The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 11 5622-5626
Copyright © 2004 by The Endocrine Society
Increased Release of Cervical Nitric Oxide in Spontaneous Abortion before Clinical Symptoms: A Possible Mechanism for Preabortal Cervical Ripening
Mervi Väisänen-Tommiska,
Tomi S. Mikkola and
Olavi Ylikorkala
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, FIN-00029 Helsinki, Finland
Address all correspondence and requests for reprints to: Dr. Olavi Ylikorkala, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, P.O. Box 140, FIN-00029 Helsinki, Finland. E-mail: olavi.ylikorkala{at}hus.fi.
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Abstract
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Nitric oxide (NO) affects cervical ripening. We studied cervical NO release in women with nonviable pregnancy before signs of abortion. Women with missed abortion (n = 56), blighted ovum (n = 36), or tubal pregnancy (n = 7) were selected by means of vaginal ultrasonographic examination from a population seeking early pregnancy termination; 140 women with amenorrhea-matched normal gestation were studied as controls. Cervical fluid samples were assessed for NO metabolites (Nox) by means of Griess reaction. Cervical fluid Nox was more often detectable in women with missed abortion (90%) and blighted ovum (87%) than in the control women (55%; P = 0.01), and Nox levels in women with missed abortion [median, 59.4 µmol/liter; 95% confidence interval (CI), 30.3–81.8] and blighted ovum (25.6 µmol/liter; 95% CI, 14.1–53.0) were 14 and 6 times higher (P < 0.001 and P = 0.002, respectively) than in the control group (4.3 µmol/liter; 95% CI, <3.8 to 6.4). Nox levels in women with tubal pregnancy were normal. In women with nonviable pregnancy, the lower the level of progesterone, expressed as a percentage of that in the control women, the higher (r = –0.69; P < 0.001) the level of cervical fluid Nox, and those with low pretreatment Nox levels failed to abort completely after mifepristone-misoprostol or expectant management more often (P = 0.04) than women with high Nox levels (28% vs. 4%); no such relationship was seen in the control group. Increased preabortal cervical NO release may contribute to cervical ripening and the onset of clinical abortion.
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Introduction
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NITRIC OXIDE (NO) is produced through NO synthase (NOS), which is expressed in three isoforms: neuronal, inducible, and endothelial NOS (1). All of these isoforms are present in the various cells of the uterine cervix (2, 3, 4). The expression of NOS isoforms and the release of NO in the cervix have been shown to increase with advancing gestational age and during cervical ripening (2, 3, 5, 6, 7, 8, 9, 10, 11). These human data and those from animal and in vitro studies (5, 7, 11), imply that in pregnancy, cervical NO stimulation may be important in cervical ripening.
Approximately 10–15% of clinically detected pregnancies end in spontaneous abortion (12, 13). Half of these cases are caused by early death of the fetus as a result of various genetic or other aberrations; this is defined as missed abortion (14). One third of the cases of spontaneous abortion are caused by blighted ovum syndrome, when no fetus or only a rudimentary fetus has developed (14). Implantation may occur in a Fallopian tube in approximately 1% of all pregnancies (15). These early pregnancy failures can be detected as random findings during ultrasonographic examination before bleeding or other signs of abortion have occurred (15, 16). Uterine quiescence can thus persist, at least for some time, in these conditions even though the circulating levels of human chorionic gonadotropin (hCG) and progesterone are low (17). The combination of nonviable pregnancy and uterine quiescence may be associated with changes in NO in the uterus and/or cervix in humans, because in animals, a fall in progesterone inhibits the release of NO in the uterus and stimulates it in the cervix (5, 11). These opposing changes in NO production should result in the start of uterine contractions and cervical ripening (5, 6, 7, 9, 11). Because no human data existed, we studied cervical NO release in women with spontaneous abortion or with tubal pregnancy before any bleeding or other signs of abortion had occurred.
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Subjects and Methods
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With the permission of the local ethics committee, we studied, by means of vaginal ultrasonography, a population (n = 2200) seeking termination of early pregnancy for socio-economic reasons between September 1, 2002, and September 30, 2003. In this population we identified 99 women with missed abortion (n = 56), blighted ovum (n = 36), or tubal pregnancy (n = 7; Table 1
). Ultrasonographic criteria for missed abortion were a dead fetus of 5–14 mm in size, and those for blighted ovum were an irregular gestational sac at least 20 mm in diameter revealing no fetal echo (14, 15). Tubal pregnancy was defined as a positive hCG test and ultrasonographic evidence of uterine emptiness and tubal mass; the diagnosis was confirmed by means of laparoscopy in three women. Otherwise, all of these women were healthy and reported no uterine bleeding or contractions; the diagnosis of nonviable pregnancy came as a surprise to them. On pelvic examination, no bleeding was seen, and the cervixes appeared closed. Cervical length, as assessed by ultrasonography, exceeded 30 mm in each case, but no tonometric assessment of cervical opening was carried out. The sizes of the uteri were smaller than approximated from the duration of amenorrhea. For a control group, we selected 140 healthy women (also seeking termination) with comparable weeks of gestation who all carried a living fetus corresponding in size to the duration of gestation. No subject had any evidence of vaginal or cervical infection, as also confirmed by normal findings in Pap smears and negative cervical chlamydia test results.
Cervical fluid samples were collected before palpation and clinical sampling during pelvic examination under visual control. A Dacron swab (Pur-Wraps, East Grinstead, UK) was introduced into the cervix and was kept there for precisely 20 sec. The swab was then flushed in 1.5 ml physiological saline for 2 min as described previously (10, 18). The samples were stored frozen at –21 C until assayed for nitrate/nitrite [NO metabolites (Nox)] spectrophotometrically using the Griess reaction (10, 18). The detection limit of the assay was 3.8 µmol/liter, and the intra- and interassay coefficients of variation were 1.6% and 2.4%, respectively. To reduce the impact of interassay variation, the samples were assayed in only six batches. Only the subjects with visibly clear physiological saline flushing were included, because the presence of blood in the sample results in artificially reduced levels of Nox (our unpublished observations). A serum sample collected at the time of cervical sampling was available from 110 women, and it was used for assessment of hCG levels by solid phase, two-site fluoroimmunometric assay (Auto-DELFIA, Wallac, Turku, Finland) and for assay of progesterone by coated tube RIA (Spectria, Orion Diagnostica, Espoo, Finland), using routine laboratory methods.
Fourteen control women with viable pregnancies changed their minds and continued their pregnancies, but the remaining controls and all women with nonviable intrauterine pregnancies were managed according to their own preference as follows: mifepristone (200 mg orally)-misoprostol (0.4–1.2 mg, vaginally) regimen (42 control women and 31 women with nonviable pregnancy), expectant management (19 women with nonviable pregnancy), and dilatation and curettage (84 control women and 42 women with nonviable pregnancy). Three women with tubal pregnancy underwent laparoscopic excision of the conceptus, whereas four other women with such pregnancies were managed expectantly. The women were seen at a follow-up visit 2–3 wk after inclusion, when complete abortion was defined as emptiness of the uterine cavity in ultrasonography and/or a urinary hCG level less than 500 IU/liter.
Categorical data were analyzed by linear regression, 
2 tests, and the Armitage test for trend. Medians with 95% confidence intervals (CIs) were used to describe Nox levels. The Nox values were analyzed by nonparametric tests, such as the Mann-Whitney U test, the Kruskal-Wallis one-way ANOVA test, and Spearman’s rank correlation test. All tests were two-sided. P < 0.05 was considered statistically significant. The data for hCG and progesterone were analyzed as absolute values and also on a relative scale when hCG and progesterone concentrations in the nonviable pregnancies were expressed as percentages of the mean levels of these hormones at the same gestational point in the control group.
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Results
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The study groups were largely comparable, but the women in the nonviable intrauterine pregnancy groups were slightly older than the women in the control group (Table 1
). In addition, the duration of amenorrhea in the tubal pregnancy group was shorter than that in the other groups, and women with blighted ovum had previously more often experienced miscarriage than the controls (Table 1). As expected, the mean levels of hCG in the missed abortion and blighted ovum groups were low (45% and 24% vs. the controls), and hCG levels in tubal pregnancy (two samples) were only 2% of the mean level in the control group (Table 1). The mean level of serum progesterone in the missed abortion and blighted ovum groups were also low (81% and 68% vs. the controls), and in tubal pregnancy, the progesterone level was only 5% of the mean value in the control group. There was a significant relationship between serum hCG and progesterone concentrations when taking all subjects into account (n = 110; r = 0.51; P < 0.001), in the combined nonviable intrauterine pregnancy group (n = 30; r = 0.62; P < 0.001), and in the control group (n = 78; r = 0.40; P < 0.001).
In the missed abortion and blighted ovum groups there was a higher (P = 0.01) detection rate of cervical fluid Nox (90% and 87%, respectively) than in the control group (55%; Table 2). Women with missed abortion or blighted ovum had higher cervical fluid Nox levels than the control women, but overlapping was also seen (Table 2 and Fig. 1). In addition, the Nox concentration in the missed abortion group was significantly higher than that in the blighted ovum group (Table 2). In contrast, the tubal pregnancy group did not differ from the control group with regard to cervical fluid Nox (Table 2 and Fig. 1). Taking all subjects into account (n = 239), parous women (median, 13.3 µmol/liter; 95% CI, 6.2–18.8) had higher (P = 0.02) cervical fluid Nox concentrations than nulliparous women (median, 6.2 µmol/liter; 95% CI, 2.1–9.4), whereas in any particular subgroup, parity was not a factor with regard to Nox. The duration of amenorrhea was not a determinant of cervical fluid Nox, but in the combined nonviable intrauterine pregnancy group, women with a history of previous miscarriage had higher (P = 0.02) Nox levels (n = 21; median, 73.9 µmol/liter; 95% CI, 52.2–95.1) than women without such a history (n = 71; median, 20.0 µmol/liter, 95% CI, 12.6–46.4).
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TABLE 2. The presence and concentrations of cervical fluid Nox in women with missed abortion, blighted ovum, tubal pregnancy, or viable pregnancy
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FIG. 1. Levels of cervical fluid Nox in women with missed abortion (n = 56), blighted ovum (n = 36), tubal pregnancy (n = 7), or normal intrauterine pregnancy (n = 140). The detection limit of assay is 3.8 µmol/liter.
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Taking all women into account and in the combined nonviable pregnancy group, no relationship was seen between serum hCG and cervical fluid Nox levels, even when hCG was expressed on a relative scale (data not shown). In contrast, absolute progesterone levels were inversely related to cervical fluid Nox concentrations (r = –0.31; P = 0.003) in the whole group (n = 110), but not in any subgroup. However, in members (n = 30) of the combined nonviable intrauterine pregnancy group, progesterone levels, expressed on a relative scale, were inversely related to those of cervical fluid Nox (r = –0.69; P < 0.001; Fig. 2).
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FIG. 2. Relative levels of progesterone (percentages of the mean in the control group) in members of the combined nonviable pregnancy group (n = 30) in relation to cervical fluid Nox levels (r = –0.69; P < 0.001). ND, Not detectable.
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The likelihood of experiencing incomplete abortion after mifepristone-misoprostol or expectant management in the missed abortion or blighted ovum group was higher (P = 0.04) in women with low cervical fluid Nox concentrations than in those with high pretreatment Nox levels (28% vs. 4%; Table 3). No such relationship was seen in the control group (Table 3).
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TABLE 3. The rate of complete or incomplete abortion after a mifepristone-misoprostol regimen or expectant management in women with nonviable and viable early pregnancies with regard to the group-specific median cervical fluid Nox level
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Discussion
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We show here that women experiencing spontaneous abortion have increased cervical NO release before the onset of clinical abortion. Moreover, cervical NO release was higher the lower the circulating progesterone level, which suggests a causal relationship between cervical NO release and progesterone deficiency. Taken as a whole, our data imply that the cervix may prepare itself for ripening and for the onset of clinical abortion by increasing the synthesis of NO.
With modern transvaginal ultrasonography, as used in our study, it is possible to diagnose accurately (even before the onset of bleeding and other signs of abortion) missed abortion and blighted ovum, which together constitute approximately 80% of cases of spontaneous abortion (14, 15, 16). Tubal pregnancy was also correctly diagnosed in our study. Moreover, normal findings in ultrasonographic examination of early pregnancy accurately predict pregnancy maintenance to term in 95–97% of cases (15, 19, 20). Thus, we are confident that the vast majority of the pregnancies in the control group were indeed normal, and this was seen at least in the 14 women who changed their decision to undergo pregnancy termination and delivered healthy infants at term. Thus, our study groups of nonviable and viable pregnancies were correctly formed.
We assessed cervical NO release by measuring the levels of Nox by means of the Griess reaction, as in previous studies (10, 18). This method is reproducible and accurately reflects the availability of NO, e.g. after the application of glyceryl trinitrate (10). Moreover, it is known from animal experiments that infection-induced stimulation of NOS can be assessed by the amount of Nox released (21). Thus, we are confident that Nox measurement illustrates the release of NO in cervico-uterine tissues. Cervical fluid Nox concentrations are not dependent on dietary Nox intake (10) or on plasma Nox levels (10); therefore, no dietary restrictions were followed in this study. The presence of blood in cervical fluid results in artificially reduced Nox levels (our unpublished observations), and therefore, we carefully excluded all women whose cervical fluid samples were visibly bloody, perhaps as a result of sampling-induced trauma or as a sign of imminent abortion. Moreover, even if a microscopic amount of blood had been present in a sample, it could not explain the increased levels of Nox in the nonviable intrauterine pregnancy groups. It has also been shown that infections with accompanying release of cytokines and prostaglandins stimulate NO production (11, 21); therefore, we excluded subjects with any sign of cervico-vaginal infection, as far as clinically possible. Our data do not allow us to deduce which isoforms of NOS were primarily responsible for the increased Nox levels in our subjects, but inducible NOS is the most likely candidate because it is abundantly expressed in the cervical cells (2, 3) and is readily up-regulated by various endocrine or paracrine factors in both cervix and endomyometrium (11, 22).
Several explanations can be offered for the elevation of cervical NO levels in women with nonviable intrauterine pregnancy before the onset of clinical signs. First, it should be asked whether elevated NO in the cervix or endomyometrium could have been lethal to the fetus and a cause of abortion, because NO is a toxic free radical gas. This speculation might be supported by our finding that a history of previous miscarriage in the combined nonviable pregnancy group was associated with elevated cervical NO release. No other data, however, support this hypothesis, and we believe that increased cervical NO is more a secondary consequence of abortion rather than a primary cause.
Next, the following explanations should be considered. First, lipopolysaccharide-induced abortions are accompanied by elevated release of NO in the dying fetus, decidua, and/or fetal membranes in animal experiments (22, 23). No such human data exist, but if spontaneous abortion in humans mimics induced abortion in animals, the remnants of the conceptus may release NO excessively, which could leak, as either NO or Nox, into the cervical canal. This view is supported by our finding that cervical fluid Nox levels were elevated only in cases of intrauterine abortion, not in tubal ones. Moreover, this speculation gains support from our finding that missed abortion, with potentially more abundant remnants of conception, was characterized by higher cervical fluid Nox levels than cases of blighted ovum. Second, it is possible that increased cervical NO release is a specific phenomenon in abortion, perhaps triggered by a fall in serum progesterone concentrations. This is supported by the results of animal experiments showing that progesterone has opposing effects on NO release in the endomyometrium and cervix; it up-regulates NO release in the former, but down-regulates it in the latter (5, 6, 7, 11). Thus, progesterone insufficiency could well have stimulated the cervical release of NO in our nonviable intrauterine pregnancy groups. A rise in cervical NO levels may be needed for preabortal cervical softening and subsequent opening, which are essential for the safe passage of conceptional remnants in response to subsequent uterine contractions.
We could not assess NO release in the endomyometrium, but uterine quiescence may suggest that endomyometrial NO release, controlling uterine quiescence to at least some degree (11), may still have been normal in our subjects. Thus, the timing of NO release may be important: first comes stimulation in the cervix and later, perhaps, inhibition in the endomyometrium. It was unfortunate that we had no cervical tonometric equipment to evaluate whether subclinical cervical softening had already started in our subjects and whether there is any relationship between it and cervical Nox.
Finally, we must, of course, take into account the possibility that spontaneous abortion is often associated with local inflammatory reaction in the cervix, and this may result in the stimulation of NO release through prostaglandins (6, 8, 11) or cytokines (6, 9, 11). Also, many other hormones, such as inhibins (24, 25, 26), may be involved in spontaneous abortion and may have secondarily stimulated cervical NO release in our subjects. Regardless of the primary or secondary character of increased cervical NO release in the nonviable intrauterine pregnancy group, NO may soften the cervix. This receives support from findings that vaginal administration of NO releasing agent ripens a tight cervix during pregnancy (27, 28, 29, 30).
A low cervical fluid Nox concentration predicted the rate of incomplete abortion after medical or expectant management of nonviable pregnancy. This may further substantiate a claim for the role of cervical NO in the process of abortion, especially when Nox levels did not predict the outcome of medical termination in viable pregnancies with unstimulated cervical fluid Nox. Our data suggest that high cervical fluid Nox levels could perhaps be used for the selection of subjects with nonviable early pregnancy for medical or expectant management. Furthermore, it is possible that women with nonviable pregnancy and low Nox levels might benefit from the administration of NO releasing agent before the medical induction of abortion.
In conclusion, spontaneous abortion is preceded by increased release of cervical NO before the initiation of uterine contractions. This may soften the cervix and facilitate the clinical onset and course of abortion.
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Footnotes
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This work was supported by the Clinical Research Fund of Helsinki University Central Hospital, the Research Foundation of Orion Corp., the Foundation of Emil Aaltonen, and the Finnish-Norwegian Medical Foundation.
Abbreviations: CI, Confidence interval; hCG, human chorionic gonadotropin; NO, nitric oxide; NOS, NO synthase; Nox, NO metabolite.
Received February 13, 2004.
Accepted July 27, 2004.
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M. Vaisanen-Tommiska, R. Butzow, O. Ylikorkala, and T. S. Mikkola
Mifepristone-induced nitric oxide release and expression of nitric oxide synthases in the human cervix during early pregnancy
Hum. Reprod.,
August 1, 2006;
21(8):
2180 - 2184.
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Abstract
Introduction
