Effects of tocolytic treatment with ritodrine on cardiovascular autonomic regulation.

OBJECTIVE: To study the acute effects of tocolytic treatment with intravenous ritodrine on cardiovascular autonomic regulation. DESIGN: Validated methods to assess cardiovascular autonomic nervous function-heart rate and blood pressure variability and vagal cardiac baroreflex sensitivity-were measured before and during ritodrine infusion. SETTING: Turku University Central Hospital, Turku, Finland. SAMPLE: Twelve pregnant women admitted to hospital for threatened preterm labour. METHODS: Electrocardiogram and continuous noninvasive finger blood pressure signals were recorded in each woman, resting in a supine position. Autoregressive spectrum analysis was used to quantify short term heart rate and blood pressure variability. Vagal cardiac baroreflex sensitivity was measured as the bradycardia response to an intravenous bolus injection of phenylephrine. MAIN OUTCOME MEASURES: Vagal cardiac baroreflex sensitivity and spectrum analysis indices of short term heart rate and blood pressure variability. RESULTS: Ritodrine significantly decreased vagal cardiac baroreflex sensitivity as well as total (0.00-0.40 Hz), low frequency (0.04-0.15 Hz) and high frequency (0.15-0.40 Hz) power bands of the heart rate variability spectrum. Ritodrine significantly increased mean heart rate and the low frequency power band of the systolic blood pressure variability spectrum. CONCLUSIONS: In pregnant women with threatened preterm labour intravenous administration of ritodrine decreases vagal cardiac baroreflex sensitivity and vagal modulation of heart rate, and increases sympathetically mediated blood pressure variability. Decreased baroreflex sensitivity and heart rate variability are known to be associated with a poor prognosis in some patient groups, so the effects of ritodrine tocolysis may be unfavourable in women with impaired circulatory homeostasis.     

Poly-plethysmographic study on the effects of ritodrine on the cardiovascular system of patients in labour

The effects of ritodrine infusion on the cardiovascular system of six women in threatened or premature labour are reported. In contrast to other betamimetics, ritodrine caused a moderate rise in systolic blood pressure, the corresponding fall in diastolic pressure leading to a widened pulse pressure but no risk of hypotension. Ritodrine caused a rise in cardiac output, and was well tolerated by the patients. Special care should be taken in treating patients with known heart disease.     

Pharmacodynamics of ritodrine in pregnant women during preterm labor

We evaluated the relationship of ritodrine concentration to several maternal variables and to fetal heart rate in 17 women who received the drug for inhibition of preterm labor. Ritodrine was measured by high-performance liquid chromatography with electrochemical detection. Ritodrine increased maternal and fetal heart rate and decreased serum potassium in a dose-related manner, but wide variability was noted between patients and within individual patients. Tachyphylaxis of the maternal heart rate response to continuing treatment with ritodrine was seen in at least seven women. Maternal blood pressure, serum glucose concentration, and frequency of uterine contractions were changed by ritodrine treatment, but the changes in these variables were not closely correlated to the concentration of ritodrine (r less than or equal to 0.30 in all cases). The maximal infusion rate and the concentration of ritodrine in maternal serum after 4 hours of treatment were significantly (p less than 0.001) correlated with the frequency of uterine contractions prior to treatment. Successful inhibition of labor was achieved with serum concentrations of 15 to 31 ng/ml in 10 of 17 women; in six of the other seven women, labor could not be inhibited in spite of serum concentrations of 90 to 146 ng/ml. Side effects, such as hypotension, vomiting, chest discomfort, and shortness of breath, were most commonly observed when the infusion rate and concentration of ritodrine were increasing.     

Magnesium sulfate and ritodrine hydrochloride: systemic and uterine hemodynamic effects

Effects of magnesium sulfate and ritodrine hydrochloride on cardiovascular physiologic characteristics were studied in 70 human subjects treated for preterm labor. Systemic and uterine hemodynamic effects were investigated in five pregnant rhesus monkeys. Systolic blood pressure was minimally affected by either agent. Diastolic pressure, while not affected by magnesium sulfate, decreased 26.3% during ritodrine therapy. Maternal and fetal heart rates were minimally affected by magnesium sulfate. Ritodrine increased maternal and fetal heart rates significantly. In the monkeys, magnesium sulfate increased uterine and placental blood flows (by the microsphere technique) but failed to alter cardiac output. Ritodrine produced an increase in cardiac output but decreased perfusion pressure. Placental blood flow decreased by an average of 27.6%. Ritodrine would therefore seem contraindicated with a compromised fetal environment. Magnesium sulfate, by not altering perfusion pressure, may have a beneficial effect on uterine hemodynamics. These specific and distinct differences in cardiovascular and hemodynamic effects should be considered when either magnesium sulfate or ritodrine is selected as a tocolytic agent.     

Circadian rhythm of frequency-domain measures of heart rate variability in pregnancy

Objective To examine frequency domain measures of heart rate variability and their circadian rhythms in pregnancy.
Design A longitudinal study.
Setting University hospital in Turku, Finland.
Participants Sixteen healthy women between 11 and 27 weeks of pregnancy; 12 women before pregnancy; and four women postpartum.
Main outcome measures Heart rate variability as measured in frequency domain from 24-hour ambulatory electrocardiography.
Results Pregnancy was associated with a lower standard deviation of R-R intervals (   P < 0.01  ), with reduced very low (   P < 0.05  ), low (   P < 0.01  ), and high frequency (   P < 0.05  ) power spectral components of heart rate variability. The high frequency power was lower at night in pregnancy, but similar in the daytime in pregnant and nonpregnant women.
Conclusions Pregnancy is associated with an overall reduction in heart rate variability, most markedly reflected in the low frequency component. This suggests altered baroreflex or sympathetic modulation of heart rate, and decreased vagal activation at night.     

Maternal and fetal cardiovascular effects of transdermal glyceryl trinitrate and intravenous ritodrine.

OBJECTIVE: To determine the maternal and fetal cardiovascular effects of transdermal glyceryl trinitrate compared with ritodrine for acute tocolysis. METHODS: Sixty women in preterm labor were enrolled in this study that was part of a multicenter study of glyceryl trinitrate. Once randomized, the women received transdermal glyceryl trinitrate or intravenous ritodrine for acute tocolysis. Measurements of maternal pulse, blood pressure (BP), and fetal heart rate (FHR) were recorded for up to 24 hours and compared over the treatment course. RESULTS: Changes from baseline in mean maternal heart rate, FHR, and maternal BP (mean arterial pressure [MAP]) were compared between the glyceryl trinitrate and ritodrine groups over the entire treatment course. The mean change from baseline in maternal heart rate was 21.1 beats per minute less (95% confidence interval [CI] 15.7, 26.5, P < .001), and the mean maternal heart rate was 21.8 beats per minute lower (95% CI 16.9, 26.7, P < .001) in the glyceryl trinitrate group. The mean change in FHR was 9.2 beats per minute less (95% CI 3.8, 14.6, P = .001) and the mean FHR significantly lower (6.9 beats per minute, 95% CI 1.9, 11.9, P = .008) during glyceryl trinitrate treatment. Ritodrine had a significantly hypotensive effect on MAP (95% CI -4.3, 0.0, P = .03). Mean arterial pressure was not significantly different over the treatment course. CONCLUSION: At doses required for acute tocolysis, transdermal glyceryl trinitrate had minimal effects on maternal pulse, BP, and FHR, and significantly fewer adverse cardiovascular effects than intravenous ritodrine. Thus, transdermal glyceryl trinitrate might be a safer treatment for women in preterm labor.     

Double-blind evaluation of ritodrine sustained release for oral maintenance of tocolysis after active preterm labour

Objective To evaluate the effect of ritodrine sustained release capsules for maintaining uterine quiescence after successful treatment of active preterm labour.
Design Multicentre placebo-controlled trial. Setting Five teaching hospitals in the Netherlands.
Participants Women (   n = 95  ) at less than 35 weeks of gestation in whom active preterm labour had been stopped with intravenous ritodrine.
Interventions Women received either two 40 mg ritodrine sustained release capsules (   n = 50  ) or identical placebo capsules (   n = 45  ) three times a day for seven days.
Results The proportion of women who received another course of active treatment was significantly smaller with the sustained release than with placebo (1 of 50 versus 11 of 45:   P = 0.003  ) as was the number delivering because of preterm labour during treatment (0 of 50 versus 4 of 45:   P = 0.04  ). There were no other significant differences between the two groups.
Conclusions Maintenance treatment with ritodrine sustained release capsules after arrest of preterm labour reduces the risk of recurrences of preterm labour that necessitate treatment or precipitate delivery.     

Cardiovascular effects of ritodrine tocolysis: a new noninvasive method to measure pulmonary capillary pressure during pregnancy

The cardiovascular effects of ritodrine tocolytic therapy were assessed by noninvasive simultaneous recordings of indirect carotid pulse, electrocardiogram (ECG), phonocardiogram, and M-mode echocardiogram in 12 patients in preterm labor. The study was performed before and during infusion, and afterward when the patient was on oral drug therapy. Ritodrine therapy increased heart rate, left ventricular fractional shortening, pre-ejection period/left ventricular ejection time ratio, and cardiac index. A progressive rise in pulmonary capillary pressure was observed in all patients, exceeding 18 mmHg (the threshold for the development of pulmonary congestion) in six patients. Systolic arterial pressure, left ventricular end-diastolic dimension, and plasma protein oncotic pressure remained unchanged during therapy. Ritodrine therapy resulted in a significant drop in diastolic blood pressure and peripheral vascular resistance. This noninvasive means of measuring cardiovascular parameters, including pulmonary capillary pressure, may be useful in monitoring patients who develop significant cardiovascular side effects during tocolytic therapy.     

Ampicillin-metronidazole treatment in idiopathic preterm labour: a randomised controlled multicentre trial

Objective To determine whether treatment with ampicillin and metronidazole in women with threatened idiopathic preterm labour will prolong the gestation and reduce maternal and neonatal infectious morbidity.
Design Randomised controlled double-blind trial.
Setting Six obstetric departments in the Copenhagen area.
Population One hundred and twelve women with singleton pregnancies, with threatened idiopathic preterm labour and intact amniotic membranes at 26 to 34 weeks of gestation.
Methods Random allocation to eight days intravenous and oral treatment with ampicillin and metronidazole, or placebo.
Main outcome measures Number of days from admission to delivery, gestational age at delivery, rates of preterm delivery, low birthweight, maternal infections and neonatal infections.
Results Treatment with ampicillin and metronidazole was associated with a significant prolongation of pregnancy (admission to delivery 47.5 days versus 27 days,   P < 0.05  ), higher gestational age at delivery (37 weeks versus 34 weeks,   P < 0.05  ), decreased incidence of preterm birth (42% versus 65%,   P < 0.05  ), and lower rate of admission to neonatal intensive care unit (40% versus 63%,   P < 0.05  ), when compared with placebo treatment. Antibiotic treatment had no significant effects on infectious morbidity.
Conclusions Treatment with ampicillin and metronidazole in women with threatened idiopathic preterm labour significantly prolonged the gestation, but had no effects on maternal and neonatal infectious morbidity.     

Metabolic and cardiovascular changes during prolonged ritodrine infusion in fetal lambs

Prophylaxis of threatened premature labor with ritodrine may lead to prolonged fetal exposure to the drug. To investigate the direct consequences of this, 11 fetal lambs were given ritodrine hydrochloride for periods of 2-4 days by continuous intravenous infusion at 5 or 10 micrograms/minute (1-3 micrograms/minute/kg estimated fetal weight). These dosages had no measurable effects on the ewes. In the fetus, measurements confirmed and extended the results of earlier short-term experiments, but differences from the effects of long-term maternal ritodrine infusion imply little placental transfer of the drug in sheep. Ritodrine had little or no effect on mean arterial pressure, blood pH, pCO2, plasma alpha-amino acid nitrogen, or growth hormone, but resulted in marked hypoxemia, tachycardia, hyperlactacidemia, hyperglycemia, and hyperinsulinemia during the first 24-48 hours of infusion. Despite continued ritodrine infusion, heart rate and the metabolic parameters returned toward normal within 72 hours. Hypoxemia persisted longer, but tended to lessen after 2 days of infusion. The results indicate that tachyphylaxis to ritodrine develops in the fetal lamb during prolonged administration, but that when fetal well-being is already compromised, ritodrine's effects on oxygenation and lactacidemia could jeopardize fetal survival.     

Spontaneous preterm birth of liveborn infants in women at low risk in Australia over 10 years: a population-based study

Objectives  To describe a 10-year trend in preterm birth.
Design  Population-based study.
Setting  Australia.
Population  All women who gave birth during 1994–03.
Methods  The proportion of spontaneous preterm births (greater than or equal to 22 weeks of gestation and less than 37 completed weeks of gestation) was calculated by dividing the number of women who had a live spontaneous preterm birth (excluding elective caesarean section and induction of labour) by the total number of women who had a live birth after spontaneous onset of labour (excluding elective caesarean section and induction of labour). This method was repeated for the selected population of women at low risk.
Main outcome measure  Preterm birth rates among the overall population of women; preterm birth among all women with a spontaneous onset of labour; and preterm birth in a selected population of women who were either primiparous or multiparous, non-Indigenous; aged 20–40 years and who gave birth to a live singleton baby after the spontaneous onset of labour.
Results  Over the 10-year study period, the proportion of all women having a live preterm birth in Australia increased by 12.1% (from 5.9% in 1994 to 6.6% in 2003). Among women with a spontaneous onset of labour, there was an increase of 18.3% (from 5.7 to 6.7%). Among the selected population of low-risk women after the spontaneous onset of labour, the rate increased by 10.7% (from 5.6 to 6.2%) among first time mothers and by 19.2% (4.4–5.2%) among selected multiparous women.
Conclusions  Over the 10-year period of 1994–03, the rate of spontaneous preterm birth among low-risk women having a live singleton birth has risen in Australia.     

Increased sympathetic activity present in early hypertensive pregnancy is not lowered by plasma volume expansion.

OBJECTIVE: To evaluate whether sympathetic activity is increased in early-onset hypertensive pregnancy and whether this can be influenced by management with plasma volume expansion. METHODS: The study group consisted of 74 subjects, of which 37 had early-onset hypertensive disorders of pregnancy (preeclampsia or gestational hypertension with fetal growth restriction), who were included at 24 to 34 weeks in a randomized controlled trial of management with (n = 18) or without (n = 19) plasma volume expansion. Heart rate and blood pressure variabilities, LF/HF ratio for heart rate, baroreflex sensitivity, and phase difference at low frequency (LF approximately 0.1 Hz) were calculated by spectral analysis from continuous heart rate and blood pressure recordings of the finger pulse wave (Portaprestrade mark, TNO). Measurements were performed at inclusion, after 20 to 40 hours and after 65 to 100 hours. The control group consisted of 29 women with a normal pregnancy and 8 women who had late-onset preeclampsia after 34 weeks. Controls were measured at 32 weeks. All controls had a normal blood pressures at that time. RESULTS: LF variability of heart rate and blood pressure were significantly higher and baroreflex sensitivity was significantly lower in early-onset patients compared with normal controls. A significant trend towards higher LF variability of blood pressure and lower baroreflex sensitivity was found from normal controls to late-onset controls to early-onset patients. Parameters of sympathetic activity were not influenced by plasma volume expansion. CONCLUSION: Sympathetic activity was increased in early-onset hypertensive pregnancy. However, this was not affected by management with plasma volume expansion, suggesting that hypovolaemia in preeclampsia is a secondary phenomenon.     

Comparison of vagal baroreflex function in nonpregnant women and in women with normal pregnancy, preeclampsia, or gestational hypertension

OBJECTIVE: Our aim was to compare baroreflex function among nonpregnant women and among women with normal pregnancy, preeclampsia, or gestational hypertension. STUDY DESIGN: Baroreflex function was tested in 20 women with preeclampsia, in 20 age- and gestational age-matched normotensive gravid women, in 20 age-matched nonpregnant women, and in 20 nonmatched women with gestational hypertension. The baroreflex was measured by several modalities. RESULTS: Vagal baroreflex gain measured by cross-spectral analysis of parallel spontaneous heart rate and blood pressure changes is significantly decreased in normal pregnancy (15.8 +/- 7.2 vs 10.8 +/- 4.1 ms/mm Hg; P = 0.001), in comparison with vagal baroreflex gain in nonpregnant women. Baroreflex gain is further reduced in preeclamptic pregnancy (10.8 +/- 4.1 vs 7.2 +/- 2.6 ms/mm Hg; P = 0.003) and in gestational hypertension (10.8 +/- 4.1 vs 6.5 +/- 2.7 ms/mm Hg; P = 0.001), compared with that in normal pregnancy. Similar differences were seen with other baroreflex testing modalities. CONCLUSIONS: The normal reduction of baroreflex gain in pregnancy is further depressed in subjects with hypertensive disorders of pregnancy.     

Climacteric vasomotor symptoms do not imply autonomic dysfunction

Objective To study whether oestrongen replacement therapy has an effect on autonomic haemodynamic control in postmenopausal women.
Design A placebo-controlled, prospective, randomised, double-blind cross-over trial.
Population Fourteen healthy postmenopausal women who had had a hysterectomy, of whom 12 were double-blind.
Methods At the end of each treatment period we conducted autonomic nervous system tests: the Valsalva manoeuvre, the deep breathing test, study at rest and the active orthostatic test. Baroreflex sensitivity was evaluated non-invasively from the Valsalva manoeuvre. Heart rate variability was assessed in time and frequency domains during supine rest and standing. Serum oestradiol was also measured and the previous two weeks' symptoms were assessed.
Results Autonomic nervous function was mostly normal for age and unchanged by oestrogen. Vasomotor symptoms were not associated with autonomic dysfunction. Baroreflex sensitivity was 13.3 ms/mmHg (SD 7.4 ms/mmHg) with placebo and 10.5 ms/mmHg (SD 5.4 ms/mmHg) with oestrogen (   P = 0.052  ). This was mostly due to a fall in three of the highest indices. In the orthostatic test the 30 s blood pressure overshoot in two women exceeded the normal 90% confidence interval upper limit, making the mean response strong, especially in the symptomatic group (   n = 7  ). Oestrogen attenuated this overshoot.
Conclusions Oestrogen did not have a consistent effect on the autonomic nervous system. Oestrogen attenuated a highly sensitive baroreflex and a strong 30 s blood pressure rise in the orthostatic test. This minor effect of oestrogen could be due to the fact that, in general, women with menopausal symptoms do not have impaired autonomic haemodynamic control. The effect of oestrogen in women with autonomic nervous system dysfunction remains to be studied.     

The influence of physiological parameters on long term heart rate variability in healthy preterm infants

The instantaneous heart rate shows a variation around the mean heart rate caused by cardioregulatory mechanisms which are mediated through the sympathetic and vagal autonomic nervous system. To gain more insight into the influence of physiological parameters on neonatal heart rate variability a study was performed in four healthy preterm newborns during the first five days of life. Instantaneous heart rate, respiration rate, transcutaneous pO2, blood pressure and behaviour were recorded during 40 minutes four times a day. Long term heart rate variability was calculated as the difference between p95 and p5 of instantaneous heart rate values sampled during three minutes. A clear relationship between long term variability and age (maturity of the autonomic nervous system), respiration rate (respiratory sinus arrhythmia or a tidal volume mediated effect) and behaviour (increase of sympathetic tone during REM sleep) was found. No influence of blood pressure, heart rate, and transcutaneous pO2 within physiological ranges could be detected. The relative influence of the different physiological parameters on heart rate variability has to be established before the value of heart rate variability as a monitoring tool in neonatal intensive care can be investigated.     

Pharmacokinetics and pharmacodynamics of ritodrine after intramuscular administration to pregnant women

To define the pharmacokinetics and pharmacodynamics of ritodrine after intramuscular injection, we administered 5 or 10 mg ritodrine into the gluteus or deltoid muscles of 12 pregnant volunteers. Six women received 5 mg and six received 10 mg into each muscle group on different days. We withdrew blood samples before and 12 times in the 6 hours after ritodrine injection. Blood pressure and heart rate were recorded at each time. Ritodrine was measured by high-performance liquid chromatography. Peak ritodrine concentrations (mean +/- SD) after a single 5 mg injection in the deltoid or gluteus were 38 +/- 13 and 26 +/- 8 ng/ml, respectively. After a 10 mg dose in the deltoid or gluteus, peak concentrations were 59 +/- 30 and 47 +/- 22 ng/ml, respectively. Although higher, the peak plasma concentrations after injections into the deltoid were not significantly greater than those after injection into the gluteus. None of the pharmacokinetic parameters differed according to dose or injection site. The pharmacodynamic effects of ritodrine were unaffected by injection site, but ritodrine caused a dose-related increase in heart rate and systolic blood pressure and a dose-related decrease in diastolic blood pressure. After a 10 mg injection, the maximal changes in heart rate, systolic, and diastolic blood pressure were 22%, 10%, and 19%, respectively. However, mean blood pressure was not altered by either the 5 or 10 mg dose. These findings indicate that there are few differences in pharmacokinetic parameters between deltoid and gluteal injection of ritodrine. The single intramuscular injection of 5 or 10 mg ritodrine results in labor-inhibiting concentrations with clinically insignificant cardiovascular effects.     

Vaginosonographic velocimetry in uterine arteries before and after administration of beta-mimetics.

OBJECTIVE: To investigate the effect of surgical procedures at 15 weeks gestation (amniocentesis or cervical cerclage), with or without post-operative ritodrine prophylaxis, on uterine blood flow velocity waveforms and maternal heart rate. DESIGN: A quasi-randomized observational study. SETTING: University Department of Obstetrics and Gynaecology, Vienna. SUBJECTS: Sixty women having a genetic amniocentesis for advanced maternal age and 57 women having elective cervical cerclage for previous preterm labour or recurrent miscarriage. INTERVENTIONS: The women in each group were allocated either to receive prophylactic ritodrine postoperatively or to receive no ritodrine treatment. Allocation used the year of birth of the woman (odd years received ritodrine, even years received no treatment). All the women had vaginal ultrasound velocimetry studies in both mainstem uterine arteries through the parametrium before the surgical procedure and again after the procedure. The ritodrine-treated women in the cerclage group received intraveneous ritodrine hydrochloride (0.2 mg/min) and those in the amniocentesis group received 60 mg ritodrine/day orally. MAIN OUTCOME MEASURES: Uterine artery blood flow velocity waveform indices: A/B ratio and pulsatility index (PI) and maternal heart rate before and after the surgical procedure. RESULTS: The only statistically significant difference in haemodynamic values between those obtained before the procedure and those obtained after the procedure with or without prophylactic ritodrine was seen in the women who had cervical cerclage with postoperative intravenous ritodrine. The mean A/B ratio decreased from 2.69 (SD 1.17) to 2.11 (SD 0.44), and the mean PI from 1.62 (SD 0.47) to 1.21 (SD 0.3) and the mean maternal heart rate increased from 82.6 (SD 11.1) to 99.4 (SD 15.7). There were no other statistically significant differences between before and after haemodynamic values. CONCLUSIONS: There are no clinically relevant effects of amniocentesis and cervical cerclage on uterine blood flow velocity waveforms.     

Granulocyte-colony stimulating factor for the treatment of ritodrine-induced neutropenia

We report on three pregnant women with ritodrine-induced neutropenia who were successfully treated with granulocyte-colony stimulating factor (G-CSF). The neutropenia occurred after continuous intravenous infusion of ritodrine for preterm labor. Ritodrine was discontinued and G-CSF was administered. Neutrophil counts returned to normal an average of 4.3 days after the administration. No infectious morbidity or adverse side-effects occurred in the mothers or infants. G-CSF is one possible treatment in women with ritodrine-induced neutropenia.     

Randomised comparison between a loading and incremental dose model for ritodrine administration in preterm labour

Objective To compare a new loading dose regimen for intravenous ritodrine administration in preterm labour with the conventional dose regimen.
Design Multicentre randomised trial using numbered opaque sealed envelopes.
Setting Five teaching hospitals in the Netherlands.
Participants Women (   n = 203  ) in preterm labour at less than 34 weeks of gestation.
Interventions Women received either a loading dose ritodrine infusion followed, as soon as tocolysis was reached, by a decrease in infusion rate or the conventional schedule of increasing doses until uterine quiescence was achieved.
Results Frequency of successful tocolysis (71 %) and duration of treatment (55 h) were similar in both groups, but the loading dose schedule was better tolerated with fewer adverse events. Also the number of dose adjustments was smaller than in the incremental dose group (   P < 0.001  ). Overall, the differences between the two regimens were unexpectedly small.
Conclusions Despite the small differences, the loading model is easier to apply, requires fewer dose adjustments, is better tolerated with less side effects, and reduces the likelihood of clinical error.     

Nifedipine concentration in maternal and umbilical cord blood after nifedipine gastrointestinal therapeutic system for tocolysis

Objective  To determine nifedipine concentrations in maternal plasma at steady state, and maternal and umbilical cord plasma at delivery, after tocolysis with nifedipine gastrointestinal therapeutic system (GITS) tablets.
Design  Prospective clinical pharmacokinetic study.
Setting  Department of Obstetrics at the Zurich University Hospital.
Population  Pregnant women treated for threatened preterm labour.
Methods  GITS dosage titrated to clinical response (30–150 mg/day). Nifedipine concentrations by high-performance liquid chromatography and turbo ion spray tandem mass spectrometry.
Main outcome measures  Steady-state nifedipine concentrations in maternal blood and nifedipine concentrations in maternal and corresponding umbilical cord blood at delivery.
Results  Steady-state nifedipine concentrations (micrograms/l, mean ± SE) were 54 ± 6 (all doses, n = 31), 38 ± 8 (60 mg/day, n = 13), and 92 ± 12 (150 mg/day, n = 7) ( P < 0.002). Umbilical cord and maternal concentrations both declined in a ln-linear regression with elimination half-lives of 20.4 and 17.4 hours. Linear regression showed a correlation between umbilical and maternal concentrations of 0.77 ± 0.1 ( n = 21, mean ± SE).
Conclusions  Steady-state plasma nifedipine concentrations after repeated dosing with nifedipine GITS 30–150 mg/day in pregnant women with preterm labour do not exceed 100 micrograms/l; fetal levels are 77% of maternal levels.