial determinations of hematocrit, platelet count, liver function tests, uric acid, creatinine clearance, and 24-hour urinary protein excretion. Fetal evaluation included serial ultrasonography for fetal growth, nonstress test, and/ or biophysical profile at least twice a week and cord blood gas measurements. During the initial hospitalization, clinical management included measurement of blood pressure four times daily, urine by dipstick twice daily, and maternal weight every other day. Patients were given a regular hospital diet, and no other medications were used except for prenatal vitamins and iron supplements. In addition, patients were instructed to report the development of persistent headaches, visual disturbances, epigastric and/or right upper-quadrant pain, uterine contractions, or vaginal bleeding. All blood pressure recordings were performed by two experienced nurses who were assigned to the antepartum ward where the patients were hospitalized. Blood pressures were recorded with the patient in a semirecumbent position with the cuff positioned at heart level. The results of all blood pressure measurements were pooled, and an average was calculated for each patient. Reliable patients with stable maternal and fetal conditions who did not have proteinuria (protein <300 mg per 24 hours) and had average blood pressures persistently < 140 mm Hg systolic and <90 mm Hg diastolic
Nifedipine vs no therapy in preeclampsia 881
Volume 167 Number 4, Part 1
then managed on an ambulatory basis. These patients were instructed to have relative bed rest at home, and then they were evaluated in the antepartum testing area for maternal and fetal well-being at least twice a week. During ambulatory management the patient was hospitalized again if there was any evidence of disease progression and/ or if acute hypertension or significant proteinuria developed. All clinical decisions regarding management and timing of delivery were left to the attending faculty and house staff. No efforts were made to arrest spontaneous onset of labor before the thirtyseventh week. Analysis of data included comparisons of maternal blood pressure, laboratory findings, days of antepartum maternal hospitalization, days gained during management, and perinatal outcome. Perinatal outcome included gestational age at delivery, birth weight, placental weight, cord blood gas measurements, incidence of preterm birth, and incidence of small-for-gestationalage (SGA) infants. Gestational age was determined on the basis of obstetric criteria including early examinations and ultrasonography before 24 weeks' gestation. The diagnosis of SGA was made if the birth weight was below the 10th percentile according to the growth curves of Brenner et al. l " Results were expressed as mean ± SD. Statistical analysis used Student's t test, X2, and Fisher's exact test when applicable. Serial changes in blood pressures and laboratory values between the groups and within each treatment group were examined by analysis of variance for repeated measurements. A value of p < 0.05 was considered significant. Results
The study groups were very similar at the time of randomization with respect to various clinical findings (Table I) and laboratory findings (Table II). Eighty-five patients (85%) in the no-therapy group had proteinuria >300 mg per 24 hours (range 304 to 3600 mg), and the remaining 15 patients had proteinuria of <300 mg per 24 hours (range 96 to 299 mg). On the other hand, eighty-three patients (83%) in the nifedipine group had proteinuria >300 mg per 24 hours (range 302 to 3700 mg), and the remaining 17 patients had proteinuria of <300 mg per 24 hours (range 64 to 287 mg). All patients who had proteinuria <300 mg per 24 hours at the time of randomization had proteinuria of at least 2 + on dipstick on two occasions 6 hours apart. Three patients were lost to follow-up after randomization (one in the no-therapy group and two in the nifedipine group) and therefore were not included in the follow-up analyses. Two patients in the no-therapy group and three in the nifedipine group were noncompliant with the study protocol. Nonetheless, all were included in the blood pressure analyses up to the time
-
160
-
130
C)
::I:
E E
C. £Xl
en
(,) .-
0
tn
>-
o •
Notherapy Nifedipine
150 140
120 110
-
C)
::I:
E E
-
C. £Xl
-
(,) .-
o
tn
as .C
Fig. 1. Blood pressure (mean ± SD) in patients with no therapy (white bars) or treated with nifedipine (black bars). Asterisk, p < 0.0001 for systolic and diastolic blood pressures. In addition, within nifedipine group p < 0.0001 for systolic and diastolic pressures by analysis of variance for repeated measurements.
they became noncompliant, and all were included in the outcome data. Thus a total of 99 women in the notherapy group and 98 in the nifedipine group were included in the final analyses. Fig. 1 compares the systolic and diastolic blood pressures at time of entry and during treatment between the two groups. There were no differences in blood pressure at entry. However, during treatment, the nifedipine group had significantly lower average systolic blood pressure «p < 0.0001), and diastolic blood pressure (p < 0.0001). In addition, the nifedipine group demonstrated a significant drop in blood pressure during treatment (p < 0.0001), whereas the no-therapy group exhibited no change. Table III compares the mean laboratory tests at delivery between the two groups. There were no signifi-
882
Sibai et al.
October 1992 Am J Obstet Gyneco1
Table III. Indications for delivery
Term gestation Severe hypertension Pre term labor or rupture of membranes Suspected SGA Abnormal FHR testing Low platelets or HELLP syndrome Other
Table V. Pregnancy outcome
No therapy (n = 99)
Nifedipine (n = 98)
54 18* 13
50 9* 12
4 5 3
8 8 5
2
5
No therapy*
Antepartum hospitalization (days) Pregnancy prolongation (days) Cesarean section (No. and %) Abruptio placentae (No. and %) HELLP syndrome (No. and %)
Nifedipine*
12.6 ± 7.9
12.3 ± 10.3
22.3 ± 13.5
22.5 ± 15.7
35 (35%)
42 (43%)
2 (2%)
3 (3%)
2 (2%)
4 (4%)
FHR, Fetal heart rate; HELLP, hemolysis, elevated liver enzymes, and low platelets. *p < 0.05.
HELLP, Hemolysis, elevated liver enzymes, and low platelets. *No significant difference for any categories studied.
Table IV. Laboratory findings at delivery
pine group received such management. The number of days of antepartum maternal hospitalization ranged from 3 to 48 in the no-therapy group, and it ranged from 3 to 63 in the nifedipine group. However, the average number of days was similar between the two groups. In addition, there were no differences between the groups with respect to pregnancy prolongation, incidence of cesarean section, or incidence of abruptio placentae. Pregnancy outcome was subsequently analyzed after exclusion of patients in both groups who had proteinuria of <300 mg per 24 hours at the time of randomization. The mean number of days of antepartum hospitalization and the number of days of pregnancy prolongation were similar in both groups. There were 101 births (two twins) in the no-therapy group and 99 births (one set of twins) in the nifedipine group. No fetal or neonatal deaths occurred in either group. There were no differences between the groups in average placental weight (605 ± 176 gm for no therapy vs 588 ± 183 gm for nifedipine). Table VI summarizes the neonatal outcome in the two study groups. There were no differences with respect to gestational age at delivery, birth weight, or number of days spent in the special care nursery. In addition, the two groups had similar frequencies of preterm infants and infants considered to be SGA. Table VII compares the neonatal cord blood values in the two groups. There were no differences with respect to any of the measurements studied. In addition, the two groups had similar frequencies of cord pH values <7.20.
(mean ± SD) No therapy*
Platelets (x 103 I mm') Creatinine (mg/dl) Uric acid (mg/dl) Creatinine clearance (mil min) Proteinuria >5 gm/24 hr
250 0.86 6.2 104
±
66
±
28
± 0.16 ± 1.3
10
Nifedipine*
232 ± 82 0.87 ± 0.21 6.3 ± 1.5 110 ± 39 16
*No significant difference for any categories studied.
cant differences between the two groups with respect to either platelet count or renal function tests. During treatment, 10 patients (10%) in the no-therapy group demonstrated nephrotic range proteinuria (>5 gm per 24 hours) as compared with 16 (16%) in the nifedipine group having such a finding. This difference was not statistically significant. Table IV compares the indications for delivery in the two groups. Severe hypertension as an indication was significantly more frequent (p < 0.05) in the no-therapy group. On the other hand, fetal compromise (suspected SGA and/ or abnormal testing) as an indication was more frequent in the nifedipine group (16% vs 9%, P < 0.09, odds ratio 2: 1). Interestingly, 12 patients (12%) in the nifedipine group were delivered preterm «37 weeks' gestation) after the onset of spontaneous labor and/or rupture of membranes while receiving nifedipine at 100 to 120 mg per day. Two patients in the no-therapy group were delivered because of cerebral manifestations (headaches, visual symptoms), whereas three patients in the nifedipine group were delivered because of severe ascites and two because of severe epigastric pain. Table V compares the pregnancy outcomes in the two groups. Thirty-eight patients in the no-therapy group received ambulatory management after the initial hospitalization, whereas 45 patients in the nifedi-
Comment
This study is the largest and first prospective, randomized trial comparing no therapy to the use of nifedipine in the management of mild preeclampsia remote from term. All patients studied were youn~ and primigravid with documented evidence of "pure" preeclampsia (persistent hypertension on bed rest with
Nifedipine vs no therapy in preeclampsia 883
Volume 167 Number 4, Part 1
substantial proteinuria). In addition, no other antihypertensive medications were used in either study group. In contrast, almost all previous studies describing the use of nifedipine to treat hypertension in pregnancy have included patients with various parities and various forms of hypertension (with and without proteinuria).81" In addition, nifedipine was used in association with other antihypertensive drugs S- ll or it was compared with hydralazine. '211 We found that nifedipine was effective in reducing maternal systolic and diastolic blood pressures in women with mild preeclampsia. However, this reduction in maternal blood pressure was not associated with a reduced number of antepartum hospital days in the nifedipine group. In addition, the use of nifedipine led to a lower incidence of delivery for severe hypertension (9%) as compared with the no-therapy group (18%). However, such reduction in incidence of severe hypertension in the nifedipine group was not associated with a concomitant improved pregnancy prolongation when compared with the no-therapy group. This was due to the fact that a larger percentage of patients in the nifedipine group (16%) were delivered for fetal reasons (abnormal antepartum testing and fetal growth retardation), as compared with the no-therapy group (9%). Consequently, the two groups had similar gestational ages at the time of delivery and similar birth weights. In addition, the incidence of preterm births, SGA infants, and infants admitted to the special care nursery were similar in the two groups. Nifedipine has potent activity against uterine contractions, and it has been recommended as a tocolytic for patients with spontaneous pre term labor. '9 . 2o Our findings reveal that nifedipine is not suitable for the prevention or treatment of premature labor in women with preeclampsia. Indeed, 12% of the patients in the nifedipine group had spontaneous preterm labor and/or rupture of the membranes while receiving tocolytic doses (100 to 120 mg per day). Interestingly, this incidence was similar to the respective incidence found in the no-therapy group. These findings argue against any potential benefits from using nifedipine for this purpose. We also found that the use of nifedipine had no beneficial effects on renal function tests. It is interesting to note that the serial changes in proteinuria were similar in both groups. This finding is in agreement with those of Rubin et al. lo and Fenakel et al. li In addition, nifedipine had no beneficial effects on platelet count. In fact, the serial changes in platelet counts, as well as the mean platelet counts at delivery, were similar in both groups. Moreover, the incidence of thrombocytopenia (platelet count < 100 X 10 3 / mm') was similar in both groups. This finding is in disagreement with the conclusions of previous investigators. 10. II. 14
Table VI. Neonatal outcome No therapy* (n = 101)
Nifedipine* (n = 99)
Gestational age at delivery
36.7 ± 2.5
36.1 ± 2.8
<37 wk (No. and %) Birth weight (gm) <10th (No. and %) Admitted to special care nursery (No. and %) Days in special care nursery
41 (41 %) 2509 ± 728 13 (13%) 21 (21%)
49 (49%) 2403 ± 769 15 (15%) 30 (30%)
22.5 ± 15.3
22.9 ± 20.1
(wk)
*No significant difference for any categories studied.
Table VII. Neonatal cord blood values
Blood pH <7.20 (No. and %) Blood Peo 2 Blood P02 Base deficit
No therapy (n = 85)
Nifedipine (n = 87)
7.27 ± 0.07 11 (13%) 51 ± 9.5 24 ± 7.8 -1.8 ± 2.9
7.27 ± 0.07 9 (10%) 52 ± 10 24 ± 8.5 -1.7 ± 3.4
The use of calcium channel blockers in the pregnant animal model was reportedly associated with a reduction in placental blood flow and in the development of fetal hypoxemia and acidosis when reviewed by Moretti et al. 17 However, their use in human pregnancy was not associated with any reported adverse perinatal outcome. 8-12.1420 The use of nifedipine in preeclamptic gestations in this study had no adverse effects on either utero placental blood flow or fetal hypoxemia. It is important to note that the neonatal birth weights and the incidence of SGA infants were similar in both groups. In addition, neonatal cord blood gas findings and the incidence of cord blood acidosis (pH <7.20) were similar in both groups. The goals of therapy for preeclampsia must always be safety of the mother first and then delivery of a live infant that will not require intensive and prolonged neonatal care. Previous randomized studies of antihypertensive drugs for mild preeclampsia have noted a reduction in the incidence of delivery for severe maternal hypertension. I However, the use of these drugs has not been associated with improved perinatal outcome when compared with results in well-matched control groups. I Similarly, it appears that nifedipine therapy for mild preeclampsia remote from term does not reduce the number of days of maternal hospitalization and does not improve perinatal outcome when compared to bed rest alone. REFERENCES I. Sibai BM. Management of preeclampsia. Clin Perinatol 1991; 18:793-808.
884
Sibai et al.
2. Gilstrap LC, Cunningham GF, Whalley PJ. Management of pregnancy induced hypertension in the nulliparous patient remote from term. Semin PerinatoI1978;2:73-81. 3. Sibai BM, Gonzalez AR, Mabie WC, Moretti M. A comparison of labetalol plus hospitalization versus hospitalization alone in the management of preeclampsia remote from term. Obstet GynecoI1987;70:323-7. 4. Mathews DD. A randomized controlled trial of bed rest and sedation or normal activity and non-sedation in the management of non-albuminuric hypertension in late pregnancy. Br] Obstet Gynaecol 1977;84:108-14. 5. Feeney]G. Hypertension in pregnancy managed at home by community midwives. BM] 1984;2888:1046-7. 6. Rubin PC, Butters L, Clark DM, et al. Placebo controlled trial of atenolol in treatment of pregnancy associated hypertension. Lancet 1983;1:431-4. 7. Pickles Cj, Symonds EM, Broughton-Pipkin F. The fetal outcome in a randomized double-blind controlled trial of labetalol versus placebo in pregnancy-induced hypertension. Br] Obstet Gynaecol 1989;96:38-43. 8. Walters BN], Redman CWG. Treatment of severe pregnancy-associated hypertension with the calcium antagonist nifedipine. Br] Obstet Gynaecol 1984;91 :330-6. 9. Constantine G, Beevers DG, Reynolds AL, Luesley DM. Nifedipine as a second line antihypertensive drug in pregnancy. Br] Obstet GynaecoI1987;94:1136-42. 10. Rubin PC, Butters L, McCake R. Nifedipine and platelets in preeclampsia. Am] Hypertens 1988;1:175-7. 11. Greer lA, Walker ]], Bjornsson S, Calder AA. Second line therapy with nifedipine in severe pregnancy-induced hypertension. Clin Exp Hypertens [B] 1989;B8:277-92.
October 1992 Am J Obstet Gynecol
12. Seabie S], Moodley], Becker P. Nifedipine in acute hypertension emergencies in pregnancy. S Afr Med ] 1989; 76:248-50. 13. Barton]R, Hiett AK, Conover WB. The use ofnifedipine during the postpartum period in patients with severe preeclampsia. AM] OBSTET GYNECOL 1990;162:788-92. 14. Fenakel K, Fenakel G, Appelman Z, et al. Nifedipine in the treatment of severe preeclampsia. Obstet Gynecol 1991;77:331-7. 15. Lindow SW, Davies N, Davey DA, Smith ]A. The effect of sublingual nifedipine on utero placental blood flow in hypertensive pregnancy. Br ] Obstet Gynaecol 1988; 95:1276-81. 16. Pirhonen ]P, Erkkola RU, Ekblad UU. Uterine and fetal flow velocity waveforms in hypertensive pregnancy: the effect of single dose of nifedipine. Obstet Gynecol 1990;76:37-41. 17. Moretti MM, Fairlie FM, Akl S, Khoury AD, Sibai BM. The effect of nifedipine therapy on fetal and placental Doppler waveforms in preeclampsia remote from term. AM] OBSTET GYNECOL 1990;163:1844-8. 18. Brenner WE, Edelman DA, Hendricks CH. A standard of fetal growth for the United States of America. AM] OBSTET GYNECOL 1976;126:575-82. 19. Reed WD, Welby DE. The use of calcium antagonist (nifedipine) to suppress preterm labour. Br] Obstet Gynaecol 1986;93:933-7. 20. Mari G, Kirshon B, Moise K, et al. Doppler assessment of the fetal and uteroplacental circulation during nifedipine therapy for preterm labor. AM ] OBSTET GYNECOL 1989; 161: 1514-8.
Bound volumes available to subscribers Bound volumes of the AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY are available to subscribers (only) for the 1992 issues from the Publisher, at a cost of $68.00 for domestic, $95.76 for Canada, and $91.00 for international for Vol. 166 (January-June) and Vol. 167 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the JOURNAL name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby- Year Book, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis, MO 63146-3318, USA; phone (800) 325-4177, ext. 4351, or (314) 453-4351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular JOURNAL subscription.