For some years, oral misoprostol in early pregnancy has been associated with multiple congenital abnormalities in humans,1–3 believed to be due to disruption of vascular flow to the fetus during early pregnancy by misoprostol,1 but there has been no clinical evidence for it. Uterine blood flow impairment by ergotamine administration4 or clamping of the uterine artery during pregnancy5 was shown to be associated with multiple congenital abnormalities.
It is believed that misoprostol might cause uterine arterial vasoconstriction that subsequently leads to teratogenicity,1–3 but vasoconstrictive effects of misoprostol have been shown only in vitro with use of isolated uterine arteries.6 The objective of this study was to assess prospectively changes in Doppler resistance indices (RIs) of uterine arteries in a group of women in early pregnancy to determine vasoconstrictive effects of misoprostol.
Materials and Methods
A prospective observational study was performed between May 20, 1996, and April 22, 1997, approved by the Clinical Research Ethics Committee of The Chinese University of Hong Kong. Healthy women with normal singleton gestations were recruited at admission for legal, surgical termination of pregnancy. Exclusion criteria were cardiac disease, history of elevated intraocular pressure, known allergy to prostaglandins (PGs), and history of epilepsy. Each subject was given an explanation and signed a consent form before commencement of the study.
Transvaginal ultrasonography was performed before misoprostol administration and 1 hour later with an Aloka Echo Camera SSD-2000 (Aloka Company, Ltd., Tokyo, Japan). A 5-MHz transvaginal Doppler ultrasound probe (UST-980P-5; Aloka Company, Ltd.) was used for the Doppler studies. Assessed in the first ultrasound were fetal heart rate (FHR; beats per minute) and both uterine arteries' A/B ratios (UA-A/B) and pulsatility indices (UA-PI). The uterine arteries were examined at the level of the internal os where the artery approaches the uterus laterally. The internal os was viewed first in the sagittal plane. The probe then was turned to the transverse position and angled upward toward the long axis of the uterus. The vascular bundles were then visible and pulsations could be seen in real time, helping to identify the uterine arteries. The characteristic blood-flow velocity waveforms were obtained by placing the Doppler gate over the identified vessel. Three optimal and similar consecutive waveforms were used for analysis for each uterine artery.
After the first ultrasound, each woman received one 200-μg oral tablet of misoprostol (Cytotec; G. D. Searle and Co., Skokie, IL). One hour later, the second ultrasound was done and the same measurements were made. Surgical termination of pregnancy was done after the second ultrasound. All Doppler RIs were measured by the same investigator (AO-KT). Intraobserver errors were 8.3% for UA-PI and 11.1% for UA-A/B.
Statistical analyses were done on a personal computer with use of the Statistical Package for Social Sciences 6.0 (SPSS Inc., Chicago, IL). The paired t test was used for testing differences before and after administration of misoprostol. P < .05 was considered statistically significant.
Forty-one pregnant women seeking termination of pregnancy at 7–15 completed gestational weeks were recruited. We were unable to recruit women at less than 7 weeks' gestation because women usually do not present for termination of pregnancy before 7 weeks. One woman was excluded from the study by mistake because we thought asthma was a contraindication for the use of misoprostol. Forty women were chosen as a convenient sample and their data were analyzed. A post hoc sample size and power analysis (done with use of the computer software package Pass 6.0 [NCSS Statistical Software, Kaysville, UT]) showed a power (1–β) of 90% for the calculations.
The mean (± standard deviation [SD]) age of the women was 28.3 ± 8.6 years. Mean (± SD) gestational age at the time of misoprostol administration was 10.8 ± 1.8 weeks. Mean (± SD) parity was 1.5 ± 1.3. Ten of the subjects were at less than 9 weeks' gestation, 23 were at 9–12 weeks' gestation, and seven were at more than 12 weeks' gestation. There were 12 nulliparas and 28 multiparas.
The right uterine artery was identified in 37 women. Because of technical difficulties, the left uterine artery could be identified in only 22 women. Doppler RIs (UA-A/B and UA-PI) of the right and left uterine arteries increased significantly after misoprostol administration (Table 1). Those changes indicated that single doses of 200 μg oral misoprostol constricted the uterine arteries significantly 1 hour after administration.
Fetal heart rate could be measured in all 40 women. No significant changes in FHR were noted 1 hour after misoprostol administration (Table 1). None of the fetuses died during that period, suggesting that single doses of 200 μg oral misoprostol had minimal observable immediate effects on the fetuses.
The findings of this study further support the possible relationship between misoprostol-associated teratogenicity in early pregnancy and uterine artery blood-flow impairment.1,5,7 In the study by Gonzalez et al,1 infants of mothers who had received subtherapeutic doses of misoprostol for the termination of pregnancy had major limb deformities. The most distinctive phenotypes were arthrogryposis confined to the legs and terminal transverse-limb defects with or without Möbius sequence. Prostaglandin infusion during pregnancy also was related to hemorrhage in the fetal brain-stem nuclei.8 In rats, restriction of blood flow to the uterus was associated with similar brain-stem lesions and limb deformities in offspring, and it was postulated that the cause was probably transient ischemic-hypoxic insults to the fetuses.5,7
Misoprostol is a known potent vasodilator in most vascular beds.9–11 However, misoprostol-induced vasoconstrictions have been reported in the limbs10 as well as kidneys12 of humans. In the laboratory, it also hasbeen shown that PGE2, PGF2α, PGD2, and PGI2 constrict isolated human uterine arteries and that vasoconstriction is mediated through prostanoid receptors that are present in the blood vessels.6 We confirmed in the current study that the effects of misoprostol on uterine arteries of pregnant women are vasoconstrictive and that vasoconstriction could occur as soon as 1 hour after the administration of a low dose of oral misoprostol.
In this study, the left uterine artery could be identified in only 22 women, due to the difficulty encountered when pulsed-wave Doppler was used to determine the incident angle of sampled vessels and due to the tortuous anatomy and the pulsatility of small vessels in the uterine circulation. With the pulsed-wave technique, the blood flow must be measured from a vessel large enough to be seen by real-time ultrasonography to be reproducible.13 Those problems can be solved with the use of color Doppler, which was not available at our institution at that time, and in many cases attempts to identify the left uterine artery were abandoned because of patient discomfort.
Doppler velocimetry for quantifying flow has been used to measure flow rate in blood vessels.14,15 However, this technique is limited in clinical practice because there are several sources of error.16 One is measurement of the vascular cross-sectional area. Any error made in measuring vessel diameter is amplified significantly when volume flow is calculated. Another source of inaccuracy is determination of the angle of insonation. The main problem is the difficulty in achieving uniform insonation because of beam inhomogeneity. Because of those difficulties in quantifying flow, blood-flow velocity waveforms commonly have been interpreted as RIs, to distinguish patterns associated with high and low resistance in distal vascular trees.17 Abnormal uterine artery Doppler waveforms, such as diastolic notching, also have been noted in abnormal pregnancies,18,19 but they were not noted in this study.
Uterine artery blood-flow volume and velocity increase gradually until the end of 9 weeks' gestation and then rapidly from 10 to 16 weeks' gestation.20 Uterine artery vessel size increases linearly and uterine artery RI is the inverse of volume of velocity.20 We used the paired t test to test differences in characteristics before and after administration of misoprostol. Between-subject variability therefore was removed, allowing us to concentrate on within-subject differences.
The dose of misoprostol used in this study was subtherapeutic for termination of pregnancy (reported effective doses range from 400 to 1000 μg [in divided oral doses]21–23). However, we showed that subtherapeutic doses of misoprostol caused uterine artery vasoconstriction, although the significance of that level of vasoconstriction to the fetus has yet to be determined. We believe that a similar study involving subtherapeutic doses of misoprostol in animal models should be done so that teratogenic effects, particularly the dose-effect relationship, of uterine artery vasoconstriction can be investigated. On the clinical side, subtherapeutic doses of prostanoid abortifacients could lead to multiple congenital malformations, which has clinical implications, particularly with regard to illegal abortion and the use of misoprostol for treating gastric ulcers in reproductive-age women.
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