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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Okayama University Medical School, Okayama, Japan.
Address reprint requests to: Mikiya Nakatsuka, MD, PhD, Department of Obstetrics and Gynecology, Okayama University Medical School, 2-5-1 Shikata, Okayama-City, Okayama, 700-8558, Japan; E-mail: mikiya{at}cc.okayama-u.ac.jp.
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ABSTRACT |
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METHODS: We measured plasma levels of adrenomedullin of 100 pregnant women in the midluteal phase of a nonpregnant cycle (control group: n = 62; recurrent pregnancy loss group: n = 38). We measured the pulsatility index (PI) in the uterine arteries by transvaginal pulsed Doppler ultrasonography at the same time.
RESULTS: The plasma level of adrenomedullin in women with recurrent pregnancy loss (5.6 ± 1.9, mean ± standard deviation) was significantly higher (P > .001) than that in control women (3.6 ± 1.7). Uterine arterial PI of women with recurrent pregnancy loss (2.70 ± 0.47) was significantly higher (P >.001) than that in control women (2.09 ± 0.39). Plasma level of adrenomedullin had a significant positive correlation with uterine arterial PI both in the control group (r = .58, P < .001) and in the recurrent pregnancy loss group (r = .78, P < .001). Both plasma adrenomedullin concentration (7.2 ± 2.3) and uterine arterial PI (3.06 ± 0.36) were significantly high in women with antiphospholipid antibodies.
CONCLUSION: Plasma adrenomedullin may serve as a useful biochemical marker for recurrent pregnancy loss caused by impaired uterine perfusion.
The causes of recurrent pregnancy loss are classified as genetic, anatomic, hormonal, metabolic, immunologic, microbiologic, and environmental.1 Several lines of study using new diagnostic methods have suggested that certain thrombophilic disorders such as antiphospholipid antibodies or factor V Leiden are causes of recurrent pregnancy loss.1,2 Uterine receptivity is of great importance in achieving a normal pregnancy and is regulated by a number of factors including uterine perfusion. However, vascular changes associated with the pathology of recurrent pregnancy loss have not been fully elucidated. Frates et al3 have reported that resistance index in the uterine artery at 6 to 13 weeks’ gestation does not allow prediction of pregnancy outcome in patients with recurrent pregnancy loss. However, we have shown that uterine arterial blood flow resistance in the midluteal phase of a nonpregnant cycle is high in women with unexplained recurrent pregnancy loss and even higher in women with recurrent pregnancy loss accompanied by antinuclear antibodies.4
Antiphospholipid antibody syndrome, which is an autoimmune disease with coagulopathy and vascular dysfunction, has been known to be associated with recurrent pregnancy loss.5 Previous pulsed Doppler studies on pregnant women with antiphospholipid antibodies suggest that elevated blood flow resistance in the uterine artery may predict adverse pregnancy outcome, although it is controversial.6–9
Adrenomedullin, a 52-amino acids-ringed, structured peptide, mediates vasodilatory properties through the second messenger cyclic adenosine, 3',5'-monophosphate.10 The adrenomedullin gene is expressed in most organs including adrenal gland, cardiovascular system, central nervous system, kidney, respiratory tract, gastrointestinal tract, skin, and blood cells.11 In the reproductive system, uterine endometrium, ovarian follicle and corpus luteum, placental trophoblasts, and fetal membranes are known to express adrenomedullin. However, the main source of plasma adrenomedullin is considered to be vascular endothelial cells and vascular smooth muscle cells.12
Moving from low to high altitude is associated with an increase in plasma adrenomedullin presumably related to the degree of hypoxia experienced by the subjects.13 The plasma level of adrenomedullin is elevated in various diseases including hypertension, diabetes, cardiac failure, septic shock, or systemic lupus erythematosus, which are often associated with pathologic processes of the vasculature.10–12,14 Furthermore, culture studies on vascular smooth muscle cells or endothelial cells have shown that oxidative stress increases adrenomedullin production.15 These reports suggest that plasma adrenomedullin may increase in compensation for vascular dysfunction.
In this prospective study, we evaluated vascular changes in women with recurrent pregnancy loss by measuring uterine arterial blood flow resistance by pulsed Doppler ultrasonography and correlated these findings with plasma adrenomedullin concentrations.
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MATERIALS AND METHODS |
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Subjects consisted of two groups: healthy women with one or less pregnancy losses (control group: n = 62) and women with two or more sequential spontaneous pregnancy losses (recurrent pregnancy loss group: n = 38). Women who were selected for the control group did not have any abnormal findings in routine examinations for female factors, but their partners had oligospermia or erectile dysfunction. All control women had previous or subsequent normal delivery. There was a patient with systemic lupus erythematosus in the recurrent pregnancy loss group. None of our subjects, except for this patient, had any diseases such as cardiac diseases, renal failure, hypertension, diabetes, or systemic lupus erythematosus. None of our subjects were on any medication.
At the time of enrollment and measurement, 17 of the 38 women in the recurrent pregnancy loss group were multiparous, whereas 42 of the 62 women in the control group were multiparous. Multiparous women with recurrent pregnancy loss in the present study had experienced intrauterine fetal death after 22 weeks’ gestation and/or live birth by treatment with a low dose of aspirin and/or heparin.
Antinuclear antibodies were detected by indirect immunofluorescence. In the present study, antiphospholipid antibodies included anticardiolipin antibodies (immunoglobulin G and immunoglobulin M) and anti-ß2 glycoprotein I antibodies detected by enzyme-linked immunosorbent assay (MBL, Nagoya, Japan; and Yamasa, Choshi, Japan, respectively), and lupus anticoagulant detected by diluted Russell viper venom time (MBL). More than one of these abnormalities were detected on two separate occasions, at least 6 months apart.16
In the midluteal phase of a nonpregnant cycle (between the fifth and eighth postovulatory day determined by basal body temperature and/or ultrasonography of the ovaries), venous blood was taken into a container with ethylenediamine tetraacetic acid and aprotinin. After centrifugation, the plasma was stored at -40C until assay. The plasma adrenomedullin concentration was measured by immunoradiometric assay (Cosmic Corporation, Tokyo, Japan).
In the midluteal phase of a nonpregnant cycle (on the same day when blood sample for plasma adrenomedullin was obtained), transvaginal pulsed Doppler ultrasonography was performed using an Aloka SSD-1700 scanner (Aloka Ltd., Tokyo, Japan), and the average pulsatility index (PI) in the bilateral uterine artery was calculated. Blood flow evaluations were performed in the morning to avoid fluctuation caused by the circadian rhythm of uterine artery blood flow.4
The maximum thickness of the endometrium was measured as the maximum distance between each myometrial–endometrial interface through the central longitudinal axis of the uterus. We evaluated the endometrial morphology according to the classification proposed by Gonen and Casper.17 A multilayered endometrium consists of a prominent outer and central hyperechogenic line and inner hypoechogenic region. The ratio of the hyperechoic endometrial area, which increases during the luteal phase, was calculated according to the following formula: hyperechoic endometrial area ratio = (endometrial thickness – thickness of inner hypoechogenic region)/endometrial thickness.4
The data were tested by F test and Kolmogorov–Smirnov test and found to be normally distributed. Subsequent statistical analysis was performed using Student t test or Fisher exact probability test, and a P value < .05 was considered statistically significant. Data are presented as mean ± standard deviation. The correlation between the plasma adrenomedullin concentration and other indices was evaluated by Pearson correlation coefficient.
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RESULTS |
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) and no significant correlation between these values and plasma adrenomedullin concentration. There was a significant difference in endometrial thickness and PI in the uterine artery between the control group and the recurrent pregnancy loss group, whereas there was no significant difference in the hyperechoic endometrial area ratio between the groups. There was no significant difference in uterine arterial PI between multiparous women and nulliparous women both in the control group and in the recurrent pregnancy loss group (data not shown).
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) and in the recurrent pregnancy loss group (r = .78, P < .001) (Figure 1B).
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) and even higher in women with antiphospholipid antibodies (Table 3). Among women without antinuclear antibodies or among women without antiphospholipid antibodies, plasma adrenomedullin in the recurrent pregnancy loss group was significantly higher than that in the control group.
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) and even higher in women with antiphospholipid antibodies (Table 5). Among women without antinuclear antibodies or among women without antiphospholipid antibodies, the uterine artery PI in the recurrent pregnancy loss group was significantly higher than that in the control group.
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DISCUSSION |
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In the present study, average concentration of plasma adrenomedullin in control women was 3.9 pmol/L. Normal plasma concentration of adrenomedullin has been reported in the range of 1 to 14 pmol/L,11 with most values between 1 and 4 pmol/L. The sole exception is the value in nonpregnant women reproted by Hata et al,18 which is clearly outside of the normal range (61.2 pmol/ L), although the reason for this is unclear.11 The values of adrenomedullin in plasma may vary by using different immunoassay systems.11
In the present study, a patient with systemic lupus erythematosus in the recurrent pregnancy loss group, whose uterine arterial PI was elevated (3.28), showed elevation of adrenomedullin in plasma (8.2 pmol/L). None of our subjects, except for this patient, had any diseases such as cardiac diseases, renal failure, hypertension, diabetes, or systemic lupus erythematosus. However, plasma adrenomedullin levels observed in women with recurrent pregnancy loss (5.6 pmol/L in average and 12.5 pmol/L in maximum) were similar to the values reported in patients with hypertension,19 mitral stenosis,20 primary aldosteronism,21 or systemic lupus erythematosus.22
Adrenomedullin has been known to reduce the contractile response of isolated rat uterus, which has adrenomedullin binding sites.23 The physiologic increase of plasma adrenomedullin during pregnancy is considered to suppress uterine contraction and increase uterine perfusion.11 However, we observed that elevation of plasma adrenomedullin was closely correlated with elevation of uterine arterial blood flow resistance in women with recurrent pregnancy loss. Although the pathophysiologic roles of adrenomedullin in recurrent pregnancy loss have not been fully elucidated, this peptide may serve as a biochemical marker to identify women with recurrent pregnancy loss associated with impaired uterine perfusion.
Both uterine arterial PI and plasma adrenomedullin concentration in women with antinuclear antibodies were significantly higher than those in women without antinuclear antibodies. Although antinuclear antibodies are associated in some way with miscarriage including implantation failure in in vitro fertilization,24 the presence of antinuclear antibodies does not predict subsequent pregnancy loss.25 Women with antinuclear antibodies in the recurrent pregnancy loss group might have other subclinical autoimmune vasculopathy or coagulopathy because a greater part of them had antiphospholipid antibodies. Antiphospholipid antibodies interfere with syncytialization of the trophoblasts and cause decidual vasculopathy.5 During pregnancy, these pathologic changes may cause elevation of uterine arterial PI and subsequent pregnancy loss.9 However, in nonpregnant women with antiphospholipid antibodies, vascular damage caused by antiphospholipid antibodies26,27 is likely to elevate uterine arterial PI and plasma adrenomedullin concentration, which we observed in the present study.
Hata et al have reported that adrenomedullin is lower in preeclampsia compared with uncomplicated pregnancies.18 However, a more recent study has reported no difference in plasma adrenomedullin between preeclamptic and normotensive pregnant women, although adrenomedullin concentrations in amniotic fluid were found to be higher in preeclampsia.28 Preeclampsia is known to be associated with vascular dysfunction manifesting hypertension and elevated uterine arterial PI.29,30 Because production of adrenomedullin is physiologically upregulated during pregnancy, regulation of adrenomedullin gene expression and peptide synthesis in pregnant women may be different from those in nonpregnant women. Roles of adrenomedullin in complicated pregnancy remain to be clarified.
Adrenomedullin has interaction with various bioactive molecules including nitric oxide, prostaglandins, atrial natriuretic peptide, renin, aldosterone, norepinephrine, arginine vasopressin, endothelin-1, and adrenocorticotropic hormone.10 We have previously reported that there is no significant difference in serum nitric oxide metabolite level between control women and women with recurrent pregnancy loss.4 However, various vasoactive molecules may be involved in pathology of recurrent pregnancy loss associated with impaired uterine perfusion. Further investigation on plasma adrenomedullin and the other vasoactive molecules, and uterine arterial blood flow in women with recurrent pregnancy loss may help elucidate a novel aspect of pathophysiology in pregnancy loss.
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Footnotes |
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doi:10.1016/S0029-7844(03)00481-2
Received November 27, 2002. Received in revised form February 20, 2003. Accepted March 13, 2003.
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REFERENCES |
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2. Li TC. Recurrent miscarriage: Principles of management. Hum Reprod 1998;13:478–82.
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