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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Rambam Medical Center; andFaculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Address reprint requests to: Israel Thaler, MD, Rambam Medical Center, Department of Obstetrics and Gynecology, POB 9602, Haifa 31096, Israel; E-mail: thaler{at}netvision.net.il.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Thirty-minute recordings of FHR and fetal movements, before (stage I) and after (stage II) sublingual administration of 5 mg of isosorbide dinitrate, a nitric oxide donor, were obtained in 20 women with pregnancy-associated hypertension.
RESULTS: Baseline FHR in stage I did not differ significantly from that in stage II (140.9 ± 2.0 beats per minute and 137.5 ± 2.1 beats per minute, respectively). There were no significant differences between stage I and II in the number (9.67 ± 1.14 versus 9.56 ± 1.07), amplitude (26.14 ± 1.03 versus 24.5 ± 0.85 beats per minute), and duration (36.03 ± 1.46 versus 34.04 ± 1.57 seconds) of heart rate accelerations. During stage II, the number (1.39 ± 0.43) and duration (26.9 ± 1.38 seconds) of heart rate decelerations did not change significantly as compared with stage I (1.67 ± 0.33 and 26.23 ± 1.13 seconds, respectively). However, the amplitude of heart rate decelerations was significantly higher in stage I compared with stage II (-19.36 ± 1.44 versus -14.38 ± 1.55 beats per minute, respectively). There were more fetal body movements during stage II than stage I (12.39 ± 2.8 versus 9.72 ± 2.0), but the difference was not statistically significant.
CONCLUSION: Based on numeric analysis of FHR records, our data suggest that short-acting donors of nitric oxide can be administered safely to patients with pregnancy-associated hypertension.
Preeclampsia, a major cause of maternal and perinatal morbidity, is characterized by increased pressor sensitivity and peripheral resistance, activation of the coagulation cascade, and hypoperfusion of many vascular beds.1 Impairment of nitric oxide production by the vascular endothelium has been implicated in the pathogenesis of preeclampsia. Although endothelium-derived nitric oxide has been implicated in the maintenance of low placental blood flow resistance in normal pregnancy,2,3 it has been suggested that basal and stimulated nitric oxide activity is impaired in the fetoplacental circulation during preeclampsia.4,5 A reduction of placental nitric oxide synthase activity was demonstrated in preeclampsia, which may have an adverse effect on placental hemodynamics, as reflected by the development of the high impedance fetoplacental circulation.6 Indeed, placental nitric oxide synthase activity was significantly lower in women with abnormal umbilical artery flow velocity waveforms as compared with women with a normal flow pattern.7 Despite these data, studies on the role of nitric oxide in preeclampsia have yielded conflicting results. For example, in established preeclampsia, production of nitric oxide was higher in the uteroplacental, fetoplacental, and peripheral circulation than in normotensive pregnancies.8 This increase was related to a compensatory mechanism, offsetting the pathologic effects of preeclampsia.
Increased Doppler resistance indices in the umbilical artery in hypertensive pregnancies is consistent with adverse perinatal outcome.9,10 The observation that Larginine, a precursor of nitric oxide, reverses the adverse pregnancy changes induced by nitric oxide synthase inhibition11 have led investigators to study the efficacy of exogenous nitric oxide donors in the treatment and prevention of preeclampsia. Preliminary results were encouraging, demonstrating improvement in uteroplacental and fetoplacental blood flow, a reduction in maternal blood pressure (BP), and decreased platelet activation.12–17
However, concerns were raised regarding the possible detrimental effect this treatment may have on an already compromised fetus, as is often the case in pregnancy hypertension. To date, there is little information in the literature that addresses this issue. Therefore, we undertook this study in an attempt to investigate, based on fetal heart rate (FHR) and fetal activity patterns, whether this treatment modality may have adverse effects on the fetus in patients with hypertension.
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MATERIALS AND METHODS |
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The study was performed in two stages, each lasting 30 minutes. In the first stage (stage I), all measurements were obtained before a nitric oxide donor was administered. In the second stage (stage II), the measurements were obtained after each woman was given a sublingual tablet of 5 mg of isosorbide dinitrate (Dexxon, Haifa, Israel). In this manner, each woman served as her own control.
In stage I, 30-minute recordings of FHR and uterine contractions were obtained, using an HP 50A (Hewlett Packard Company, Boblingen, Germany) FHR recorder. During the recordings, the women were placed in the left lateral recumbent position. Each woman was asked to press a hand-held button each time she felt the baby moving. Fetal heart rate, uterine contractions, and fetal movement data were sampled into a computer via a digital serial interface and stored in a file for subsequent analysis.
Measurements of maternal BP, heart rate, and the ratio between peak-systolic to end-diastolic flow velocity (S/D) in the umbilical arteries were obtained at the beginning of FHR recordings and every 5 minutes thereafter, for a total of 30 minutes. Maternal BP and heart rate were recorded by an automatic BP recorder (BP-10015, Nippon Colin, Tokyo, Japan). This recorder employs the oscillometric method, whereby oscillations in cuff pressure, reflecting arterial pulsations, are detected. Changes in the amplitude of these oscillations over time are analyzed by a microcomputer to calculate the systolic and diastolic BP. Mean arterial pressure was calculated as diastolic BP +(1/3 x [systolic BP – diastolic BP]).
Blood flow velocity waveforms in the umbilical artery were obtained from a segment of the umbilical cord near the placental insertion via a 3.5-MHz duplex scanner (ESI 2000, Elscint Ltd., Haifa, Israel). A high-pass filter (100 Hz) was used to eliminate low-frequency signals originating from vessel wall movements. Blood flow velocity waveforms were continually recorded, taking care to place the sample volume in the same arterial segment. All waveforms were recorded on a video recorder with a built-in clock (National NV-180EN, Matsushita Electric Industrial Co., Osaka, Japan). Measurements of S/D were obtained off-line by video replay. Each value obtained was calculated as the mean of three consecutive similar waveforms. All Doppler measurements were obtained by the same operator.
The same protocol was employed in stage II, with each patient serving as her own control. Initially, each patient was asked to place the tablet sublingually until completely dissolved (this occurred within 90 seconds). Time count commenced once isosorbide dinitrate was administered.
A set of programs was employed for processing the sampled FHR recordings, as previously described.18 Artifacts were detected by an error-rejection algorithm, whereas missing data were linearly interpolated. Fetal heart rate features, including accelerations, decelerations, and beat-to-beat variation were then numerically calculated. All the calculated parameters, as well as fetal movements and uterine contractions data, were stored in a database for subsequent retrieval and statistical data analysis. Fetal heart rate variation was calculated as the range in heart rate each minute (beats per minute) and as the root mean square of the deviation from the baseline for each minute. The range was calculated as the difference between minimum and maximum heart rates. The mean minute range and the mean minute root mean square value were measured over the total recording time.
Statistical analyses were performed using the SAS statistical package (SAS Institute, Cary, NC). Data (for mean BP, maternal heart rate, and S/D) were analyzed for comparison between means with analysis of variance for repeated measures. Multiple comparisons with baseline were performed with the Dunnett test. The paired t test was used to evaluate FHR, uterine contractions, and fetal movements data. Power analysis was performed to determine how large a difference could be detected with the number of patients in the study. A difference of one standard deviation could be detected with a power of 90%. A value of P < .05 was considered statistically significant. Results are expressed as the mean ± 1 standard error of the mean.
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RESULTS |
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After isosorbide dinitrate administration, the average fail time of FHR recordings (132.9 ± 26.0 seconds) did not differ significantly from that during the control period (154.5 ± 30.5 seconds). There was no significant change in FHR baseline during the two study periods (140.9 ± 2.0 beats per minute in stage I and 137.5 ± 2.1 beats per minute in stage II).
There were no significant changes in the characteristics of FHR accelerations during the two study periods. The number of accelerations was 9.67 ± 1.14 in stage I and 9.56 ± 1.07 in stage II. Accelerations in stage I had a slightly higher amplitude (26.14 ± 1.03 beats per minute) and duration (36.03 ± 1.46 seconds) compared with stage II (24.5 ± 0.85 beats per minute and 34.04 ± 1.57 seconds, respectively). The mean interacceleration interval was shorter in stage I than in stage II (135.5 ± 10.4 seconds versus 142.3 ± 12.1 seconds).
Table 1
summarizes characteristics of FHR decelerations. The average number of FHR decelerations during stage I was higher than in stage II, but the difference was not significant (1.67 ± 0.33 and 1.39 ± 0.43, respectively). The mean amplitude of FHR decelerations was significantly greater in stage I than in stage II (-19.36 ± 1.44 beats per minute and -14.38 ± 1.55 beats per minute, respectively, P < .02). The mean duration of FHR decelerations did not significantly differ between the two study periods (26.23 ± 1.13 seconds in stage I and 26.9 ± 1.38 seconds in stage II). The mean deceleration area was significantly greater in stage I (250.7 ± 17.8 beats per minute * second) than in II (198.5 ± 18.5 beats per minute * second, P < .05).
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). The mean minute range and the root mean square deviation from baseline were higher in stage I (25.6 ± 2.12 and 9.85 ± 1.0 beats per minute) compared with stage II (23.78 ± 1.71 and 8.83 ± 0.89 beats per minute, respectively), but the difference was not statistically significant.
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). The average number of uterine contractions during stage I was 3.11 ± 0.32 with a mean duration of 73.7 ± 5.28 seconds compared with 2.78 ± 0.48 and 66.0 ± 3.47 seconds, respectively, in stage II. The differences were not statistically significant.
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DISCUSSION |
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The beneficial effects of nitric oxide donors in preeclamptic patients and in pregnant women identified to be at risk for developing preeclampsia on the basis of abnormal uterine artery Doppler waveforms at 24–26 weeks’ gestation have been described.12–16,19 In these studies, a significant decrease in Doppler resistance indices in the uterine arteries after administration of nitric oxide donors was reported. A less consistent response was observed in the umbilical artery, ranging from a significant decrease in Doppler resistance indices12,14,15 to a lack of any significant change.13,16 In the present study, a significant decrease in S/D in the umbilical artery was observed, similar to a previous study using the same treatment.15
A substantial decrease in mean maternal BP was reported in all studies in which donors of nitric oxide were administered to preeclamptic patients.13–17,20,21 There were no significant changes, however, in Doppler resistance indices in the fetal middle cerebral artery or in the umbilical artery.13,14,16 In the present study, mean maternal BP decreased by 9.5%, 20 minutes after isosorbide dinitrate administration. Despite this decline in maternal BP, FHR patterns improved, and an increase in the number of fetal movements was observed. This beneficial effect could be attributed to an improved uteroplacental blood flow. In a previous study, the same dose of sublingual isosorbide dinitrate caused a 27% decline in S/D in the uterine artery in patients with gestational hypertension.15 A similar observation was also reported in other studies where different donors of nitric oxide were administered.12–14,16,19 This fall in uterine artery resistance could increase intervillous blood flow, offsetting the fall in maternal BP.
Improved intervillous flow may also be related to the effect of nitric oxide donors on myometrial contractility. Nitric oxide is a potent relaxant of smooth muscle and may play a role in maintaining uterine quiescence during pregnancy.22 It has been tested as a tocolytic agent in animal models and in preliminary clinical trials, with promising results.23 We have observed a moderate but insignificant reduction in the frequency and duration of uterine contractions after administration of isosorbide dinitrate. Donors of nitric oxide may also diminish uterine tone and decrease the intensity of uterine contractions. These effects could further improve uteroplacental perfusion and counterbalance the fall in maternal BP. Indeed, when a long-term treatment using transdermal isosorbide dinitrate was applied to preeclamptic women with oligohydramnios, a gradual increase in amniotic fluid volume was observed over a course of a few days,17 emphasizing the beneficial role of nitic oxide during pregnancy. In contrast, subcutaneous infusion of L-nitroarginine methyl ester, an inhibitor of nitric oxide synthesis, caused hypertension, fetal growth restriction, and increased mortality rates in pregnant rats.24
Since its introduction more than two decades ago,25,26 the nonstressed FHR monitoring test continues to be the most commonly used modality for the evaluation of fetal status during the antepartum period. Automated analysis of the FHR records was recently introduced in an attempt to achieve reproducible, objective analysis27,28 that would eliminate such problems as inter- and intraobserver variability29,30 and enable rapid numeric analysis of a large body of data.
Based on automated analysis of FHR, we have shown that short-acting nitric oxide donors can be administered safely to patients with hypertension. This treatment was associated with improved FHR patterns, increased number of fetal movements, decreased Doppler resistance indices in the umbilical artery, and decreased mean maternal BP. As we examined the short-term effects of nitric oxide donors on FHR in a relatively small group of patients, these results justify further investigation with the use of long-acting donors of nitric oxide (eg, slow release dermal patches) in patients with hypertension and preeclampsia.
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Footnotes |
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Received November 26, 2001. Received in revised form April 2, 2002. Accepted April 18, 2002.
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REFERENCES |
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2. Gude NM, King RG, Brennecke SP. Role of endothelium-derived nitric oxide in maintenance of low fetal vascular resistance in placenta. Lancet 1990;336:1589–90.[Medline]
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