Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis

Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis James E. Ferguson II, MD, Donald C. Dyson, MD: R. Harold Holbrook, Jr, MD, Thomas Schutz, BA, and David K. Stevenson, MD" Santa Clara and Stanford, California Recent investigations have indicated that nifedipine, a calcium channel entry blocker, may be useful in the treatment of preterm labor. This prospective, randomized study compares cardiovascular and metabolic effects measured in association with sublingual and oral administration of nifedipine with those noted with the intravenous and oral administration of the ~-adrenergic agent ritodrine. Serial measurements of cardiovascular parameters, hematocrit, electrolytes, glucose, blood urea nitrogen, creatinine, calcium, and serum glutamic-oxaloacetic and glutamic-pyruvic transaminase were compared between groups. Sublingual and oral nifedipine caused minimal cardiovascular alterations. At doses sufficient to achieve tocolysis, ritodrine caused more pronounced cardiovascular changes than nifedipine. Both agents had a hemodilutional effect, but nifedipine was not associated with alterations in serum electrolytes or a dramatic hyperglycemia. On the basis of this study, it appears that the use of nifedipine for preterm labor management is associated with hemodilutional changes but not the adverse cardiovascular or metabolic effects often associated with ritodrine tocolysis. (AM J OSSTET GVNECOL 1989;161 :788-95.)

Key words: Nifedipine, ritodrine, premature labor, tocolysis

Currently a variety of pharmacologic agents are used to treat preterm labor, but only the J3-adrenergic agent ritodrine has a Food and Drug Administration-labeled indication for such therapy.' The use of J3-adrenergic agents, however, can be associated with undesirable cardiovascular and metabolic side effects. I. 2 These potential side effects prompted evaluation of an alternate tocolytic agent. Because of their relaxing effects on the myometrium, calcium channel entry blockers show promise. Preliminary studies with nifedipine have suggested that it can inhibit labor while producing few apparent side effects. 3-5 However, knowledge of possible cardiovascular or metabolic effects associated with the sublingual and oral routes of administration of nifedipine in the pregnant patient is limited. We conducted this study to evaluate cardiovascular and metabolic responses to nifedipine, and to compare them with changes noted with the J3-adrenergic agent ritodrine.

Material and methods BetweenJuly 1984 and June 1986, patients with preterm labor occurring between 24 and 36 completed From the Department of Obstetrics and Gynecology, a KaISer· Permanente Hospital, and the Departments of Gynecology and Obstetncs and Pediatncs/ Stanford UniversIty School of Medicine. Supported WI part by a Mellon Foundatwn Fellowship Award and National Intitutes of Health grants RR-81 and HD-14426. Presented at the Ninth Annual Meetzng of the Society of Perinatal Obstetricians, New Orleans, Louisiana, February 2-4, 1989. Reprint requests:]. E. Ferguson II, MD, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, UniverSIty of Virginia School of Mediczne Charlottesville, VA 22908. 616113712

788

weeks of gestation were eligible for enrollment into the study. Informed consent as approved by the Stanford University Committee for Protection of Human Subjects in Research and the Kaiser Permanente Human Subject'S Committee was obtained from each patient. Patients with the following maternal factors were excluded: tocolytic exposure during the current pregnancy, diabetes, hyperthyroidism, cardiac disease, severe preeclampsia-eclampsia, abruptio placentae, chorioamnionitis, multiple gestation, hydramnios, and cervical dilatation >4 cm. Fetal distress, severe intrauterine growth retardation, dead fetus, or fetal anomaly incompatible with life constituted fetal factors for exclusion. Preterm labor was defined as regular uterine contractions with a documented change in cervical dilatation or effacement before 36 completed weeks' gestation. Once preterm labor was diagnosed and written consent had been obtained, the assignment group was determined by opening a sequentially numbered sealed envelope, randomized by the use of a random number table, with the patients stratified according to cervical dilatation ($2 em or >2 but $4 em) and whether the patient had intact or ruptured membranes. An intravenous infusion of 5% dextrose in lactated Ringer's solution at 100 mIl hour was administered to all patients after an initial 200 ml fluid bolus. An electrocardiogram was obtained from each patient before and at 12 hours of treatment. Fetal heart rate and uterine activity were monitored continuously during the study. Cervical cultures for group B J3-hemolytic streptococcus and Neisseria gonorrhoeae were obtained. The use of amniocentesis and steroid administration followed our standard

Volume 161 Number 3

practice as previously described. 6 Tocolysis was attempted in each group of patients for 48 hours in patients with ruptured membranes and through 36 completed weeks of gestation in patients whose membranes were intact. Nifedipine tocolysis was initiated with a 10 mg capsule given sublingually. Patients were instructed to bite the capsule between their molars and, if possible, to avoid swallowing to facilitate sublingual absorption. If uterine contractions persisted after 20 minutes, a similar dose was repeated at intervals of 20 minutes, up to a maximal total dose of 40 mg during the first hour of treatment. If sublingual tocolysis stopped the uterine activity, then oral therapy with 20 mg of nifedipine was initiated 6 hours after the last sublingual capsule. This dose was repeated at 4 to 6-hour intervals, or if clinically indicated to continue tocolysis, occasionally at ~ore frequent intervals. During treatment in the ritodrine group the infusion rate was begun at 50 fLg/min and increased by 50 fLg/min every IS to 30 minutes in response to continued uterine activity until uterine contractions were inhibited, 350 fLg/min was reached, or unacceptable side effects developed. Thereafter the infusion rate was decreased by 50 fLg/min and was then maintained at that rate for 12 hours. After 12 hours the infusion rate was decreased by 50 fLg/min every 2 hours until 100 fLg/min was reached. If uterine contractions recurred, the sequence was repeated. Oral therapy (10 to 20 mg every 4 to 6 hours) was started 30 minutes before discontinuation of intravenous ritodrine. Tocolysis was considered to have been achieved when the treating physician determined that uterine contractions were stopped. At that time no further sublingual nifedipine therapy was given or the infusion rate of ritodrine was decreased to the maintenance rate. In both study groups, fluid intake was limited to 2400 mll24 hr, and volume of total intake and urine output was recorded. Patients were allowed no oral intake except when sips of water were permitted to swallow oral medications. Blood urea nitrogen, creatinine, calcium, serum glutamic-oxaloacetic and glutamic-pyruvic transaminase levels were measured before therapy and after 24 hours of treatment. Hematocrit, glucose, sodium, potassium, chloride, and bicarbonate levels were measured before therapy ~nd after 8, 16, and 24 hours of treatment. Th,e anion gap was determined for these intervals from the following formula: (sodium + potassium) - (chloride + bicarbonate). A baseline hemogram also was obtained for all patients. Patients were positioned in left lateral recumbency for cardiovascular measurements. The superior arm was used and Korotkoff phase 4 documented the diastolic pressure. Mean arterial pressure was calculated with the standard formula. The pulse rate was determined by counting the pulse for 1 full minute. Patients in each group had a minimum of two pretreatment blood pressure and pulse rate determinations. In the

Cardiovascular and metabolic effects of nifedipine

789

patients who received nifedipine, systolic and diastolic blood pressures and pulse rate were measured 5, 10, and 20 minutes after each sublingual dose, then hourly until the first oral dose. During oral administration these parameters were measured before successive doses and at 5, 10, and 20 minutes, and 2, 4, ;wd 6 hours after each dose during the first day. In the patients who received ritodrine, similar parameters were determined at the time of and 10 minutes, 20 minutes, 2 hours, and 4 hours after each change in the intravenous infusion rate and every hqur once a stable infusion rate was determined. Statistical analyses were performed with the use of an unpaired t test for comparison between the two treatment groups at specific time points (baseline and interval values), paired t test and assessment of difference patterns for comparison of serial interval values to baseline values within a treatment group, and X2 analysis with Yates correction for continuity. Additionally, a two-way analysis of variance with comparison of least-square means to identify specific differences was used to evaluate the effects of time and treatment, and the interaction of time and treatment. Linear regression was used to determine if there was any correlation between cumulative nifedipine dose over 24 hours on a milligram per kilogram basis and changes from baseline in the 24-hour metabolic parameters.

Results Twenty-seven patients were randomly assigned to the nifedipine group and 26 to the ritodrine group. Cardiovascular data were not available for analysis from one of the nifedipine patients, and metabolic data were unavailable from one patient in the ritodrine group. During oral therapy, only patients who received 20 mg doses of nifedipine at 6-hour intervals in the initial 24 hours are reported. To evaluate possible differences between the two treatment groups at the same clinical end point (i.e., after uterine contractions had stopped), we compared cardiovascular effects at similar time intervals in both groups. Comparisons were made between cardiovascular values recorded at 20 minutes and between averaged values recorded from 2 to 4 hours after the last sublingual dose or the intravenous infusion rate necessary to stop uterine contractions in patients in the nifedipine and ritodrine groups, respectively. Various factors that could have affected the study outcome are shown in Table I and indicate that the groups are comparable. Pretreatment values and the cardiovascular responses to sublingual nifedipine administration for the 26 patients in whom sublingual tocolysis was evaluated are shown in Fig. 1, A. Twenty patients required fOQr sublingual doses, four required three doses, and two patients required only two sublingual doses. When compared with pretreatment values, the systolic blood

790 Ferguson et al.

September 1989 Am J Obstet Gynecol

Table I. Maternal factors of study patients randomly selected to receive nifedipine or ritodrine tocolysis

A 20

III

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100

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80

0..0 (Xl

00

I:!

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120 100

< 0.05] Pulse

80

12O

GI

[

~ll1oo 0..15

Nifedipine

Rltodrine

Age (yr)* Gestational age (wk)* White blood 'cell count* Parity 0 >0 Cervical dilatation (cm) ::52 > 2,::54 Premature rupture of membranes Betamethasone use

26.6 ± 5.2 30.7 ± 3.0 11.1 ± 3.8

25.9 ± 5.5 30.8 ± 2.3 12.7 ± 3.8

14/27 13/27

16/26 10126

22 / 27 5 / 27 6 / 27

20/26 6/26 6 / 26

23/27

23/26

*Mean ± SD ; none of these was significantl y different by Student's t test or X2 analysis. where appropriate,

.

~t:.80 ~. CXl

Classification

60 00 0 .

n.s .

•••• P < 0.05

L

Time

Fig. 1. A, Effects of sublingual nifedipine on systolic and di· astolic blood pressure, mean arterial pressure (MAP) , and pulse rate. Vertical arrows indicate timing of administration of 10 mg of nifedipine. Solzd symbols represent p < 0.05, compared with baseline values. B, Effects of oral nifedipine on systolic and diastolic blood pressure, mean arterial pressure (MAP) , and pulse rate. Velt lcal arrows indicate timing of administration of 20 mg of nifedipine. Solzd symbols represent p < 0.05 compared with baseline values. Values expressed as mean ± SD.

pressure statistically did not change during sublingual dosing or during the 6-hour inteval after the last sublingual dose. However, diastolic blood pressure was decreased by 4 torr 10 minutes after the initial dose (P = 0.018). Additional doses caused little further decrease in diastolic blood pressure when compared with diastolic values recorded just before subsequent sublingual doses (i.e., at 20, 40, or 60 minutes after the initiation of treatment). The lowest mean diastolic pressure was 62.2 torr. The diastolic blood pressure remained decreased through 3 hours after the last sublingual dose (p = 0.044) and then returned toward pretreatment values. Changes in the mean arterial pressure occurred during the interval when diastolic blood pressure was decreased; however, because systolic blood pressure did not change significantly, the decreases in diastolic blood pressure were not always associated with statistically significant decreases in mean arterial pressure. The pulse rate increased 10 minutes

after the initial dose (p = 0.002) when compared with baseline values and remained elevated through 3 hours after the last sublingual dose. When compared with pulse values recorded just before subsequent sublingual doses, only the increased value recorded 20 minutes after the third sublingual dose was statistically greater (P = 0.018). The maximal mean pulse rate was 98 beats/ min and occurred 1 hour after the last sublingual dose. The cardiovascular responses of patients who received 20 mg of nifedipine orally at exactly 6-hour intervals are shown in Fig. 1, B. Values at 5, 10, and 20 minutes, and 2, 4, and 6 hours after each oral dose are compared with those measured just before each dose. Systolic blood pressure did not change significantly during oral therapy. Whereas diastolic blood pressure did decrease somewhat after each oral dose, when compared with predose values, only the decrease at 20 minutes after the second oral dose was statistical1y significant (p = 0.03). The mean arterial pressure demonstrated a similar pattern of change. After each oral dose, the pulse rate increased when compared with values measured before each dose. Statistically significant increases in pulse rate were consistently noted 20 minutes after each oral dose. Maximal pulse increases and diastolic blood pressure and mean arterial pressure decreases were similar in magnitude to those measured during sublingual administration. Fig. 2 shows the cardiovascular response to stepwise increases with equal doses in the infusion rate of ritodrine in the 26 patients who were evaluated. The cardiovascular parameters depicted were obtained 15 to 30 minutes after the particular infusion rate was initiated. There was no significant change in systolic blood pressure, but diastolic and consequently mean arterial pressures decreased . Pulse rate increased significantly.

Cardiovascular and metabolic effects of nifedipine

Volume 161 Number 3

These changes were progressive until the 200 J..Lg/min infusion rate was reached. Thereafter they changed little, but remained significantly different from baseline values. In Table II, cardiovascular parameters measured in patients in both the nifedipine and ritodrine groups at the specified intervals after tocolysis was achieved are compared to baseline values and to each other. In the nifedipine patients, when interval values were compared with baseline values, systolic and mean arterial blood pressure did not change statistically, whereas the decreased diastolic blood pressure and the increased pulse rate were statistically significant at each interval. In the ritodrine patients in whom tocolysis was achieved, the labor-inhibiting rate was 221 ± 74 J..Lg/min(mean ± SD), and the mean maintenance rate was 165 ± 53 J..Lg/min. Systolic blood pressure did not change statistically when values from the ritodrine patients at each interval were compared to baseline; however, the decreased diastolic blood pressure and mean arterial pressure and the increased pulse rate were statistically significant at both intervals. When the nifedipine and ritodrine groups were compared, baseline values did not differ statistically for any of the cardiovascular parameters, nor did systolic blood pressure values differ when compared at either interval. Comparison between groups revealed that diastolic blood pressure and mean arterial pressure were statistically lower and the pulse rate statistically higher in the ritodrine group at both intervals after tocolysis. Values for metabolic parameters that were obtained at baseline and after 24 hours of treatment are shown in Table III. In patients who received nifedipine, there was a decrease in blood urea nitrogen and serum glutamic-pyruvic transaminase values at 24 hours when compared to baseline (p = 0.0042 and p = 0.004, respectively). Although the absolute differences between baseline and 24-hour values were minimal, the decreased calcium values in both the nifedipine and ritodrine groups were statistically significant (p = 0.0004 and p = 0.0058, respectively). When values from patients in the two treatment groups were compared at baseline and 24 hours of treatment, no significant differences existed. Glucose values after 8,16, and 24 hours of treatment were significantly increased in both groups when compared with their respective baseline values (Fig. 3, A). Values in the ritodrine group also were statistically greater than values in the nifedipine group at 8 and 16 hours of therapy. Decreases in hematocrit were noted in both groups over time; the comparisons of interval to baseline values in each treatment group are shown in Fig. 3, B. Only the values at 8 hours of treatment differed significantly when interval values were compared between groups.

791

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Fig. 2. Systolic and diastolic blood pressure, mean arterial pressure (MAP), and pulse rate measured after stepwise increases with equal doses in the infusion rate of ritodrine. Solid symbols represent p < 0.05, compared with baseline values. Values expressed as mean ± SD.

Serum electrolyte values are tabulated in Table IV. Sodium values did not change with time in either group. During therapy, potassium values remained unchanged in the nifedipine group, but fell significantly in the ritodrine group, When comparisons were made between groups at the 8-, 16-, and 24-hour intervals of therapy, ritodrine values were lower (p = 0.0001, P = 0.0001, and p = 0.0001, respectively), Chloride values were unchanged over time in the nifedipine group, but increased significantly in the ritodrine group at 8 and 16 hours of treatment. Only the values at 24 hours of therapy differed between groups (p = 0.004). As shown in Table IV, interval values for bicarbonate did not differ from baseline in the nifedipine group; however, they decreased in the ritodrine group, When comparisons were made at the 8-, 16-, and 24-hour intervals of therapy between groups, the lower values in the ritodrine patients were only significant at the 8- and 16-hour comparisons (p = 0.005, P = 0.001, respectively). The anion gap did not change significantly over time in either group, but the anion gap was greater in the ritodrine group at the 8-hour determination when compared with the nifedipine group (p = 0.0001) and at the 16-hour comparison (p = 0,025).

792

Ferguson et al.

September 1989 Am J Obstet Gynecol

Table II. Comparison of cardiovascular parameters at 20 minutes and 2 to 4 hours after the last sublingual dose or intravenous infusion rate necessary to achieve tocolysis Baseline (pretreatment)

Value*

111.3 112.0 68.5 68.3 82.8 82.9 83.2 85.4

Nif Rit Nif Rit Nif Rit Nif Rit

Systolic pressure (torr) Diastolic pressure (torr) Mean arterial pressure (torr) Pulse (beats/min)

20 min 111.1 113.8 64.5 53.3 80.0 73.5 95.2 122.1

± 12.6 (n = 21)

± 8.7 ± 8.7 ± 7.4 ± 9.3 ± 7.1 ± 10.5 ± 9.0

(n = 23) (n = 21) (n = 23) (n = 21). (n = 23) (n = 21) (n = 23)

2-4 hr

± 11.2 (n = 21)

± 14.6 (n ± 8.3 (n ± 11.9 (n ± 8.3 (n ± 11.0 (n ± 13.2 (n ± 16.7 (n

110.6 109.6 63.5 51.8 79.2 71.0 90.1 123.2

23) 21)U 23)t 21)t 23)t = 21)U = 23)t = = = = =

± 11.5 (n = ± 10.7 (n = ± 9.4 (n = ± 8.0 (n = ± 9.5 (n = ± 7.6 (n = ± 9.3 (n = ± 13.1 (n =

21) 23) 21)U 23)t 21)* 23)t 21)U 23)t

Ni[, Nifedipine; Rlt., ritodrine. *Values are mean ± SD; number of subjects in parentheses. tp < 0.05 (compared with baseline value). *p < 0.05 (comparison between values in nifedipine and ritodrine patients at specified interval).

Table III. Comparison of maternal baseline and 24-hoUl: values for blood urea nitrogen, creatinine, calcium, and serum glutamic-oxaloacetic and glutamic-pyruvic transaminase Value*

Baseline (pretreatment)

Group

Nif Rit Nif Rit Nif Rit Nif Rit Nif Rit

Blood urea nitrogen (mg/l00 ml) Creatinine (mg/100 ml) Calcium (mg/ 100 ml) Serum glutamic-oxaloacetic transaminase (IU) Serum glutamic-pyruvic transaminase (IU)

7.1 7.5 0.63 0.68 8.9 8.8 20.3 18.0 18.0 15.4

± 2.1 (n ± 2.8 (n ± 0.13 (n ± 0.17 (n ± 0.4 (n ± 0.4 (n ± 9.5 (n ± 8.9 (n ± 9.0 (n ± 7.2 (n

24 hr

23) 24) 25) 23) = 25) = 23) = 26) = 24) = 26) = 23)

4.7 6.6 0.61 0.64 8.4 8.4 14.6 17.8 10.7 12.9

= = = =

± 1.4

(n = 14)t

± 0.14 ± 0.15 ± 0.4 ± 0.4 ± 10.9 ± 10.0 ± 4.7 ± 5.8

(n (n (n (n (n (n (n (n

± 2.9 (n

11) 14) = 11) = 14)t = lO)t = 14) = 11) = 14)t = 11) =

=

Ni[, Nifedipine; Rlt., ritodrine. *Values are mean ± SD; number of subjects in parentheses. tp < 0.05 (compared with baseline value).

Table IV. Comparison of maternal baseline values with interval values for serum levels of sodium, potassium, chloride, and bicarbonate and anion gap

Value*

Group

Sodium (mEq/L) Potassium (mEq/L) Chloride (mEq/L) Bicarbonate (mEq/L) Anion gap (mEq/L)

Nif Rit Nif Rit Nif Rit Nif Rit Nif Rit

Testing Interval

Baseline (pretreatment)

137.0 137.5 3.8 3.9 108.9 107.6 20.5 21.3 11.5 12.6

± ± ± ± ± ± ± ± ± ±

2.5 2.4 0.3 0.2 2.8 3.5 2.7 2.6 3.9 3.5

(n (n (n (n

(n (n (n (n (n (n

= 24) = 22) = 26) = 25) = 24) = 22) = 24) = 22) = 24) = 22)

8 hr

136.1 137.9 3.9 3.2 109.7 109.1 20.3 17.9 10.1 14.0

± ± ± ± ± ± ± ± ± ±

1.6 2.4 0.3 0.3 2.3 2.3 2.4 3.3 2.1 3.8

(n (n

(n (n

(n (n (n (n

(n (n

= 22)t = 20) = 22)t = 22)* = 22) = 20) = 22)t = 20)* = 22)t = 20)

I

16 hr

136.2 137.5 3.8 3.4 109.0 110.4 20.9 18.0 10.1 12.5

± ± ± ± ± ± ± ± ± ±

2.2 2.4 0.3 0.4 2.9 2.1 2.2 2.7 2.0 3.3

(n (n (n (n (n (n (n (n (n (n

= 18) = 18) = 21)t = 21)* = 18) = 18H = 18)t = 18)* = 21)t = 18)

I

24 hr

137.4 138.4 3.8 3.3 109.3 111.9 19.9 18.5 12.0 11.2

± ± ± ± ± ± ± ± ± ±

1.7 2.2 0.3 0.4 2.8 3.0 2.2 3.5 2.4 4.1

(n (n (n (n (n (n (n (n

(n (n

= 20) = 17) = 21)t = 21)t = 20)t = 17)* = 20) = 17H = 20) = 17)

Nif., Nifedipine; Rit., ritodrine. *Values are mean ± SD; number of subjects in parentheses. tp < 0.05 comparison between values in the nifedipine and ritodrine patients at the specified interval. *p < 0.05 compared with baseline value.

The 24-hour values for blood urea nitrogen, creatinine, serum glutamic-oxaloacetic and glutamic-pyruvic transaminase, hematocrit, glucose, sodium, potassium, chloride, bicarbonate, and anion gap were compared

with their respective baseline values and compared with the cumulative nifedipine dosage over 24 hours expressed on a milligram per kilogram basis. There were no significant correlations.

Cardiovascular and metabolic effects of nifedipine

Volume 161 Number 3

Comment

Nifedipine has been used with increasing frequency for the treatment of pre term labor, but the possibility that sublingual and oral nifedipine may cause cardiovascular or metabolic alterations had not been intensively investigated. Neither nifedipine nor ritodrine caused a significant change in systolic blood pressure during treatment. However, dramatically different results were noted between the two agents when diastolic and mean arterial pressure changes were evaluated (Figs. 1, A and B, and 2). Although statistically significant declines in diastolic blood pressure occurred after sublingual nifedipine administration, values at the time of maximum mean change still represented 92% of control and are unlikely to be of physiologic significance. During oral nifedipine administration, diastolic pressure also fell, but the decrease was significant in only one instance; the value represented 89% of control. Diastolic blood pressure decreases during ritodrine administration were more dramatic, and the magnitude and timing of the decreases approximated values previously reported when ~-adrenergic agents were used. 7 • 8 The maximum mean decrease (16 torr) occurred after the 300 J.Lg/min infusion rate; the diastolic blood pressure at that time was only 77% of control. In addition, the pattern of change of diastolic blood pressure was different after nifedipine and ritodrine tocolysis. During nifedipine therapy, the diastolic pressure decreased initially but then remained relatively stable during additional doses. Conversely, increasing infusion rates of ritodrine were associated with progressive decreases in diastolic and mean arterial pressure until the 200 J.Lg/min infusion rate was reached, at which time they tended to plateau. Increased pulse rates were noted in both patient groups. The magnitude of change was markedly different, however, probably reflecting the differences in diastolic and mean arterial pressure changes. The exaggerated response to ritodrine and minimal alterations with nifedipine treatment are apparent (Table II). Similar differences between tocolytic treatment groups have previously been reported when insignificant cardiovascular changes were found after magnesium sulfate administration, compared with dramatic differences found during ritodrine infusion. 7 Since magnesium sulfate is functionally a calcium channel entry blocker, the similar significant differences between treatment groups we report in cardiovascular responses should perhaps have been expected. When sublingual and oral nifedipine therapy are compared, it is interesting to note that pulse increases occurred 10 minutes after the first sublingual dose, but only 20 minutes after successive oral doses. In addition, although few significant changes in diastolic or mean arterial pressure occurred during oral therapy, when they did occur they were not noted before 20 minutes. These findings are similar to those noted by Raemsch

A

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36 35

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34 33 32 31 30

29 28

I

0

I

I

8

16

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Time (hr)

Fig. 3. Glucose values (A) and hematocrit values (B) (mean ± SEM) before and during nifedipine or ritodrine tocolysis. Solid symbols represent p < 0.05 compared with baseline values. Cross, p < 0.05 (comparison between values in nifedipine and ritodrine patients at specified interval).

and Sommer9 and suggest a more rapid absorption and distribution of nifedipine after sublingual administration. Our findings support the contention of McAllister lO that biting the capsule facilitates absorption of the liquid drug and lessens the time until the pharmacodynamic effects are observed when compared with oral administration of an intact capsule with the time delay before the capsule dissolves in the stomach and the drug is absorbed. This report provides the initial documentation of the cardiovascular changes of increased pulse rate and decreased diastolic pressure after the sublingual administration of nifedipine to treat pre term labor. Similar cardiovascular changes were noted with oral administration. The changes after oral administration are consistent with those reported by Ulmsten, 3 who used 30 mg as the initial dose, but discrepant from results of Read and Wellby,< who, using the same dosage schedule, did not note significant changes in the pulse rate or diastolic blood pressure. This discrepancy may be related to differences in the timing of measurement of the cardiovascular parameters. Our study also contrasts the effects on metabolic parameters produced by the tocolytic agents nifedipine and ritodrine. It is well recognized that nifedipine ad-

794

Ferguson et al.

ministration in nonpregnant patients causes vasodilatation and a resultant increase in plasma and extracellular volume.ll The fall in hematocrit, calcium, and blood urea nitrogen levels recorded in patients in this study is consistent with the recognized vasodilatation and increased plasma volume. Ritodrine also affects fluid balance. Hemodilutional decreases in hematocrit and colloid osmotic pressure regularly accompany the clinical use of l3-adrenergic tocolytic agents. 1. 2 In this study ritodrine was noted to cause a fall in calcium and a decrease in hematocrit during therapy. The decrease in hematocrit exceeded that noted with nifedipine at 8 hours of therapy. We were especially interested in potassium values after nifedipine administration because hypokalemia has been documented previously in nonpregnant patients receiving nifedipine. 12 In the patients studied in the nifedipine group, potassium levels remained unchanged, as did the remainder of the electrolytes studied and the anion gap. Conversely, the ritodrine patients exhibited the same changes in electrolyte concentrations that have been previously documented and. discussed. 2. 13. 14 Therefore differences between treatment groups in these parameters, when present, were the result of alterations of values in the ritodrine patients. Because of the lack of change of the bicarbonate and anion gap in the nifedipine group of patients, it thus seems likely that this form of tocolysis is not associated with the increases in serum lactate and pyruvate that are commonly seen and responsible for the increase anion gap in patients receiving ritodrine. 13• 14 There were marked differences in the magnitude of response demonstrated between groups for serum glucose concentrations. Patients in the ritodrine group exhibited the classic hyperglycemic response, with maximum values at 8 hours after initiation of infusion, with subsequent return toward baseline. Nifedipine patients demonstrated a modest degree of hyperglycemia. It was important to evaluate nifedipine's effect on glucose levels, because although most studies have documented that calcium channel entry blockers do not alter glucose homeostasis to a clinically relevant degree, some studies, (especially those with glucose loading and nifedipine doses >30 mg/day) have shown increased blood glucose and decreased insulin levels. 15 The mechanism is thought to involve blockade by nifedipine of a voltage-dependent "late" calcium channel of the pancreatic l3-cell, which normally allows the further ingress of calcium and subsequent release of insulin. 15 Because all patients received a continuous intravenous infusion of a 5% glucose solution, we cannot discern if the increased glucose levels in the nifedipine patients were the direct result of nifedipine administration through the mechanism outlined above, a result of glucosecontaining intravenous fluids, or both. The hypergly-

September 1989 Am J Obstet Gynecol

cemia noted with ritodrine was certainly much more dramatic when compared with that found with nifedipine administration, suggesting that nifedipine may be preferable if glucose homeostasis is a concern. We have provided the initial documentation of cardiovascular responses after the sublingual use of nifedipine for tocolysis and evaluated possible metabolic changes. On the basis of this study, it appears that the use of nifedipine for preterm labor tocolysis is associated with hemodilutional changes but not the untoward and unwanted cadiovascular or metabolic effects reported with ritodrine tocolysis. Since animal studies with nifedipine have resulted in discrepant findings related to uteroplacental perfusion,16. 17 a concern that presently limits the clinical use of calcium channelblocking drugs is their possible effect on uteroplacental blood flow in the human. Carefully controlled human investigations that evaluate fetal response to nifedipine tocolysis are necessary before nifedipine is considered for routine clinical use in human pregnancies. REFERENCES 1. Benedetti TJ. Maternal complications of parenteral betasympathomimetic therapy for premature labor. AM] OBSTET GYNECOL 1983;145:1-6. 2. Ferguson II ]E, Holbrook RH ]r, Stevenson DK, Hensleigh PA, Kredentser D. Adjunctive magnesium sulfate does not alter metabolic changes associated with ritodrine tocolysis. AM] OBSTET GYNECOL 1987;156:103-7. 3. Ulmsten U. Treatment of normotensive and hypertensive patients with preterm labor using oral nifedipine, a calcium antagonist. Arch Gynecol 1984;236:69-72. 4. Read MD, Wellby DE. The use of a calcium antagonist (nifedipine) to suppress preterm labour. Br] Obstet Gynaecol 1986;93:933-937. 5. Kaul AF, Osathanondh R, Safon LE, Frigoletto FD, Friedman PA. The management of preterm labor with the calcium channel-blocking agent nifedipine combined with the beta-mimetic terbutaline. Drug Intell Clin Pharm 1985; 19:369-71. 6. Ferguson II ]E, Hensleigh PA, Gill P. Effects of betamethasone on white blood cells in patients with premature rupture of the membranes and preterm labor. AM] OBSTET GYNECOL 1984; 150:439-41. 7. Thiagarajah S, Harbert GM, Bourgeois FJ. Magnesium sulfate and ritodrine hydrochloride: systemic and uterine hemodynamic effects. AM ] OBSTET GYNECOL 1985; 153:666-74. 8. Wager], Fredholm B, Lunell N-O, Persson B. Metabolic and circulatory effects of intravenous and oral salbutamol in late pregnancy in diabetic and nondiabetic women. Acta Obstet Gynecol Scand [Suppl] 1982; 108;41-6. 9. Raemsch KD, Sommer ]. Pharmacokinetics and metabolism of nifedipine. Hypertension 1983;5(suppl II): II-18-II-24. 10. McAllister RG Jr. Kinetics and dynamics of nifedipine after oral and sublingual doses. Am] Med 1986;81(suppl 6A):2-5. 11. Kleinbloesem CH. General introduction and aim of the investigations. In: Nifedipine: clinical pharmacokinetics and haemodynamic effects. Den-Haag, Netherlands: ]H Pasman's,1985:13. 12. Lederballe Pedersen 0, Mikkelsen E, Christensen N], Kornerup H], Pedersen EB. Effects of nifedipine on plasma renin, aldosterone and catecholamines in arterial hypertension. Eur] Clin Pharmacol 1979;15:235-40.

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13. Richards SR, Change FE, Stempel LE. Hyperlactacidemia associated with acute ritodrine infusion. AM] OBSTET GyNECOL 1983; 146: F5. 14. Kirkpatrick C, Quenon M, Desir D. Blood anions and electrolytes during ritodrine infusion in preterm labor. AM] OBSTET GYNECOL 1980;138:523-7. 15. Trost BN, Weidmann P. Effects of nitrendipine and other calcium antagonists on glucose metabolism in man.] Cardiovasc Pharmacol 1984;6:986-95.

Cardiovascular and metabolic effects of nifedipine

16. Veille ]C, Bissonnette ]M, Hohimer AR. The effect of a calcium channel blocker (nifedipine) on uterine blood flow in the pregnant goat. AM ] OBSTET GYNECOL 1986; 154: 1160-3. 17. Harake B, Gilbert RD, Ashwal S, Power GG. Nifedipine: effects on fetal and maternal hemodynamics in pregnant sheep. AM] OBSTET GYNECOL 1987;157:1003-8.

Prolactin levels in umbilical cord blood of human infants: Relation to gestational age, maternal complications, and neonatal lung function C. Richard Parker, Jr., PhD: Paul C. MacDonald, MD: David S. Guzick, MD," John C. Porter, PhD,b Charles R. Rosenfeld, MD,b and John C. Hauth, MD' Birmingham, Alabama, and Dallas, Texas The ontogeny of serum prolactin and its relation to several variables, especially lung function, in 543 neonates was studied. Umbilical cord serum prolactin levels rose between 24 and 42 weeks' gestation, correlating significantly (p < 0.001) with gestational age (r = 0.44) and birth weight (r = 0.32). Among infants of similar ages, however, there was no variation in serum prolactin level as a function of birth weight, sex, Apgar scores, or delivery method. Infants of women with pregnancy-induced hypertension had higher than normal prolactin levels; infants of diabetic women had normal prolactin levels. At 31.5 to 37 weeks' gestation, infants who developed respiratory distress syndrome had lower serum prolactin levels than those whose lung function was normal or else was abnormal from causes other than respiratory distress syndrome. The risk for respiratory distress syndrome was higher in newborns whose prolactin level was low (10th percentile) than in infants whose prolactin level was high (90th percentile). These results are suggestive that prolactin may playa role in fetal lung maturation. (AM J OSSTET GYNECOL 1989;161 :795-802.)

Key words: Prolactin, respiratory distress syndrome (RDS), hyaline membrane disease, human fetal lung, pregnancy The role of prolactin in lactation and the factors that serve to regulate pituitary prolactin production in adult humans are reasonably well characterized. On the other hand, the determinants of fetal pituitary prolactin production and the role circulating prolactin serves in the

From the Department of Obstetrics and Gynecology, Umversity of Alabama at BIrmingham: and the Green Center for ReproductIve Biology Sciences and Departments of Obstetncs and Gynecology and Pedzatncs, Umverslty of Texas Southwestern MedIcal Schoof.! These studies were supported by grants HD22969 and HD13912 from the National InstItutes of Health. Presented at the Ninth Annual Meeting of the Society of Pennatal Obstetricians, New Orleans, LOUISIana, February 2-4, 1989. Reprint requests: C. Richard Parker, Jr., PhD, Department of Obstetrics and Gynecology, Untverstty of Alabama at Blrmzngham, UAB Station, BirmIngham, AL 35294. 6/6/14095

developing human are less well established. Two tissues in the fetus that may be regulated by prolactin are the lung and adrenal cortex. Serum levels of prolactin and the weight of the adrenals increase in concert during fetal development, 1 before the rise in the lecithin/ sphingomyelin ratio in amniotic fluid! Moreover, an augmentation of surfactant lipid synthesis in lung tissue by prolactin has been reported by some, but not all, investigators (see reference 3 for review). It also has been proposed that prolactin may, along with adrenocorticotropin, participate in regulation of adrenal steroid production in human adults· and fetuses." If prolactin does, indeed, stimulate steroid production in the fetal adrenals, then prolactin also could play an indirect role in fetal lung maturation by means of inducing adrenal secretion of glucocorticoids and/or androgens that

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