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Uterine artery blood flow velocity waveforms in pregnant women with müllerian duct anomaly: A biologic model for uteroplacental insufficiency
Uterine artery blood flow velocity waveforms in pregnant women with müllerian duct anomaly: A biologic model for uteroplacental insufficiency Sergio Leible, MD,a Hernan Muñoz, MD,a Roderick Walton, MD,a Valeria Sabaj, MD,a Francisco Cumsille, PhD,b and Waldo Sepulveda, MDc Santiago, Chile OBJECTIVE: The purpose of this study was to determine whether there are demonstrable alterations in uterine artery blood flow in pregnant women with müllerian duct anomaly. STUDY DESIGN: Flow velocity waveforms obtained from the placental and nonplacental uterine arteries were studied at 18 to 24 weeks’ gestational age in 15 pregnant women with müllerian duct anomaly and in 30 controls. The systolic/diastolic ratios were compared and correlated with the degree of placental laterality and perinatal outcome. RESULTS: Systolic/diastolic ratio in the uterine artery was abnormal in 80% of the cases and in 10% of controls (p < 0.0001). A completely lateral placenta was found in 10 of 15 women of the study group and only in 1 of the 30 controls (p < 0.0001). Women with müllerian duct anomaly had higher systolic/diastolic ratios in the nonplacental uterine artery than those with a normal uterus (median 4.3, range 2.0 to 7.4 vs median 2.8, range 2.0 to 4.0; p < 0.001). Twelve of 15 women of the study group had poor perinatal outcome compared with 4 of the 30 controls (p < 0.001). Among those women with poor perinatal outcome, 11 of 12 (92%) in the study group and only 1 of the 4 (25%) in the control group had an abnormal systolic/diastolic ratio in the uterine arteries (p < 0.05). CONCLUSION: There is a clear association between placental laterality and high systolic/diastolic ratio in the nonplacental uterine artery in pregnant women with müllerian duct anomaly who had poor perinatal outcome. This finding suggests that unilateral placental implantation could lead to functional exclusion of one uterine artery from the uteroplacental circulation and could explain pregnancy complications in women with developmental fusion defects of the uterus. (Am J Obstet Gynecol 1998;178:1048-53.)
Key words: Uterine artery, Doppler ultrasonography, müllerian duct anomaly, placental location, preeclampsia, intrauterine growth restriction
With modern Doppler ultrasonographic equipment it is now possible to study hemodynamic aspects of the uterine circulation throughout human pregnancy in a noninvasive fashion. Previous studies on flow velocimetry of the uteroplacental circulation have shown a progressive decrease in the resistance index values of the uterine artery with advancing gestation,1 probably as the result of physiologic transformation of spiral and radial arteries to uteroplacental vessels.2, 3 It has been suggested that
From the Department of Obstetrics and Gynecologya and the Clinical Epidemiology Center,b Jose Joaquin Aguirre Hospital, University of Chile, and the Fetal Medicine Center, Department of Obstetrics and Gynecology, Clinica Las Condes.c Received for publication August 1, 1997; revised October 21, 1997; accepted October 31, 1997. Reprint requests: Sergio Leible, MD, Department of Obstetrics and Gynecology, Hospital Jose Joaquin Aguirre, University of Chile, Santos Dumont 999, Santiago Norte, Chile. Copyright © 1998 by Mosby, Inc. 0002-9378/98 $5.00 + 0 6/1/87329
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women with elevated resistance index values in the uterine artery during the second trimester may have incomplete transformation of uteroplacental vessels and are at risk for intrauterine growth restriction (IUGR) and preeclampsia to develop.4, 7 Another factor that determines resistance index values of the uterine artery during pregnancy is placental location; the uterine artery near the placental insertion frequently shows lower resistance index values than the one on the opposite side.8, 10 The high rate of pregnancy complications associated with uteroplacental insufficiency in women with müllerian duct anomaly is well known.11-14 Although a vascular alteration has been suggested as the pathophysiologic mechanism for these complications,12 as yet there is no evidence supporting this hypothesis.14 The purpose of this study was to determine whether there are demonstrable uterine artery blood flow alterations in pregnant women with developmental fusion defects of the uterus, and, if so, the association with placental location and perinatal outcome.
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Fig. 1. Schematic representation of placental location in relation to uterine midline. Left, Type 1; middle, type 2; right, type 3.
Material and methods During the 3-year period from June 1993 to May 1996, 17 pregnant women with müllerian duct anomaly were prospectively recruited for a cross-sectional study with Doppler ultrasonographic assessment of the uteroplacental circulation between 18 and 24 weeks’ gestational age. Two cases were lost to follow-up; therefore 15 pregnancies formed the basis of this study. According to the criteria of The American Fertility Society,15 uterine anomalies were classified as bicornuate in 7 cases, septate in 7 cases, and didelphys in 1 case. The diagnosis of müllerian duct anomaly was made by hysterography before pregnancy in five women and by high-resolution ultrasonographic examination16 during the first trimester of pregnancy in the remaining 10 cases. The diagnosis was confirmed by internal and external manual exploration of the uterus at the time of cesarean section in 14 cases. In the remaining woman, who delivered spontaneously, the differential diagnosis between septate and bicornuate uterus was made by transvaginal ultrasonography 6 months after delivery.17 The control group was composed of 30 pregnant women with a normal uterine cavity, who underwent Doppler ultrasonographic examination at similar gestational ages. These women had no pregnancy complications at the time of recruitment and were randomly selected from those women attending our ultrasonography unit during the same period. None of them had postpartum evidences of uterine anomaly. Gestational age was calculated from the last menstrual period and confirmed by first-trimester scan. If there was a discrepancy between ultrasonography and dates ≥7 days, the gestational age determined by ultrasonography was considered for analysis. Ultrasonographic assessment was performed transabdominally by the same operator (S.L.) with high-resolution equipment with pulsed and color Doppler capabilities (Philips P700, Philips Ultrasound Industry, Santa Ana, Calif., and HDI 3000, Advanced Technology Laboratories, Seattle) with a 3.5 MHz curvilinear probe. Color Doppler imaging was used to identify the uterine artery at the point where it crossed the external iliac artery. The systolic/diastolic (S/D) ratio was then measured in the right and left uterine arteries; the artery of
Table I. Reference values for S/D ratio of placental and nonplacental uterine arteries between 18 and 24 weeks’ gestation Nonplacental uterine artery
Placental uterine artery
Weeks’ gestation
50th percentile
95th percentile
50th percentile
95th percentile
18 19 20 21 22 23 24
2.7 2.6 2.5 2.5 2.3 2.3 2.1
3.7 3.6 3.5 3.4 3.4 3.4 3.1
2.3 2.2 2.2 2.1 2.0 1.9 1.7
3.3 3.2 3.1 3.0 2.9 2.7 2.6
the same side of placental location was named the placental uterine artery and the other the nonplacental uterine artery. The intraobserver coefficient of variation was 7%. The S/D ratio was considered abnormal when any of the uterine arteries had an S/D ratio more than the 95th percentile for the gestational age previously established for our population in the placental and nonplacental uterine arteries (Table I). In addition, placental location was carefully determined and classified in relation to the midline in three subgroups: type 1, when the placenta was located preferentially in the midline, either in the anterior, posterior, or fundal aspect of the uterine cavity; type 2, when the placenta was lateral but it crossed the midline; and type 3, when the placenta was lateral but it did not cross the midline (Fig. 1). In addition, the distance between the lower edge of the placenta and the internal cervical os was measured; a distance of ≤2 cm was considered a low-lying placenta. Details on pregnancy outcome were obtained from the medical records or by contacting the referring obstetricians or the women themselves. For the purposes of this study, IUGR was defined as a birth weight less than the 10th percentile according to the nomogram for Chilean newborns,18 and preterm delivery was when birth occurred before 35 weeks’ gestational age. Hypertension, defined as a systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg, was designated as severe if two or more systolic values obtained 4 or more
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Table II. Study group
Case
Gestation Maternal (wk) age (yr)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
22 18 22 21 20 22 22 21 24 22 19 22 23 23 24
30 18 36 21 34 38 22 34 26 34 31 35 38 26 31
Placental type
Uterus
Placental uterine artery S/D ratio
3 3 3 3 3 3 3 2 3 3 2 3 2 2§ 2§
Septate Bicornuate Bicornuate Septate Bicornuate Bicornuate Bicornuate Septate Septate Septate Septate Bicornuate Septate Bicornuate Didelphys
3.5* 3.4* 3.0* 2.0 3.0 2.3 3.9* 2.1 3.0* 2.4 2.2 2.3 2.7 1.2 1.6
Nonplacental uterine artery S/D ratio 7.4* 7.1* 5.5* 5.1* 5.0* 4.8* 4.3* 4.3* 4.2* 4.2* 3.7* 3.5* 3.0 2.2 2.0
Birth weight (gm) 460† ‡
2680 2100 1800 3420 2550 2390 1700 2950 2600 2600 2130 3140 3200
Gestational age at delivery Weight (wk) percentile 30 21 38 37 35 39 38 36 35 40 38 40 35 40 38
<5 <5 <10 <5 >10 <5 <10 <5 <10 <10 <5 <10 >10 >10
Preeclampsia – – – Eclampsia + – – + + – + – – – –
*S/D ratio >95th percentile. †Stillbirth. ‡Miscarriage. §Low-lying placenta.
hours apart were ≥160 mm Hg or if two or more diastolic values were ≥110 mm Hg. Preeclampsia was defined as hypertension plus proteinuria (≥300 mg/24 hr). Severe preeclampsia was defined as severe hypertension and proteinuria or urinary protein excretion ≥5 gm/day with any degree of hypertension. Women were considered to have eclampsia if they met the criteria of preeclampsia and had convulsions. Normal pregnancy outcome was defined as a term delivery of a live infant with adequate weight for gestational age and the absence of preeclampsia. Outcome was considered abnormal in the case of stillbirth, preterm delivery, preeclampsia, or IUGR. The data of continuous variables were expressed as median and range. Mann-Whitney U test was used to compare maternal age, gestational age, S/D ratio of the uterine artery, birth weight, and gestational age at delivery between the study and the control groups. Wilcoxon’s signed rank test was used to compare S/D ratios of placental and nonplacental uterine artery in both the study and the control groups. Fisher’s exact test was used to compare the incidence of outcome variables such as IUGR, preeclampsia, and preterm birth in the study and control groups, as well as for comparison of categorical variables between and within the groups. The null hypothesis was rejected with p < 0.05. Data were analyzed with the Stata Statistical Software: Release 4.0 (Stata Corporation, College Station, Tex.). Results There was no difference between the study and control groups in maternal age (median 31 years, range 20 to 38 years vs median 33 years, range 18 to 40 years) and gestational age at the time of ultrasonographic evaluation (median 22 weeks, range 18 to 24 weeks vs median
21 weeks, range 18 to 24 weeks). Table II shows maternal demographics, S/D ratio of both uterine arteries, placental type, and perinatal outcome in our study group. In the study group, 12 (80%) women had an abnormal S/D ratio in the uterine artery. Five women had abnormal index values in both uterine arteries, and seven women had an abnormal S/D ratio only in the nonplacental uterine artery. In contrast, only three women (10%) in the control group had an abnormal S/D ratio in the uterine artery, all of them in the nonplacental uterine artery (p < 0.0001). All women with müllerian duct anomaly had a lateral placenta; of these, 5 (33%) had a type 2 placenta and 10 (67%) had a type 3 placenta. In contrast, 16 women (53%) in the control group had a lateral placenta; of these, 15 had a type 2 (94%) and only 1 (6%) had a type 3 placenta. In the study group the S/D ratio of the uterine artery was always higher in the nonplacental than in the placental side (Fig. 2). Although the same relationship was noted in the control group when the placenta was lateral in position (n = 16), the delta S/D ratio value (expressed as the nonplacental minus the placental S/D ratio) was significantly higher in the study group than in the control group (p < 0.005) (Table III). When only women with lateral placentas (i.e., type 2 and type 3) were compared, the S/D ratio from the nonplacental uterine artery was significantly higher in the study group than in the control group (p < 0.001). However, there were no significant differences in the S/D ratio in the placental uterine artery between the groups (Table III, Fig. 3). Moreover, women with müllerian duct anomaly with a type 3 placenta had a higher S/D ratio than those with type 2 placenta in both the nonplacental (median 4.9, range 3.5 to 7.4 vs median 3.0, range 2.0 to 4.3; p =
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Fig. 3. S/D ratio of uterine arteries of placental and nonplacental sides. MDA, Müllerian duct anomaly. Lines represent median values.
Fig. 2. Transverse view of upper aspect of uterine cavity in a pregnant woman with a septate uterus. Note a lateral placenta that does not reach the midline (type 3). Lower panel shows representative blood flow velocity waveforms from placental (below left) and nonplacental (below right) uterine arteries in this case.
0.01) and placental side (median 3.0, range 2.0 to 3.9 vs median 2.1, range 1.2 to 2.7; p = 0.02). No differences in S/D ratio in the uterine arteries were found in the control group regardless of the placental type. Finally, two women in each group had a low-lying placenta; all of them had normal resistance index values in the uterine arteries. Table IV displays the pregnancy outcome in the study and control groups. Twelve of 15 women in the study group had poor perinatal outcome. There was one spontaneous pregnancy loss at 21 weeks. Of the remaining cases, 4 women had preeclampsia, one had eclampsia, and 11 fetuses had IUGR, one of whom died in utero at 30 weeks’ gestational age (Table II). In the control group only 4 women had poor perinatal outcome; 2 women had preeclampsia and 2 infants had a birth weight less than the 10th percentile. None of the women with preeclampsia in either group met the criteria for severe preeclampsia. Among women with poor perinatal outcome, 11 of 12 (92%) in the study group and 1 of 4 (25%) in the control group had an abnormal S/D ratio in the uterine arteries (p < 0.05). Among the 12 women with müllerian duct anomaly and poor perinatal outcome, there was a subgroup of five women with the worst pregnancy outcomes.
This subset included two stillbirths, one woman with eclampsia, and two newborns with birth weight <2000 gm. The S/D ratio of the nonplacental uterine artery of these five cases (cases 1, 2, 4, 5, and 9 in Table II) was significantly higher than the other 7 with better outcomes (median 5.1, range 4.2 to 7.4 vs median 4.2, range 3.0 to 5.5; p < 0.05). However, there was no difference in the placental uterine artery S/D ratio between these groups (median 3.0, range 2.0 to 3.5 vs median 2.4, range 2.1 to 3.9). Finally, a type 3 placenta was found in 9 of these 12 women (75%), including all 5 cases with the worst perinatal outcome. Comment This study demonstrates an association between abnormal uterine perfusion pattern and poor pregnancy outcome in women with müllerian duct anomaly. Our data demonstrate a particular hemodynamic event characterized by laterality of placental location, leading to discordant uterine artery velocity flow waveforms. This discordancy is mainly explained by a significant increase in the resistance index values of the nonplacental uterine artery. The association between placental location and resistance index values in the uterine artery in pregnant women with a normal-shaped uterus was first demonstrated by Kofinas et al.8 and subsequently confirmed by other investigators.9 It is therefore well established that the uterine artery from the placental side normally shows lower resistance index values than the ones from the nonplacental side. We have previously shown, in women with a normal-shaped uterus, that pregnant patients with a laterally inserted placenta in which the edge of the placenta does not reach the midline, or type 3, have the highest discordancy between resistance index values of
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Table III. S/D ratio (median and range) of placental and nonplacental uterine arteries in women with lateral (type 2 and 3) placental location
Placental side Nonplacental side Significance ∆ S/D ratio
Study group (n = 15)
Control group (n = 16)
Statistical significance
2.4 (1.2-3.9) 4.3 (2.0-7.4) p < 0.001 1.5 (0.3-0.9)
2.1 (1.8-2.6) 2.8 (2.0-4.0) p = 0.0001 0.4 (0.0-0.6)
p = 0.6 p < 0.001 p < 0.005
Study group (n = 15)
Control group (n = 30)
Statistical significance
2575 (460-3420)* 38 (30-41)* 11/14* 5/14* 2/14* 2/15 12/15
3330 (2160-4230) 39 (34-41) 2/30 2/30 1/30 0/30 4/30
Table IV. Perinatal outcome
Birth weight (gm) GA at delivery (wk) IUGR (No.) Preeclampsia (No.) Preterm birth (No.) Stillbirth (No.) Any (No.)
p = 0.0001 NS p = 0.0001 p < 0.05 NS NS p < 0.001
GA, Gestational age; NS, not significant. *Excluding one case of pregnancy loss at 21 weeks.
the nonplacental and placental uterine artery and have worse perinatal outcome than those with a more centrally inserted placenta.10 On the basis of these observations, we suggest that discordancy in uterine artery flow velocity waveforms may indicate functional exclusion of one uterine artery from the placental perfusion, leading to uteroplacental ischemia. This phenomenon may be operative in both women with müllerian duct anomaly and in those with a normal uterine cavity but a laterally inserted placenta and could be implicated in the pathophysiologic mechanism of preeclampsia and IUGR, supporting the view that uteroplacental ischemia is the common pathway for the development of these pregnancy complications.19 What is the cause of this “unilateral” placentation in women with müllerian duct anomaly? Placental insertion on the lateral rather than anterior or posterior wall of the uterine cavity and the increased resistance of the nonplacental uterine artery are interrelated phenomena that can be explained by the embryologic development of the uterus and its vasculature and by the kinetics of gestational sac growth at early stages of pregnancy. The uterus is formed by Müller’s duct fusion between 8 and 12 weeks’ gestation. Arteries and veins develop simultaneously, establishing an anastomotic medial network that joins the circulation of both hemiuteri in fusion.20 In müllerian duct anomaly, where duct fusion is incomplete, it is easy to imagine a lack of these anastomoses, especially at the level of the uterine fundus because of the caudal to cephalic course of the fusion. Therefore in cases of placental implantation in one of the two hemiuteri, the absence of medial anastomoses makes it difficult for the branches from the nonplacental uterine artery to reach the placental circulation. This fact could explain
the increased resistance index values of the nonplacental uterine artery, which may show values similar to those observed in the nonpregnant uterus.21 Placental confinement to one hemiuterus in women with müllerian duct anomaly could also be explained by features of gestational sac growth at early stages of gestational age. Indeed, human implantation normally occurs on the lateral walls of uterine cavity.22 As pregnancy progresses, the uterine cavity is filled by the growing conceptus, which almost always is central in location at 7 to 8 weeks’ gestation. In women with developmental fusion defects of the uterus, however, there is a mechanical barrier that restricts lateral growth of the gestational sac and trophoblastic vascular invasion to one hemiuterus leading to a lateral placental implantation. It is well known that in preeclampsia and IUGR there is lack of the physiologic changes of the normal pregnancy such as trophoblastic invasion of the spiral arteries.2, 3 Several studies have demonstrated an association between high resistance index values of the uterine artery at 18 to 24 weeks’ gestation and increased risk of these pathologic conditions developing, and most investigators have attributed the increased resistance index values to impaired spiral artery transformation.4-7 How can we correlate this evidence with our finding showing that unilateral placentation and high resistance index values of the nonplacental uterine artery are associated with preeclampsia and IUGR in women with müllerian duct anomaly? Preliminary observations from our group have shown that discordant resistance index values of the uterine arteries during the first trimester is strongly associated with early pregnancy loss.23 This may indicate that a unilateral abnormal uterine perfusion in the first trimester could produce ischemic insult to the cytotro-
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phoblast, which can alter its invasion capabilities, leading to an incomplete transformation of spiral arteries. This hypothesis is in keeping with the recent experimental evidence that hypoxia alters early gestation human cytotrophoblast differentiation and invasion and eventually models the placentation defects that occur in preeclampsia.24 Therefore we suggest that the mechanisms involved in abnormal uterine perfusion in women with müllerian duct anomaly differ from the nonplacental and placental side. The increased resistance index values of the nonplacental uterine artery probably represent failure of the medial anastomotic network to join the placental circulation, whereas in those cases with increased resistance of the placental uterine artery an incomplete vascular transformation could be implicated as the main etiologic factor. Supporting this observation is the fact that women with müllerian duct anomaly and abnormal index values in both uterine arteries constitute those pregnancies associated with poor pregnancy outcome. Indeed, the 5 women with abnormal uterine artery resistance index values in both uterine arteries either had pregnancy loss, stillbirth, or infants with birth weight less than the 5th percentile. Normal pregnancy outcome was noted in 3 of the 15 pregnancies complicated by müllerian duct anomaly, 2 of these had a low-lying placenta and normal resistance index values in both uterine arteries. Because the main event in preeclampsia and IUGR of placental origin is uteroplacental ischemia,19 it is possible that a low placental insertion ensures better perfusion than a high placental insertion because the placental bed in the former is closer to both uterine arteries. Moreover, a low-lying placenta could allow the participation of branches coming from the nonplacental uterine artery to the overall placental perfusion because of the existence of a more developed anastomotic network at this level. Supporting this view is the lower prevalence of preeclampsia found in pregnant women with placenta previa compared with those with normal placental insertion.25 We therefore speculate that a low placental implantation could be an adaptive phenomenon triggered by an ischemic trophoblast at early stages of pregnancy.24
REFERENCES
1. Bower S, Vyas S, Campbell S, Nicolaides KH. Color Doppler imaging of the uterine artery in pregnancy: normal ranges of impedance to blood flow, mean velocity and volume of flow. Ultrasound Obstet Gynecol 1992;2:261-5. 2. Brosens I, Dixon HG, Robertson WB. Fetal growth retardation and the arteries of the placental bed. Br J Obstet Gynaecol 1977;84:656-63. 3. Khong T, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational-age infants. Br J Obstet Gynaecol 1986;93:1049-59. 4. Campbell S, Pearce JMF, Hackett G, Cohen-Overbeek T, Hernandez C. Qualitative assessment of utero-placental flow: early screening test for high-risk pregnancies. Obstet Gynecol 1986;68:649-53.
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5. Jacobson S, Imhof R, Manning N, et al. The value of Doppler assessment of the uteroplacental circulation in predicting preeclampsia or intrauterine growth retardation. Am J Obstet Gynecol 1990;162:110-4. 6. Bewley S, Cooper D, Campbell S. Doppler investigation of uteroplacental blood flow resistance in the second trimester: a screening study for pre-eclampsia and intrauterine growth retardation. Br J Obstet Gynaecol 1990;98:871-9. 7. Bower S, Schuchter K, Campbell S. Doppler ultrasound screening as part of routine antenatal screening: prediction of preeclampsia and intrauterine growth retardation. Br J Obstet Gynaecol 1993;100:989-94. 8. Kofinas AD, Penry M, Greiss F, Meis P, Nelson L. The effect of placental location on uterine artery flow velocity waveforms. Am J Obstet Gynecol 1987;157:1539-44. 9. Bewley S, Campbell S, Cooper D. Uteroplacental Doppler flow velocity waveforms in the second trimester: a complex circulation. Br J Obstet Gynaecol 1989;96:1040-6. 10. Leible S, Jankelevich J, Muñoz H, Hasbun J, Hunneus A. Doppler color del territorio vascular utero-placentario y su relacion con la ubicacion placentaria: grupos de resistencia normal y aumentada. Rev Chil Obstet Ginecol 1994;59:457-61. 11. Andrews M, Jones H. Impaired reproductive performance of the unicornuate uterus: intrauterine growth retardation, infertility and recurrent abortion in five cases. Am J Obstet Gynecol 1982;144:173-6. 12. Fedele L, Zamberletti D, D’Alberton A, Vercellini P, Candiani GB. Gestational aspects of uterus didelphys. J Reprod Med 1988;33:353-5. 13. Ben-Rafael Z, Seidman DS, Recabi K, Serr DM, Mashiach S. Pregnancy-induced hypertension in women with congenital uterine malformations. Gynecol Obstet Invest 1990;30:101-4. 14. Marcus S, A1-Shawaf T, Brinsden P. The obstetric outcome of in vitro fertilization and embryo transfer in women with congenital uterine malformation. Am J Obstet Gynecol 1996;175:85-9. 15. The American Fertility Society. The American Fertility Society classification of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, Müllerian anomalies, and intrauterine adhesions. Fertil Steril 1988;49:944-55. 16. Pellerito J, McCarthy S, Doyle M, Glickman M, DeCherney A. Diagnosis of uterine anomalies: relative accuracy of MR imaging, endovaginal sonography, and hysterosalpingography. Radiology 1992;183:795-800. 17. Fedele L, Ferrazzi E, Dorta M, Vercellini P, Candiani G. Ultrasonography in the differential diagnosis of “double” uteri. Fertil Steril 1988;50:361-4. 18. Juez G, Lucero E, Ventura-Junca P, et al. Estudio neonatal del crecimiento intrauterino en 11543 recien nacidos chilenos de clase media 1978-1987. Rev Chil Pediatr 1989;60:198-202. 19. Roberts J, Redman C. Pre-eclampsia: more than pregnancy-induced hypertension. Lancet 1993;341:1447-51. 20. Itskovitz J, Lindenbaum E, Brandes J. Arterial anastomosis in the pregnant human uterus. Obstet Gynecol 1980;55:67-71. 21. Schulman H, Ducey J, Farmakides G, et al. Uterine artery Doppler velocimetry: the significance of divergent systolic/diastolic ratios. Am J Obstet Gynecol 1987;157:1539-42. 22. Kawakami Y, Andoh K, Mizunuma H, Kiyohiko Y, Masahiro I, Yoshito I. Assessment of the implantation site by transvaginal ultrasonography. Fertil Steril 1993;59:1003-6. 23. Leible S, Muñoz H. Discordance of resistance indices of uterine arteries predicts poor outcome in first-trimester pregnancies [abstract]. Ultrasound Obstet Gynecol 1996;8 Suppl 1:94. 24. Genvaceb O, Joslin R, Damsky CH, Polliotti BM, Fisher SJ. Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia. J Clin Invest 1996;97:540-50. 25. Leiberman J, Fraser D, Kasis A, Mazor M. Reduced frequency of hypertensive disorders in placenta previa. Obstet Gynecol 1991;78:159-60.
Key words: Uterine artery, Doppler ultrasonography, müllerian duct anomaly, placental location, preeclampsia, intrauterine growth restriction
With modern Doppler ultrasonographic equipment it is now possible to study hemodynamic aspects of the uterine circulation throughout human pregnancy in a noninvasive fashion. Previous studies on flow velocimetry of the uteroplacental circulation have shown a progressive decrease in the resistance index values of the uterine artery with advancing gestation,1 probably as the result of physiologic transformation of spiral and radial arteries to uteroplacental vessels.2, 3 It has been suggested that
From the Department of Obstetrics and Gynecologya and the Clinical Epidemiology Center,b Jose Joaquin Aguirre Hospital, University of Chile, and the Fetal Medicine Center, Department of Obstetrics and Gynecology, Clinica Las Condes.c Received for publication August 1, 1997; revised October 21, 1997; accepted October 31, 1997. Reprint requests: Sergio Leible, MD, Department of Obstetrics and Gynecology, Hospital Jose Joaquin Aguirre, University of Chile, Santos Dumont 999, Santiago Norte, Chile. Copyright © 1998 by Mosby, Inc. 0002-9378/98 $5.00 + 0 6/1/87329
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women with elevated resistance index values in the uterine artery during the second trimester may have incomplete transformation of uteroplacental vessels and are at risk for intrauterine growth restriction (IUGR) and preeclampsia to develop.4, 7 Another factor that determines resistance index values of the uterine artery during pregnancy is placental location; the uterine artery near the placental insertion frequently shows lower resistance index values than the one on the opposite side.8, 10 The high rate of pregnancy complications associated with uteroplacental insufficiency in women with müllerian duct anomaly is well known.11-14 Although a vascular alteration has been suggested as the pathophysiologic mechanism for these complications,12 as yet there is no evidence supporting this hypothesis.14 The purpose of this study was to determine whether there are demonstrable uterine artery blood flow alterations in pregnant women with developmental fusion defects of the uterus, and, if so, the association with placental location and perinatal outcome.
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Fig. 1. Schematic representation of placental location in relation to uterine midline. Left, Type 1; middle, type 2; right, type 3.
Material and methods During the 3-year period from June 1993 to May 1996, 17 pregnant women with müllerian duct anomaly were prospectively recruited for a cross-sectional study with Doppler ultrasonographic assessment of the uteroplacental circulation between 18 and 24 weeks’ gestational age. Two cases were lost to follow-up; therefore 15 pregnancies formed the basis of this study. According to the criteria of The American Fertility Society,15 uterine anomalies were classified as bicornuate in 7 cases, septate in 7 cases, and didelphys in 1 case. The diagnosis of müllerian duct anomaly was made by hysterography before pregnancy in five women and by high-resolution ultrasonographic examination16 during the first trimester of pregnancy in the remaining 10 cases. The diagnosis was confirmed by internal and external manual exploration of the uterus at the time of cesarean section in 14 cases. In the remaining woman, who delivered spontaneously, the differential diagnosis between septate and bicornuate uterus was made by transvaginal ultrasonography 6 months after delivery.17 The control group was composed of 30 pregnant women with a normal uterine cavity, who underwent Doppler ultrasonographic examination at similar gestational ages. These women had no pregnancy complications at the time of recruitment and were randomly selected from those women attending our ultrasonography unit during the same period. None of them had postpartum evidences of uterine anomaly. Gestational age was calculated from the last menstrual period and confirmed by first-trimester scan. If there was a discrepancy between ultrasonography and dates ≥7 days, the gestational age determined by ultrasonography was considered for analysis. Ultrasonographic assessment was performed transabdominally by the same operator (S.L.) with high-resolution equipment with pulsed and color Doppler capabilities (Philips P700, Philips Ultrasound Industry, Santa Ana, Calif., and HDI 3000, Advanced Technology Laboratories, Seattle) with a 3.5 MHz curvilinear probe. Color Doppler imaging was used to identify the uterine artery at the point where it crossed the external iliac artery. The systolic/diastolic (S/D) ratio was then measured in the right and left uterine arteries; the artery of
Table I. Reference values for S/D ratio of placental and nonplacental uterine arteries between 18 and 24 weeks’ gestation Nonplacental uterine artery
Placental uterine artery
Weeks’ gestation
50th percentile
95th percentile
50th percentile
95th percentile
18 19 20 21 22 23 24
2.7 2.6 2.5 2.5 2.3 2.3 2.1
3.7 3.6 3.5 3.4 3.4 3.4 3.1
2.3 2.2 2.2 2.1 2.0 1.9 1.7
3.3 3.2 3.1 3.0 2.9 2.7 2.6
the same side of placental location was named the placental uterine artery and the other the nonplacental uterine artery. The intraobserver coefficient of variation was 7%. The S/D ratio was considered abnormal when any of the uterine arteries had an S/D ratio more than the 95th percentile for the gestational age previously established for our population in the placental and nonplacental uterine arteries (Table I). In addition, placental location was carefully determined and classified in relation to the midline in three subgroups: type 1, when the placenta was located preferentially in the midline, either in the anterior, posterior, or fundal aspect of the uterine cavity; type 2, when the placenta was lateral but it crossed the midline; and type 3, when the placenta was lateral but it did not cross the midline (Fig. 1). In addition, the distance between the lower edge of the placenta and the internal cervical os was measured; a distance of ≤2 cm was considered a low-lying placenta. Details on pregnancy outcome were obtained from the medical records or by contacting the referring obstetricians or the women themselves. For the purposes of this study, IUGR was defined as a birth weight less than the 10th percentile according to the nomogram for Chilean newborns,18 and preterm delivery was when birth occurred before 35 weeks’ gestational age. Hypertension, defined as a systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg, was designated as severe if two or more systolic values obtained 4 or more
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Table II. Study group
Case
Gestation Maternal (wk) age (yr)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
22 18 22 21 20 22 22 21 24 22 19 22 23 23 24
30 18 36 21 34 38 22 34 26 34 31 35 38 26 31
Placental type
Uterus
Placental uterine artery S/D ratio
3 3 3 3 3 3 3 2 3 3 2 3 2 2§ 2§
Septate Bicornuate Bicornuate Septate Bicornuate Bicornuate Bicornuate Septate Septate Septate Septate Bicornuate Septate Bicornuate Didelphys
3.5* 3.4* 3.0* 2.0 3.0 2.3 3.9* 2.1 3.0* 2.4 2.2 2.3 2.7 1.2 1.6
Nonplacental uterine artery S/D ratio 7.4* 7.1* 5.5* 5.1* 5.0* 4.8* 4.3* 4.3* 4.2* 4.2* 3.7* 3.5* 3.0 2.2 2.0
Birth weight (gm) 460† ‡
2680 2100 1800 3420 2550 2390 1700 2950 2600 2600 2130 3140 3200
Gestational age at delivery Weight (wk) percentile 30 21 38 37 35 39 38 36 35 40 38 40 35 40 38
<5 <5 <10 <5 >10 <5 <10 <5 <10 <10 <5 <10 >10 >10
Preeclampsia – – – Eclampsia + – – + + – + – – – –
*S/D ratio >95th percentile. †Stillbirth. ‡Miscarriage. §Low-lying placenta.
hours apart were ≥160 mm Hg or if two or more diastolic values were ≥110 mm Hg. Preeclampsia was defined as hypertension plus proteinuria (≥300 mg/24 hr). Severe preeclampsia was defined as severe hypertension and proteinuria or urinary protein excretion ≥5 gm/day with any degree of hypertension. Women were considered to have eclampsia if they met the criteria of preeclampsia and had convulsions. Normal pregnancy outcome was defined as a term delivery of a live infant with adequate weight for gestational age and the absence of preeclampsia. Outcome was considered abnormal in the case of stillbirth, preterm delivery, preeclampsia, or IUGR. The data of continuous variables were expressed as median and range. Mann-Whitney U test was used to compare maternal age, gestational age, S/D ratio of the uterine artery, birth weight, and gestational age at delivery between the study and the control groups. Wilcoxon’s signed rank test was used to compare S/D ratios of placental and nonplacental uterine artery in both the study and the control groups. Fisher’s exact test was used to compare the incidence of outcome variables such as IUGR, preeclampsia, and preterm birth in the study and control groups, as well as for comparison of categorical variables between and within the groups. The null hypothesis was rejected with p < 0.05. Data were analyzed with the Stata Statistical Software: Release 4.0 (Stata Corporation, College Station, Tex.). Results There was no difference between the study and control groups in maternal age (median 31 years, range 20 to 38 years vs median 33 years, range 18 to 40 years) and gestational age at the time of ultrasonographic evaluation (median 22 weeks, range 18 to 24 weeks vs median
21 weeks, range 18 to 24 weeks). Table II shows maternal demographics, S/D ratio of both uterine arteries, placental type, and perinatal outcome in our study group. In the study group, 12 (80%) women had an abnormal S/D ratio in the uterine artery. Five women had abnormal index values in both uterine arteries, and seven women had an abnormal S/D ratio only in the nonplacental uterine artery. In contrast, only three women (10%) in the control group had an abnormal S/D ratio in the uterine artery, all of them in the nonplacental uterine artery (p < 0.0001). All women with müllerian duct anomaly had a lateral placenta; of these, 5 (33%) had a type 2 placenta and 10 (67%) had a type 3 placenta. In contrast, 16 women (53%) in the control group had a lateral placenta; of these, 15 had a type 2 (94%) and only 1 (6%) had a type 3 placenta. In the study group the S/D ratio of the uterine artery was always higher in the nonplacental than in the placental side (Fig. 2). Although the same relationship was noted in the control group when the placenta was lateral in position (n = 16), the delta S/D ratio value (expressed as the nonplacental minus the placental S/D ratio) was significantly higher in the study group than in the control group (p < 0.005) (Table III). When only women with lateral placentas (i.e., type 2 and type 3) were compared, the S/D ratio from the nonplacental uterine artery was significantly higher in the study group than in the control group (p < 0.001). However, there were no significant differences in the S/D ratio in the placental uterine artery between the groups (Table III, Fig. 3). Moreover, women with müllerian duct anomaly with a type 3 placenta had a higher S/D ratio than those with type 2 placenta in both the nonplacental (median 4.9, range 3.5 to 7.4 vs median 3.0, range 2.0 to 4.3; p =
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Fig. 3. S/D ratio of uterine arteries of placental and nonplacental sides. MDA, Müllerian duct anomaly. Lines represent median values.
Fig. 2. Transverse view of upper aspect of uterine cavity in a pregnant woman with a septate uterus. Note a lateral placenta that does not reach the midline (type 3). Lower panel shows representative blood flow velocity waveforms from placental (below left) and nonplacental (below right) uterine arteries in this case.
0.01) and placental side (median 3.0, range 2.0 to 3.9 vs median 2.1, range 1.2 to 2.7; p = 0.02). No differences in S/D ratio in the uterine arteries were found in the control group regardless of the placental type. Finally, two women in each group had a low-lying placenta; all of them had normal resistance index values in the uterine arteries. Table IV displays the pregnancy outcome in the study and control groups. Twelve of 15 women in the study group had poor perinatal outcome. There was one spontaneous pregnancy loss at 21 weeks. Of the remaining cases, 4 women had preeclampsia, one had eclampsia, and 11 fetuses had IUGR, one of whom died in utero at 30 weeks’ gestational age (Table II). In the control group only 4 women had poor perinatal outcome; 2 women had preeclampsia and 2 infants had a birth weight less than the 10th percentile. None of the women with preeclampsia in either group met the criteria for severe preeclampsia. Among women with poor perinatal outcome, 11 of 12 (92%) in the study group and 1 of 4 (25%) in the control group had an abnormal S/D ratio in the uterine arteries (p < 0.05). Among the 12 women with müllerian duct anomaly and poor perinatal outcome, there was a subgroup of five women with the worst pregnancy outcomes.
This subset included two stillbirths, one woman with eclampsia, and two newborns with birth weight <2000 gm. The S/D ratio of the nonplacental uterine artery of these five cases (cases 1, 2, 4, 5, and 9 in Table II) was significantly higher than the other 7 with better outcomes (median 5.1, range 4.2 to 7.4 vs median 4.2, range 3.0 to 5.5; p < 0.05). However, there was no difference in the placental uterine artery S/D ratio between these groups (median 3.0, range 2.0 to 3.5 vs median 2.4, range 2.1 to 3.9). Finally, a type 3 placenta was found in 9 of these 12 women (75%), including all 5 cases with the worst perinatal outcome. Comment This study demonstrates an association between abnormal uterine perfusion pattern and poor pregnancy outcome in women with müllerian duct anomaly. Our data demonstrate a particular hemodynamic event characterized by laterality of placental location, leading to discordant uterine artery velocity flow waveforms. This discordancy is mainly explained by a significant increase in the resistance index values of the nonplacental uterine artery. The association between placental location and resistance index values in the uterine artery in pregnant women with a normal-shaped uterus was first demonstrated by Kofinas et al.8 and subsequently confirmed by other investigators.9 It is therefore well established that the uterine artery from the placental side normally shows lower resistance index values than the ones from the nonplacental side. We have previously shown, in women with a normal-shaped uterus, that pregnant patients with a laterally inserted placenta in which the edge of the placenta does not reach the midline, or type 3, have the highest discordancy between resistance index values of
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Table III. S/D ratio (median and range) of placental and nonplacental uterine arteries in women with lateral (type 2 and 3) placental location
Placental side Nonplacental side Significance ∆ S/D ratio
Study group (n = 15)
Control group (n = 16)
Statistical significance
2.4 (1.2-3.9) 4.3 (2.0-7.4) p < 0.001 1.5 (0.3-0.9)
2.1 (1.8-2.6) 2.8 (2.0-4.0) p = 0.0001 0.4 (0.0-0.6)
p = 0.6 p < 0.001 p < 0.005
Study group (n = 15)
Control group (n = 30)
Statistical significance
2575 (460-3420)* 38 (30-41)* 11/14* 5/14* 2/14* 2/15 12/15
3330 (2160-4230) 39 (34-41) 2/30 2/30 1/30 0/30 4/30
Table IV. Perinatal outcome
Birth weight (gm) GA at delivery (wk) IUGR (No.) Preeclampsia (No.) Preterm birth (No.) Stillbirth (No.) Any (No.)
p = 0.0001 NS p = 0.0001 p < 0.05 NS NS p < 0.001
GA, Gestational age; NS, not significant. *Excluding one case of pregnancy loss at 21 weeks.
the nonplacental and placental uterine artery and have worse perinatal outcome than those with a more centrally inserted placenta.10 On the basis of these observations, we suggest that discordancy in uterine artery flow velocity waveforms may indicate functional exclusion of one uterine artery from the placental perfusion, leading to uteroplacental ischemia. This phenomenon may be operative in both women with müllerian duct anomaly and in those with a normal uterine cavity but a laterally inserted placenta and could be implicated in the pathophysiologic mechanism of preeclampsia and IUGR, supporting the view that uteroplacental ischemia is the common pathway for the development of these pregnancy complications.19 What is the cause of this “unilateral” placentation in women with müllerian duct anomaly? Placental insertion on the lateral rather than anterior or posterior wall of the uterine cavity and the increased resistance of the nonplacental uterine artery are interrelated phenomena that can be explained by the embryologic development of the uterus and its vasculature and by the kinetics of gestational sac growth at early stages of pregnancy. The uterus is formed by Müller’s duct fusion between 8 and 12 weeks’ gestation. Arteries and veins develop simultaneously, establishing an anastomotic medial network that joins the circulation of both hemiuteri in fusion.20 In müllerian duct anomaly, where duct fusion is incomplete, it is easy to imagine a lack of these anastomoses, especially at the level of the uterine fundus because of the caudal to cephalic course of the fusion. Therefore in cases of placental implantation in one of the two hemiuteri, the absence of medial anastomoses makes it difficult for the branches from the nonplacental uterine artery to reach the placental circulation. This fact could explain
the increased resistance index values of the nonplacental uterine artery, which may show values similar to those observed in the nonpregnant uterus.21 Placental confinement to one hemiuterus in women with müllerian duct anomaly could also be explained by features of gestational sac growth at early stages of gestational age. Indeed, human implantation normally occurs on the lateral walls of uterine cavity.22 As pregnancy progresses, the uterine cavity is filled by the growing conceptus, which almost always is central in location at 7 to 8 weeks’ gestation. In women with developmental fusion defects of the uterus, however, there is a mechanical barrier that restricts lateral growth of the gestational sac and trophoblastic vascular invasion to one hemiuterus leading to a lateral placental implantation. It is well known that in preeclampsia and IUGR there is lack of the physiologic changes of the normal pregnancy such as trophoblastic invasion of the spiral arteries.2, 3 Several studies have demonstrated an association between high resistance index values of the uterine artery at 18 to 24 weeks’ gestation and increased risk of these pathologic conditions developing, and most investigators have attributed the increased resistance index values to impaired spiral artery transformation.4-7 How can we correlate this evidence with our finding showing that unilateral placentation and high resistance index values of the nonplacental uterine artery are associated with preeclampsia and IUGR in women with müllerian duct anomaly? Preliminary observations from our group have shown that discordant resistance index values of the uterine arteries during the first trimester is strongly associated with early pregnancy loss.23 This may indicate that a unilateral abnormal uterine perfusion in the first trimester could produce ischemic insult to the cytotro-
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phoblast, which can alter its invasion capabilities, leading to an incomplete transformation of spiral arteries. This hypothesis is in keeping with the recent experimental evidence that hypoxia alters early gestation human cytotrophoblast differentiation and invasion and eventually models the placentation defects that occur in preeclampsia.24 Therefore we suggest that the mechanisms involved in abnormal uterine perfusion in women with müllerian duct anomaly differ from the nonplacental and placental side. The increased resistance index values of the nonplacental uterine artery probably represent failure of the medial anastomotic network to join the placental circulation, whereas in those cases with increased resistance of the placental uterine artery an incomplete vascular transformation could be implicated as the main etiologic factor. Supporting this observation is the fact that women with müllerian duct anomaly and abnormal index values in both uterine arteries constitute those pregnancies associated with poor pregnancy outcome. Indeed, the 5 women with abnormal uterine artery resistance index values in both uterine arteries either had pregnancy loss, stillbirth, or infants with birth weight less than the 5th percentile. Normal pregnancy outcome was noted in 3 of the 15 pregnancies complicated by müllerian duct anomaly, 2 of these had a low-lying placenta and normal resistance index values in both uterine arteries. Because the main event in preeclampsia and IUGR of placental origin is uteroplacental ischemia,19 it is possible that a low placental insertion ensures better perfusion than a high placental insertion because the placental bed in the former is closer to both uterine arteries. Moreover, a low-lying placenta could allow the participation of branches coming from the nonplacental uterine artery to the overall placental perfusion because of the existence of a more developed anastomotic network at this level. Supporting this view is the lower prevalence of preeclampsia found in pregnant women with placenta previa compared with those with normal placental insertion.25 We therefore speculate that a low placental implantation could be an adaptive phenomenon triggered by an ischemic trophoblast at early stages of pregnancy.24
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