- Email: [email protected]
Pregnancy outcomes in unicornuate uteri: a review
Pregnancy outcomes in unicornuate uteri: a review David Reichman, M.D.,a Marc R. Laufer, M.D.,b,c and Barrett K. Robinson, M.D., M.P.H.a a Department of Obstetrics and Gynecology, Brigham and Women’s Hospital; b Department of Surgery, Chief of Gynecology, Children’s Hospital of Boston; and c Department of Obstetrics and Gynecology, Division of Fertility and Reproductive Endocrinology, Brigham and Women’s Hospital, Boston, Massachusetts
Objective: To elucidate the impact of unicornuate uteri on pregnancy outcomes as evidenced by historical and contemporary studies. Design: Publications related to unicornuate uterus were identified through MEDLINE and other bibliographic databases. Setting: Literature review in an academic research environment. Patient(s): Premenopausal women with confirmed unicornuate uterus based on surgical or radiological evidence who were undergoing gynecologic and obstetrical care. Intervention(s): None. Main Outcome Measure(s): Rates of ectopic pregnancy, miscarriage, preterm delivery, intrauterine fetal demise, and live birth. Result(s): Our review revealed 20 studies of varying size and design that had commented on pregnancy outcomes in unicornuate uteri. These studies ranged in date from 1953 to 2006 and from a sample size of one to 55 patients. In total, we examined 290 women with unicornuate uterus reported in the literature. Of those patients, 175 conceived, to carry a total of 468 pregnancies. Incidence data in the literature reveal that unicornuate uterus occurs in 1:4020 women in the general population; the anomaly, however, is significantly more common in infertile women, as in women with repeated poor outcomes. Our review revealed rates of 2.7% ectopic pregnancy, 24.3% first trimester abortion, 9.7% second trimester abortion, 20.1% preterm delivery, 10.5% intrauterine fetal demise, and 49.9% live birth. Conclusion(s): Unicornuate uterus is a M}ullerian anomaly with prognostic implications for poorer outcomes during pregnancy. The rates of adverse outcomes have likely been historically overestimated. Although it is unclear whether interventions before conception or early in pregnancy such as resection of the rudimentary horn and prophylactic cervical cerclage decidedly improve obstetrical outcomes, current practice suggests that such interventions may be helpful. Women presenting with a history of this anomaly should be considered high-risk obstetrical patients. (Fertil Steril 2009;91:1886–94. 2009 by American Society for Reproductive Medicine.) Key Words: Unicornuate uterus, hemiuterus, uterus unicolis, M} ullerian anomaly
M} ullerian anomalies serve as a fascinating framework with which to understand both embryologic development and normal reproductive functioning. For those patients afflicted with such anomalies, however, their lack of normal anatomy may serve as a point of great anxiety, affecting sexual functioning, fertility, and pregnancy outcomes. It is paramount that these patients have thorough, accurate counseling regarding their treatment options and ultimate likelihood of reproductive success. Anecdotal experience, misinterpretation of older studies, and an overall lack of evidence-based data currently dominate the counseling and management of these patients, to their great disservice. Indeed, it has been said that ‘‘when a woman is found to have a congenital abnormality of the genital system she suffers both the psychological impact of having a birth defect Received October 18, 2007; revised and accepted February 20, 2008; published online April 25, 2008. D.R. has nothing to disclose. M.R.L. has nothing to disclose. B.K.R. has nothing to disclose. Correspondence to: Marc R. Laufer, M.D., Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts, 02115 (E-mail: marc. [email protected]).
1886
and the very real fear that her fertility may be impaired. Both of these factors have to be considered. The physician must be familiar with the consequences of the specific congenital abnormality on reproductive potential. This will enable him or her to provide information that accurately prognosticates the future fertility of the patient’’ (1). One such M}ullerian anomaly is the unicornuate uterus, which results from the normal differentiation of only one M}ullerian duct. The authors recently had the privilege of taking care of a pregnant patient afflicted with this anomaly, and she posed several sophisticated and pertinent questions regarding her condition and the effect it would have on her pregnancy: [1] How common are such abnormalities, and does this abnormality necessitate further screening for other disorders? [2] How does an abnormality such as this occur, and what is the likelihood that a patient’s child will be affected by the same anomalies? [3] What is the probability that such a patient will deliver a healthy child, and what specific obstetric challenges will she face on the way to that desired endpoint? [4] Are there medical or surgical interventions that could improve her likelihood of having a healthy child? Such questions prompted an investigation of the existing literature, which
Fertility and Sterility Vol. 91, No. 5, May 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2008.02.163
FIGURE 1 Buttram and Gibbons’s classification of unicornuate uterus. Reprinted with permission from reference 44.
Reichman. Pregnancy outcomes in unicornuate uteri. Fertil Steril 2009.
was largely anecdotal and incomplete, relying heavily on case reports and case series to prognosticate for these patients. Thus, it is the goal of this literature review to synthesize the data regarding the embryologic origins, incidence, obstetric and nonobstetric complications, and pregnancy outcomes associated with unicornuate uterus and to revise a counseling framework for women with unicornuate uteri who are pregnant or are planning for future pregnancy. EMBRYOLOGY The uterus forms from the fusion of the bilateral paramesonephric ducts, which are first formed at approximately 6 weeks’ gestation by invagination of coelomic epithelium. These tubular structures meet in the midline, guided by the mesonephric ducts, to form a unified body by the tenth week of gestation. The series of steps during M} ullerian development are elongation, canalization, fusion, and septal resorption. By the twentieth week of gestation, resorption of midline tissue has occurred, giving rise to the uterus, cervix, and fallopian tubes (2). Unicornuate uterus is commonly felt to result from the failure in the development of one of the paramesonephric ducts, Fertility and Sterility
either partially or completely. Partial development of one of the ducts results in a rudimentary uterine horn or anlage, whereas complete failure of the duct to develop leads to an isolated hemiuterus without a contralateral structure (3). In this model, the ovary, which forms from the urogenital ridge, is present on the affected side but may be higher in the abdomen than its normal pelvic location. It has been posited that unicornuate uterus could also be caused by failure of the urogenital ridge to develop properly, an occurrence that would result in complete absence of the kidney, M}ullerian structures, and gonad on the affected side. In fact, such patients have been reported in the literature, although this unique anatomical constellation is extremely rare; the most common finding is for the paramesonephric duct to be affected in isolation, with the ovaries present bilaterally. In 1979, Buttram and Gibbons proposed a classification schema based on the type and degree of failure of normal development of the female genital tract (4). Although this classification was revised by the American Society for Reproductive Medicine in 1988, the work of Buttram and Gibbons with respect to unicornuate uteri has remained 1887
FIGURE 2 Laparoscopic view of unicornuate uterus in situ.
Reichman. Pregnancy outcomes in unicornuate uteri. Fertil Steril 2009.
largely unchanged (5). There are four variations of the unicornuate uterus that they described (see Fig. 1): an isolated unicornuate uterus with no contralateral structure (type B) and three variations in which an anlage, or rudimentary horn, is present contralateral to the unicornuate uterus. This rudimentary horn may have a cavity that is either in communication with (type A1a) or sealed off from (type A1b) the primary uterine cavity, or it may have failed to canalize entirely and is without a cavity (type A2). A close embryologic relationship exists between the M} ullerian and Wolffian systems, as has been well described in the literature. As the mesonephric duct enters the cloaca, it induces a diverticulum, the ureteric bud, which will then differentiate into the embryologic kidney. In this way, a defect in development of the mesonephric duct can lead to a defect not only in the M} ullerian structures but also in the renal anatomy. In fact, numerous studies have confirmed a frequent coincidence of unicornuate uterus with renal anomalies. In their original study, Buttram and Gibbons reported that 31% of their patients had urinary anomalies, in which congenital absence of a kidney was the most common (4). In a study specifically looking at urinary tract anomalies associated with unicornuate uterus, Fedele et al. found a 40.5% coincidence of renal anomalies in 37 patients with unicornuate uteri, the most frequent of which was renal agenesis contralateral to the unicornuate uterus (16%) (6). Other, less frequent anomalies associated with unicornuate uterus in that study included ectopic and horseshoe kidney, double renal pelvis, and unilateral medullary sponge kidney. In a subsequent study, 28% of patients with a unicornuate uterus had complete renal agenesis contralateral to a unicornuate uterus (7). Thus, whether by computed tomography, magnetic resonance imaging (MRI), ultrasound, or intravenous pyelogram, an evaluation of the renal system is warranted whenever a unicornuate uterus is identified. 1888
Reichman et al.
Renal abnormalities, while common, are not the only anomalies seen in conjunction with unicornuate uteri. Rarely, patients have been identified in the literature who, upon surgical exploration, have had absent gonads on the affected side in addition to renal agenesis and unicornuate uterus. More common, however, is for patients with anomalous uteri to have ectopic ovarian tissue. Although these anomalies may occur in women with a normal uterus, the incidence is reported to be as high as 20% when the uterus is absent and 42% in cases of a unicornuate uterus (8). Identification of the ovaries may require additional modalities beyond routine imaging, keeping in mind that the ovary may be in an ectopic (upper abdomen, level of the pelvic brim, or the inguinal canal) location in women with reproductive tract anomalies. Nontraditional means of identification might include MRI, ultrasound, or intraoperative evaluation. INCIDENCE Calculating the incidence of such M}ullerian anomalies in the general population faces significant obstacles. The variability in the reported incidence of uterine anomalies ‘‘is due to the fact that it depends on the following variables: 1) the population studied. In recurrent pregnancy loss patients, in whom uterine malformations are more frequent, the incidence of anomalies depends on the inclusion criteria (two, three or more, late abortions, immature deliveries.) 2) prospective or retrospective character of the investigation, directed search and physician interest and awareness to find or reject an uterine anomaly, because most of the uterine malformations are clinically silent. 3) the diagnostic methods used’’ (9). It is extremely difficult to calculate the incidence of an anomaly for which many women have no adverse outcomes. Hysteroscopic and hysterosalpingographic studies have, in general, tended to overestimate the prevalence of M}ullerian anomalies in the general population because such investigations have been performed in patients with complaints of pelvic pain, abnormal uterine bleeding, and infertility (8). There have, however, been several studies that have attempted to estimate the prevalence of M}ullerian anomalies, and specifically unicornuate uterus, while at the same time attempting to minimize selection biases. In one such study, the uteri of 679 women with normal reproductive outcomes were evaluated with laparoscopy or laparotomy before tubal ligation and then by follow-up hysterosalpingography 5 months after sterilization (10). The incidence of congenital uterine anomalies was 3.2%. As might be expected, the prevalence is higher among women with adverse reproductive outcomes. For example, the incidence of M}ullerian anomalies among women with recurrent first trimester miscarriage and late first/early second trimester miscarriage was 5%–10% and >25%, respectively (9). In an attempt to remove the numerous biases associated with incidence data, Nahum’s meta-analysis examined 22 studies of fertile but otherwise unselected patients undergoing universal uterine screening, whether by routine uterine evaluation at the time of hysteroscopic tubal
Pregnancy outcomes in unicornuate uteri
Vol. 91, No. 5, May 2009
TABLE 1 Pregnancy outcomes in unicornuate uteri: Studies from 1953 to the present.
Study
Source of data
(32)
Literaturereview 1930–51/ Camp Lejeune, NC
(33)
General Jewish Hospital, Jerusalem Wilford Hall Medical Center
(34) (35) (36) (31) (4) (37)
East Bay Fertility Obstetrics/ Gynecology, Berkeley, CA Norfolk General/Johns Hopkins Hospital,1969–81 Carmel Hospital, Haifa Israel Literature review University of Milan
Population under study
Diagnostic modality
Patients, n
Cases from literature/ general obstetric population Camp Lejeune Recurrent abortion
HSG/cesarean
4
HSG/cesarean
1
Premature labor/ malpresentation Case reports of patients
Uterine exploration at delivery/HSG HSG/cesarean
1
Infertile or recurrent loss
Cesarean/HSG
5
Recurrent loss NA Primary infertility
HSG/laparoscopy NA Hystero-salpingogram þ LSC or LAP HSG
(30), intervention Serlin Maternity Hospital, bias Tel Aviv 1962–86
Known congenital uterine anomalies evaluated for r/o cervical incompetence (38) University of Pennsylvania, Referred patients with 1980–88 known anomalies (3) Johns Hopkins, 1950–90 Gynecology and infertility patients (18) Westeinde Hospital, Infertility/sterilization/ Netherlands, 1981–89 recurrent abortion/ incidental (LSC/LAP) (39) University of Alicante, Hospital obstetric / Spain gynecologic population Infertility patients/recurrent (40), intervention Tampere University abortion/cesarean Hospital, Finland, bias; IVF/horn section/LAP 1962–95 removal (15) Institute of Infertility-Valencia, Sterilization patients Spain and infertile women (41) Rabin Medical Center, Israel Abdominal pain (42) Alexandra Hospital, Greece Abdominal pain Patient with history of (22) MFM Thomas Jefferson/ uterine anomaly Pennsylvania Hospital 1995–2004 (7) Akdeniz Medical School, Abdominal pain/infertility/ recurrent loss Turkey (43) Baskent University, Turkey Patient with perimenopausal bleeding Total
5
1 31 19 7
HSG or hysteroscope
5
HSG/H/s/LSC or LAP
23
HSG/Laparoscopy/ HSG and LSC
45
HSG/ultrasound/ cesarean/LAP/LSC LAP or LSC þ HSG or H/s
23 42
HSG and LAP or LSC
8
LSC LAP Three-dimensional ultrasound/HSG/H/s
1 1 12
HSG þ LSC or LAP
55
LAP
1 290
Note: HSG ¼ hysterosalpingogram; LSC ¼ laparoscopy; LAP laparotomy; NA ¼ not available. Reichman. Pregnancy outcomes in unicornuate uteri. Fertil Steril 2009.
occlusion, sterilization, or intrauterine assessment after delivery, and analyzed these results collectively. His conclusion was that uterine malformations affect one in 594 women (8). Moreover, Nahum performed a meta-analysis of seven studies involving uterine assessment in infertility patients, Fertility and Sterility
either by hysterosalpingography or hysteroscopy in addition to laparoscopy. He thus concluded that 3.5% of infertile women possess a congenital uterine malformation, suggesting that uterine anomalies are 21 times more prevalent among infertile women than among those with normal fertility. Using weighted analysis of these findings, 0.5% of the general population, or one in 201 women, is affected by 1889
TABLE 1 Abortions first Preterm Term Intrauterine Ectopics, trimester/second deliveries, deliveries, fetal demise, Live Conceiving, n Pregnancies, n n (%) trimester, n (%) n (%) n (%) n (%) births, n (%) 4
5
0
0/0
0
5
NA
4
1
2
0
0/2
0
0
2
0
1
1
0
0/0
0
1
NA
1
4
8
0
1/0
3
5
NA
7
5
13
0
4/0; 3
1
4
1
5
1 NA 13
3 60 29
0 NA 1
3/0 29 15/2
0 10 3
0 NA 8
0 NA NA
0 24 11
NA
12
NA
0/1
3
8
NA
NA
5
5
0
1/0
1
3
0
4
20
36
1
11/2
3
19
NA
21
23
45
0
10/7
8
20
0
28
21
55
1
10/2
9
33
2
40
36
93
20
13/2
10
48
1
57
NA
16
0
6/1
4
5
NA
7
1 1 NA
2 3 12
1 1 NA
0 1/1 NA
1 0 2
0 0 NA
0 0 10
1 0 NA
38
65
3
9/10
28
15
NA
19
1
3
0
0/1
0
3
0
3
175
468
28 (6.0)
84 (17.9)/30 (6.4)
16 (3.4)
232 (49.6)
a congenital uterine anomaly (8). Various other studies have contended that unicornuate uteri constitute roughly 5% of the constellation of uterine malformations (11). By then using this apportionment of uterine anomalies among the major subtypes, and based on Nahum’s data for the incidence of congenital anomalies in the general population, we conclude that the frequency of this specific anomaly in the general population is approximately one in 4020 women. 1890
Reichman et al.
86 (18.4)
177 (37.8)
GENETICS M€ullerian anomalies are most typically noted as de novo congenital occurrences. Familial aggregates of such conditions, however, have been reported. The low frequency of affected relatives, however, is more consistent with a multifactorial, polygenic cause rather than with genetic inheritance (12). However, Nahum argues that ‘‘relatives of women with uterine defects are at higher risk for similar M} ullerian
Pregnancy outcomes in unicornuate uteri
Vol. 91, No. 5, May 2009
malformations’’ (8). Familial studies are challenging given that many of the women with these anomalies have no symptoms and can, as described above, have normal reproductive histories. HOX genes play a role in determining positional identity along the axis of the developing paramesonephric duct. HOX genes are a family of regulatory genes that encode transcription factors and are essential during embryonic development: Hoxa9 is expressed at high levels in areas that will ultimately become the fallopian tube; Hoxa10 is predominantly expressed in the developing uterus; Hoxa11 is expressed in the primordia of the lower uterine segment and cervix (13). Mutations in these genes in mice have been shown to result in reproductive anomalies (14). No doubt, countless other genes are involved in the process of M} ullerian development, and more work must be done to elucidate whether any one gene, or family of genes, directly correlates with uterine anatomy. COMPLICATIONS The challenge faced by patients with unicornuate uterus has long been thought to be pregnancy maintenance rather than impaired fertility. Patients with this anomaly have higher frequencies of spontaneous abortions in the first and second trimester, preterm labor, and abnormal fetal presentations (15). The assisted reproductive technology data, however, suggest that clinical pregnancy rates are reduced by 33% in patients with unicornuate uterus, perhaps contradicting such previous statements (16). In fact, Raga et al. reported an infertility rate of 23.7% for their patient population with unicornuate uterus (15). Explanations for decreased fertility might include diminished uterine muscle mass or absent uterine vasculature, which might diminish nutrition for the developing fetus (7). Although the mechanisms for reduced fertility in such patients have not been elucidated, the data certainly suggest that fertility is indeed impaired in these patients; more work, however, must be done to minimize confounding factors that may cloud the validity of such claims. One of the best described elements of unicornuate uterus that leads to gynecologic and obstetrical complications is the rudimentary uterine horn present in the types A1a and A1b anomalies. A small cavity within such a space may be home to functional endometrium. Gynecological problems usually include endometriosis, hematometra, hematosalpinx, and pelvic pain (17). Retrograde menstruation and metaplastic conversion of omnipotential mesothelium to functional endometrium have been hypothesized as causes of endometriosis in such cases (18). Pelvic pain is often the presenting symptom, the investigation of which will often lead to the discovery of the M} ullerian anomaly. Moreover, the rudimentary uterine horn has long been known as a liability for ectopic pregnancy. This uterine appendage can be a site of implantation that results in horn gestation. This seems straightforward in patients with type A1a malformations, whose horn cavities are in direct comFertility and Sterility
munication with the primary uterine cavity. It seems more miraculous that such a gestation could result in the A1b malformation, in which the rudimentary horn cavity is without communication to the primary uterine cavity. Transperitoneal migration of sperm is a frequent occurrence in human reproduction, and has been well established in the literature (19). This phenomenon no doubt must occur, given the plentitude of cases in the literature regarding pregnancies in A1b uterine horns. In Fedele et al.’s aforementioned study examining the link between unicornuate uterus and urinary tract abnormalities, five of the 49 patients included in the study presented with acute abdomen for ruptured rudimentary horn containing ectopic pregnancy (6). The remaining 44 in that study presented with either infertility or pelvic pain. Rupture is such a risk because most individuals are asymptomatic and there exists no communication with the vagina. For this reason, many practitioners advocate prophylactic removal of the rudimentary horn to reduce dysmenorrhea, prevent endometriosis caused by retrograde menstrual effluent, and avoid horn gestation (20, 21). Even in women in whom the uterine horn is asymptomatic, if it contains endometrium (as diagnosed on ultrasound or MRI), then it should removed laparoscopically so as to avoid retrograde menses, endometriosis, and adhesions. Beyond rudimentary horn complications, however, are those obstetrical problems that plague the unicornuate uterus itself. Unicornuate uterus has been implicated in IUGR, miscarriage, malpresentation of the fetus, preterm labor, and cervical incompetence (1). In fact, it has been reported that unicornuate uterus has the highest rate of cervical shortening, and the highest rate of spontaneous preterm birth when the cervix is shortened, of all uterine anomalies (22). Akar et al., in their 10-year retrospective study regarding pregnancy outcomes in patients presenting with infertility, recurrent pregnancy loss, or chronic pain, concluded that the reproductive performance of women with this type of uterus was poor, with a live-birth rate of only 29.2%, prematurity rate of 44%, miscarriage rate of 29%, and ectopic pregnancy rate of 4% (7). Moreover, ‘‘preterm delivery, fetal growth restriction, perinatal death and caesarean section delivery rates were 43%, 10%, 36.9% and 33.8% respectively’’ (7). Several researchers have theorized on the root cause of such poor obstetrical outcomes. Three main etiologies have been suggested to explain such outcomes: diminished muscle mass, abnormal uterine blood flow, and cervical incompetence. In patients with unicornuate uterus, gestational capacity is jeopardized by the presence of only half the full complement of uterine musculature (3). Not only are the walls of congenitally abnormal uteri thinner than normal, but their myometrium diminishes in thickness as gestation advances, causing inconsistencies over different aspects of the uterus (23, 24). This diminished muscle mass is thought to play an important role in both second trimester abortion and premature delivery (7). It has even been claimed that a high maternal serum alphafetoprotein in the absence of a structural abnormality or multiple pregnancy warrants careful inspection of uterine wall contour and thickness, as it has been shown that a thin uterine wall leads to elevated levels of 1891
121/275 (44.0%) 139/190 (73.2%) 175/351 (49.9%) 73/363 (20.1%) 15/143 (10.5%) 130/351 (37.0%) 67/276 (24.3%) 27/278 (9.7%) 8/291 (2.7%) 3/3 1/1 3/3 0/3 0/3 19/65 0/3 9/65 0/3 10/65 0/3 3/65 0/3 15/65 38/55 19/65 28/65
0/3 1/1 0/3 0/3 2/12 0/3 10/12 2/3 1/3 1/3 1/3 5/16 0/2 1/1 7/16 1/2 4/16 1/2 0/2 7/16 0/2 6/16 1/16 0/2 0/16 1/2 33/55 21/23 40/55 9/55 2/55 12/55 10/55 2/55 1/55 20/45 23/45 28/45 8/45 0/45 13/36 17/45 11/36 10/45 2/36 7/45 1/36 0/45 19/36 20/23 21/36 3/36
3/5 5/5 4/5 1/5 0/5 1/5 1/5 0/5 0/5
Reichman et al.
0/1 0/1 0/1 0/1 0/5 0/5 0/5 0/5
Reichman. Pregnancy outcomes in unicornuate uteri. Fertil Steril 2009.
0/3 8/29 1/1 13/19 0/3 24/60 11/29 0/3 10/60 3/29 0/3 3/3 29/60 17/29 3/3 15/29 0/3 2/29 0/3 1/29 4/13 5/5 5/13 1/13 1/13 1/8 7/13 1/8 0/8 0/8 0/13 5/8 4/5 7/8 3/8 1/1 1/1 1/1 0/1
0/2 1/1 0/2 0/2 2/2 2/2 0/2 2/2 0/2 5/5 4/4 4/5 0/5
Term deliveries Conception rate Live births Preterm deliveries Intrauterine fetal demise Spontaneous abortion First trimester TAB Second trimester TAB Ectopic
Total (%) (43) (7) (22) (40) (15) (41) (42) (39) (18) (3) (30) (38) (37) (4) (32) (33) (34) (35) (36) (31)
Rates of various pregnancy outcomes in unicornuate uteri from various studies.
TABLE 2 1892
maternal serum alphafetoprotein in the maternal blood stream and peritoneal cavity (17, 25). Diminished muscle mass, however, serves as a purely theoretical explanation of those obstetrical phenomena seen with unicornuate uteri, and further research must be done to establish a causal link between uterine muscle mass and adverse outcome, should one exist. Another postulated etiology for the adverse obstetrical outcomes reported in unicornuate uteri is the anomalous vasculature supplying the uterus. Disturbance in the uterine blood flow, caused by an absent or abnormal uterine or ovarian artery, could explain growth restriction or spontaneous abortion. This poor vascularity would result in impaired fetal nutrition, diminished fetal size, and higher incidence of first trimester abortion from compromised uteroplacental blood flow (3). Burchell et al. performed radiographic maps of the vascular configuration of uteri removed at hysterectomy and subsequently correlated those results with the reproductive histories of the patients in their study (26). Their work showed that patients with anomalous ascending uterine arteries had more abortions and growth-restricted infants as compared with those patients with normal vasculature. This body of work serves as possibly promising evidence that an absent uterine artery on one side could play a large role in the complexities of unicornuate pregnancy. Lastly, the cervix is often believed to be at least a part of the difficulty in maintaining a viable pregnancy in the unicornuate uterus. According to Roddick et al., cervical incompetence is caused by an abnormal ratio of muscle fibers to connective tissue in the uterine cervix (27). Should there exist a greater proportion of muscle fibers with a resultant loss of connective tissue in women with congenital uterine anomalies, a predisposition to cervical weakness would result (28). Added to this predisposition is believed to be the asymmetric downward force exerted by an anomalous uterus and the markedly increased pressure during pregnancy. Gestational cervical incompetence might then be initiated by hormonally induced relaxation of a congenitally hypermuscular cervix (29). Cervical cerclage has been attempted in many patients with unicornuate uterus, often with impressive results. Golan et al. suggested that cerclage placement be considered in all patients with uterine malformations, although in their study the number of patients with unicornuate uterus was too small to draw conclusions (30). Ambramovici et al., in a similar study, placed cerclages in women with uterine anomalies and no evidence of cervical incompetence. The spontaneous abortion rate decreased from 88% to 0, and the term delivery rate increased from 0 to 87% after placement of cerclage (31). Neither study, however, was randomized, and both lacked appropriate controls. Although several studies have suggested a benefit to routine placement of cervical cerclage early in pregnancy, none have been randomized and nearly all have lacked controls, making them subject to numerous biases. As will be revealed in our review of the existing studies, it seems unlikely that cervical incompetence plays as large a role in recurrent abortion as has been argued for, given that the bulk of pregnancy losses in unicornuate uteri occur
Pregnancy outcomes in unicornuate uteri
Vol. 91, No. 5, May 2009
during the first trimester. Various other researchers have proposed biochemical explanations to adverse outcomes as opposed to morphologic abnormalities. Blum, for example, studied eight women with second trimester losses and found that half of the study population with uterine anomalies had significantly diminished levels of serum cystine aminopeptidase, an enzyme that neutralizes oxytocin (28). DISCUSSION Our review revealed 20 studies of varying size and design that had commented on pregnancy outcomes in patients with unicornuate uteri. These studies ranged in date from 1953 to 2006 and from a sample size of one to 55 patients. In compiling our data, we excluded any patients who were accounted for elsewhere in a previous study. Several of the sources used were more or less complete than others; for instance, one study might cite numbers for ectopic pregnancy and intrauterine fetal demise, and another might not report figures for either. Rather than simply presume that these numbers were zero, we instead excluded these studies when calculating our outcome rates, modifying the denominator accordingly for that series of data. Moreover, we made note of any study in which an obvious bias, most notably intervention bias, was introduced. These studies were excluded entirely when calculating outcome rates. Having done so, we hope to present the most thorough and complete data possible, while at the same time reporting the most accurate assessment of pregnancy outcomes, excluding those data points or studies that were in any way equivocal. In total, we examined 290 women with unicornuate uterus reported in the literature. Of those patients, 175 conceived to carry a total of 468 pregnancies. Table 1 presents those studies found in the literature with varying degrees of information on pregnancy outcomes in patients with unicornuate uteri. In Table 2, we calculate the rates of various pregnancy outcomes after having excluded either biased or uncertain data. In sum, 2.7% of pregnancies were ectopic, 24.3% ended in first trimester abortion, and 9.7% ended in second trimester abortion. In another 3% of cases, the term of abortion was not specified. Another 20.1% resulted in preterm delivery, whereas 44.0% resulted in term births. Lastly, 10.5% ended in intrauterine fetal demise within the third trimester. In total, there was a live-birth rate of 49.9%, roughly half of the 351 pregnancies used to quantify that outcome. CONCLUSIONS In this review, we examined what is known regarding pregnancy in a specific type of uterine anomaly, compiling a comprehensive review of the literature on unicornuate uteri. Our intent was both academic and practical, seeking better understanding of the poorly understood process of unicornuate pregnancies as well as devising a set of statistics that could be used in the counseling of women confronting potentially worrisome pregnancies. Embryologically, unicornuate uterus can result either from incomplete development of one paraFertility and Sterility
mesonephric duct or from urogenital ridge anomalies in which coincident renal and ovarian variants are also found. Although many women go undetected with this condition, our best estimate using the incidence data in the literature is that unicornuate uterus occurs in 1:4020 in the general population; the anomaly, however, is significantly more common in infertile women, as in women with repeated poor outcomes. Although the genetics of uterine development has not been completely revealed, unicornuate uterus exhibits a multifactorial inheritance pattern, with no clear genetic link established. Many theories have been put forth as explanations of the adverse outcomes associated with unicornuate uterus, the three most common being diminished muscle mass, abnormal uterine blood flow, and cervical incompetence. Our review revealed 2.7% ectopic pregnancy, 24.3% first trimester abortion, 9.7% second trimester abortion, 20.1% preterm delivery, and 10.5% intrauterine fetal demise. Finally, we found a 49.9% live-birth rate. We hope that this review might allow clinicians to better assist patients with known anomalies in negotiating the unique anatomy and physiology of their conditions. It is important to keep in mind that such anomalies confer the need not only for additional gynecologic and obstetrical attention but also increased vigilance for renal abnormalities and gynecologic symptoms. Rudimentary uterine horn removal has become the accepted surgical approach for dysmenorrhea, ectopic pregnancy, and retrograde menstruation in such patients. Asymptomatic rudimentary horns that contain endometrium should also be removed. To our knowledge, this represents the largest and most thorough outcome review of pregnancies in patients with unicornuate uterus, and we hope it will serve as a valuable tool for counseling these patients with regard to their expected outcomes. It is important to keep in mind, of course, that the numbers presented herein represent a certain worst-case scenario, given that the patients presented in this review were predominantly brought to clinical attention by either infertility or poor outcomes. As mentioned above, many others no doubt escape detection with normal pregnancies and good outcomes and thus would skew our data favorably toward more reassuring endpoints. We hope, however, that knowing these outcomes, clinicians might be better able to counsel women on making decisions in regards to their current and future pregnancies.
REFERENCES 1. Cohen A, Chhibber G. Obstetric complications of congenital anomalies of the paramesonephric ducts. Semin Reprod Endocrinol 1986;4:59–65. 2. Engmann L, Schmidt D, Nulsen J, Maier D, Benadiva C. An unusual anatomic variation of a unicornuate uterus with normal external uterine morphology. Fertil Steril 2004;824:950–3. 3. Moutos D, Damewood M, Schlaff W, Rock J. A comparison of the reproductive outcome between women with a unicornuate uterus and women with a didelphic uterus. Fertil Steril 1992;58:88–93. 4. Buttram V, Gibbons W. Mullerian anomalies: a proposed classification (an analysis of 144 cases). Fertil Steril 1979;32:40–6.
1893
5. American Fertility Society. The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, Mullerian anomalies and intrauterine adhesions. Fertil Steril 1988;49:944–55. 6. Fedele L, Bianchi S, Agnoli B, Tozzi L, Vignali M. Urinary tract anomalies associated with unicornuate uterus. J Urol 1996;155:847–8. 7. Akar M, Bayar D, Yildiz S, Ozel M, Yilmaz Z. Reproductive outcome of women with unicornuate uterus. Aust N Z J Obstet Gynaecol 2005;45: 148–50. 8. Nahum G. Uterine anomalies: how common are they, and what is their distribution among subtypes? J Reprod Med 1998;43:877–87. 9. Acien P. Incidence of mullerian defects in fertile and infertile women. Hum Reprod 1997;12:1372–6. 10. Simon C, Martinez L, Pardo F, Tortajada M, Pellicer A. Mullerian defects in women with normal reproductive outcome. Fertil Steril 1991;56: 1192–3. 11. Lin P, Bhatnagar K, Nettleton GS, Nakajima S. Female genital anomalies affecting reproduction. Fertil Steril 2002;78:899–915. 12. Elias S, Simpson JL, Carson SA, Malinak LR, Buttram VC Jr. Genetic studies in incomplete mullerian fusion. Obstet Gynecol 1984;63:276. 13. Taylor HS. The role of Hox genes in the development and function of the female reproductive tract. Semin Reprod Endocrinol 2000;18:81–9. 14. Taylor H, Du H. Molecular regulation of mullerian development by Hox genes. Ann N Y Acad Sci 2004;1034:152–65. 15. Raga F, Bauset C, Remohi J, Bonilla-Musoles F, Simon C, Pellicer A. Reproductive impact of congenital mullerian anomalies. Hum Reprod 1997;12:2277–81. 16. Lavergne N, Aristizabal J, Zarka V, Erny R, Hedon B. Uterine anomalies and in-vitro fertilization: what are the results? Eur J Obstet Gynecol Reprod Biol 1996;68:29–34. 17. Jayasinghe Y, Rane A, Stalewski H, Grover S. The presentation and early diagnosis of the rudimentary uterine horn. Obstet Gynecol 2005;105: 1456–67. 18. Donderwinkel P, Dorr J, Willemsen W. The unicornuate uterus: clinical implications. Eur J Obstet Gynecol Reprod Biol 1992;47:135–9. 19. Nahum G, Stanislaw H, McMahon C. Preventing ectopic pregnancies: how often does transperitoneal transmigration of sperm occur in effecting human pregnancy? Br J Obstet Gynaecol 2004;111:706–14. 20. Canis M, Wattiez J, Pouly L, Mage G, Manhes H, Bruhat M. Laparoscopic management of unicornuate uterus with rudimentary horn and unilateral extensive endometriosis: case report. Hum Reprod 1990;819–20. 21. Nezhat F, Nezhat C, Bess O, Nezhat CH. Laparoscopic amputation of noncommunicating rudimentary horn after hystcroscopic diagnosis: a case study. Surg Laparosc Eudosc 1994;155–6. 22. Airoldi J, Berghella V, Sehdev H, Ludmir J. Transvaginal ultrasonography of the cervix to predict preterm birth in women with uterine anomalies. Obstet Gynecol 2005;106:553–6. 23. Nahum G. Uterine anomalies, induction of labor, and uterine rupture. Obstet Gynecol 2005;5:1150–2. 24. Achiron R, Tadmor O, Kamar R, Aboulafia Y, Diamant Y. Prerupture ultrasound diagnosis of interstitial and rudimentary uterine horn pregnancy in the second trimester: a report of two cases. J Reprod Med 1992;37:89–92.
1894
Reichman et al.
25. Zaidi J, Carr J. Rupture of pregnant rudimentary uterine horn with fetal salvage. Acta Obstet Gynecol Scand 1994;73:359–60. 26. Burchell C, Creed F, Rasoulpour M, Whitcomb M. Vascular anatomy of human uterus and pregnancy wastage. Br J Obstet Gynaecol 1978;85: 698. 27. Roddick J, Buckingham J, Danforth D. The muscular cervix—a cause of incompetency in pregnancy. Obstet Gynecol 1961;17:562. 28. Blum M. Comparative study of serum C.A.P. activity during pregnancy in malformed and normal uterus. J Perinat Med 1978;6:165. 29. Nwosu C, Soffronaff C, Bolton C. A new look at the etiology of cervical incompetence. Int J Gynaecol Obstet 1975;13:201. 30. Golan A, Langer R, Wexler S, Segev E, Niv D, David M. Cervical cerclage—its role in the pregnant anomalous uterus. Int J Fertil Womens Med 1990;35:164–70. 31. Ambramovici H, Faktor J, Pascal B. Congenital uterine malformations as indication for cervical suture in habitual abortion and premature delivery. Int J Fertil Womens Med 1983;28:161–4. 32. Baker W, Roy R, Bancroft C, McGaughey H, Dickman N, Tucker G. Congenital anomalies of the uterus associated with pregnancy: an analysis of one hundred eighteen cases from the literature with a report of nine additional cases. Am J Obstet Gynecol 1953;66:580–97. 33. Wajntraub G, Milwidsky A, Weiss D. Prevention of premature delivery in a unicornuate uterus by cervical cerclage. Acta Obstet Gynaecol Scand 1975;54:497–8. 34. Green L, Harris R. Uterine anomalies: frequency of diagnosis and associated obstetric complications. Obstet Gynecol 1976;47:427–9. 35. Beernink F, Beernink H, Chinn A. Uterus unicornis with uterus solidaris. Obstet Gynecol 1976;47:651–3. 36. 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. 37. Fedele L, Zamberletti D, Vercellini P, Dorta M, Candiani G. Reproductive performance of women with unicornuate uterus. Fertil Steril 1987;47:416–9. 38. Ludmir J, Samuels P, Brooks S, Mennuti M. Pregnancy outcome of patients with uncorrected uterine anomalies managed in a high-risk obstetric setting. Obstet Gynecol 1990;75:906–9. 39. Acien P. Reproductive performance of women with uterine malformations. Hum Reprod 1993;8:122–6. 40. Heinonen P. Unicornuate uterus and rudimentary horn. Fertil Steril 1997;68:224–30. 41. Dicker D, Nitke S, Shoenfeld A, Fish B, Meizner I, Ben-Rafael Z. Laparoscopic management of rudimentary horn pregnancy. Hum Reprod 1998;13:2643–4. 42. Daskalakis G, Pilalis A, Lykeridou K. Antsaklis. Rupture of noncommunicating rudimentary uterine horn pregnancy. Obstet Gynecol 2002;100: 1108–10. 43. Haydardedeoglu B, Simsek E, Kilicdag EB, Tarim E, Aslan E, Bagis T. A case of unicornuate uterus with ipsilateral ovarian and renal agenesis. Fertil Steril 2006;85(3):750e1–4. 44. Emans J, Laufer MR, Goldstein DP. Pediatric and adolescent gynecology. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2005.
Pregnancy outcomes in unicornuate uteri
Vol. 91, No. 5, May 2009
Objective: To elucidate the impact of unicornuate uteri on pregnancy outcomes as evidenced by historical and contemporary studies. Design: Publications related to unicornuate uterus were identified through MEDLINE and other bibliographic databases. Setting: Literature review in an academic research environment. Patient(s): Premenopausal women with confirmed unicornuate uterus based on surgical or radiological evidence who were undergoing gynecologic and obstetrical care. Intervention(s): None. Main Outcome Measure(s): Rates of ectopic pregnancy, miscarriage, preterm delivery, intrauterine fetal demise, and live birth. Result(s): Our review revealed 20 studies of varying size and design that had commented on pregnancy outcomes in unicornuate uteri. These studies ranged in date from 1953 to 2006 and from a sample size of one to 55 patients. In total, we examined 290 women with unicornuate uterus reported in the literature. Of those patients, 175 conceived, to carry a total of 468 pregnancies. Incidence data in the literature reveal that unicornuate uterus occurs in 1:4020 women in the general population; the anomaly, however, is significantly more common in infertile women, as in women with repeated poor outcomes. Our review revealed rates of 2.7% ectopic pregnancy, 24.3% first trimester abortion, 9.7% second trimester abortion, 20.1% preterm delivery, 10.5% intrauterine fetal demise, and 49.9% live birth. Conclusion(s): Unicornuate uterus is a M}ullerian anomaly with prognostic implications for poorer outcomes during pregnancy. The rates of adverse outcomes have likely been historically overestimated. Although it is unclear whether interventions before conception or early in pregnancy such as resection of the rudimentary horn and prophylactic cervical cerclage decidedly improve obstetrical outcomes, current practice suggests that such interventions may be helpful. Women presenting with a history of this anomaly should be considered high-risk obstetrical patients. (Fertil Steril 2009;91:1886–94. 2009 by American Society for Reproductive Medicine.) Key Words: Unicornuate uterus, hemiuterus, uterus unicolis, M} ullerian anomaly
M} ullerian anomalies serve as a fascinating framework with which to understand both embryologic development and normal reproductive functioning. For those patients afflicted with such anomalies, however, their lack of normal anatomy may serve as a point of great anxiety, affecting sexual functioning, fertility, and pregnancy outcomes. It is paramount that these patients have thorough, accurate counseling regarding their treatment options and ultimate likelihood of reproductive success. Anecdotal experience, misinterpretation of older studies, and an overall lack of evidence-based data currently dominate the counseling and management of these patients, to their great disservice. Indeed, it has been said that ‘‘when a woman is found to have a congenital abnormality of the genital system she suffers both the psychological impact of having a birth defect Received October 18, 2007; revised and accepted February 20, 2008; published online April 25, 2008. D.R. has nothing to disclose. M.R.L. has nothing to disclose. B.K.R. has nothing to disclose. Correspondence to: Marc R. Laufer, M.D., Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts, 02115 (E-mail: marc. [email protected]).
1886
and the very real fear that her fertility may be impaired. Both of these factors have to be considered. The physician must be familiar with the consequences of the specific congenital abnormality on reproductive potential. This will enable him or her to provide information that accurately prognosticates the future fertility of the patient’’ (1). One such M}ullerian anomaly is the unicornuate uterus, which results from the normal differentiation of only one M}ullerian duct. The authors recently had the privilege of taking care of a pregnant patient afflicted with this anomaly, and she posed several sophisticated and pertinent questions regarding her condition and the effect it would have on her pregnancy: [1] How common are such abnormalities, and does this abnormality necessitate further screening for other disorders? [2] How does an abnormality such as this occur, and what is the likelihood that a patient’s child will be affected by the same anomalies? [3] What is the probability that such a patient will deliver a healthy child, and what specific obstetric challenges will she face on the way to that desired endpoint? [4] Are there medical or surgical interventions that could improve her likelihood of having a healthy child? Such questions prompted an investigation of the existing literature, which
Fertility and Sterility Vol. 91, No. 5, May 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2008.02.163
FIGURE 1 Buttram and Gibbons’s classification of unicornuate uterus. Reprinted with permission from reference 44.
Reichman. Pregnancy outcomes in unicornuate uteri. Fertil Steril 2009.
was largely anecdotal and incomplete, relying heavily on case reports and case series to prognosticate for these patients. Thus, it is the goal of this literature review to synthesize the data regarding the embryologic origins, incidence, obstetric and nonobstetric complications, and pregnancy outcomes associated with unicornuate uterus and to revise a counseling framework for women with unicornuate uteri who are pregnant or are planning for future pregnancy. EMBRYOLOGY The uterus forms from the fusion of the bilateral paramesonephric ducts, which are first formed at approximately 6 weeks’ gestation by invagination of coelomic epithelium. These tubular structures meet in the midline, guided by the mesonephric ducts, to form a unified body by the tenth week of gestation. The series of steps during M} ullerian development are elongation, canalization, fusion, and septal resorption. By the twentieth week of gestation, resorption of midline tissue has occurred, giving rise to the uterus, cervix, and fallopian tubes (2). Unicornuate uterus is commonly felt to result from the failure in the development of one of the paramesonephric ducts, Fertility and Sterility
either partially or completely. Partial development of one of the ducts results in a rudimentary uterine horn or anlage, whereas complete failure of the duct to develop leads to an isolated hemiuterus without a contralateral structure (3). In this model, the ovary, which forms from the urogenital ridge, is present on the affected side but may be higher in the abdomen than its normal pelvic location. It has been posited that unicornuate uterus could also be caused by failure of the urogenital ridge to develop properly, an occurrence that would result in complete absence of the kidney, M}ullerian structures, and gonad on the affected side. In fact, such patients have been reported in the literature, although this unique anatomical constellation is extremely rare; the most common finding is for the paramesonephric duct to be affected in isolation, with the ovaries present bilaterally. In 1979, Buttram and Gibbons proposed a classification schema based on the type and degree of failure of normal development of the female genital tract (4). Although this classification was revised by the American Society for Reproductive Medicine in 1988, the work of Buttram and Gibbons with respect to unicornuate uteri has remained 1887
FIGURE 2 Laparoscopic view of unicornuate uterus in situ.
Reichman. Pregnancy outcomes in unicornuate uteri. Fertil Steril 2009.
largely unchanged (5). There are four variations of the unicornuate uterus that they described (see Fig. 1): an isolated unicornuate uterus with no contralateral structure (type B) and three variations in which an anlage, or rudimentary horn, is present contralateral to the unicornuate uterus. This rudimentary horn may have a cavity that is either in communication with (type A1a) or sealed off from (type A1b) the primary uterine cavity, or it may have failed to canalize entirely and is without a cavity (type A2). A close embryologic relationship exists between the M} ullerian and Wolffian systems, as has been well described in the literature. As the mesonephric duct enters the cloaca, it induces a diverticulum, the ureteric bud, which will then differentiate into the embryologic kidney. In this way, a defect in development of the mesonephric duct can lead to a defect not only in the M} ullerian structures but also in the renal anatomy. In fact, numerous studies have confirmed a frequent coincidence of unicornuate uterus with renal anomalies. In their original study, Buttram and Gibbons reported that 31% of their patients had urinary anomalies, in which congenital absence of a kidney was the most common (4). In a study specifically looking at urinary tract anomalies associated with unicornuate uterus, Fedele et al. found a 40.5% coincidence of renal anomalies in 37 patients with unicornuate uteri, the most frequent of which was renal agenesis contralateral to the unicornuate uterus (16%) (6). Other, less frequent anomalies associated with unicornuate uterus in that study included ectopic and horseshoe kidney, double renal pelvis, and unilateral medullary sponge kidney. In a subsequent study, 28% of patients with a unicornuate uterus had complete renal agenesis contralateral to a unicornuate uterus (7). Thus, whether by computed tomography, magnetic resonance imaging (MRI), ultrasound, or intravenous pyelogram, an evaluation of the renal system is warranted whenever a unicornuate uterus is identified. 1888
Reichman et al.
Renal abnormalities, while common, are not the only anomalies seen in conjunction with unicornuate uteri. Rarely, patients have been identified in the literature who, upon surgical exploration, have had absent gonads on the affected side in addition to renal agenesis and unicornuate uterus. More common, however, is for patients with anomalous uteri to have ectopic ovarian tissue. Although these anomalies may occur in women with a normal uterus, the incidence is reported to be as high as 20% when the uterus is absent and 42% in cases of a unicornuate uterus (8). Identification of the ovaries may require additional modalities beyond routine imaging, keeping in mind that the ovary may be in an ectopic (upper abdomen, level of the pelvic brim, or the inguinal canal) location in women with reproductive tract anomalies. Nontraditional means of identification might include MRI, ultrasound, or intraoperative evaluation. INCIDENCE Calculating the incidence of such M}ullerian anomalies in the general population faces significant obstacles. The variability in the reported incidence of uterine anomalies ‘‘is due to the fact that it depends on the following variables: 1) the population studied. In recurrent pregnancy loss patients, in whom uterine malformations are more frequent, the incidence of anomalies depends on the inclusion criteria (two, three or more, late abortions, immature deliveries.) 2) prospective or retrospective character of the investigation, directed search and physician interest and awareness to find or reject an uterine anomaly, because most of the uterine malformations are clinically silent. 3) the diagnostic methods used’’ (9). It is extremely difficult to calculate the incidence of an anomaly for which many women have no adverse outcomes. Hysteroscopic and hysterosalpingographic studies have, in general, tended to overestimate the prevalence of M}ullerian anomalies in the general population because such investigations have been performed in patients with complaints of pelvic pain, abnormal uterine bleeding, and infertility (8). There have, however, been several studies that have attempted to estimate the prevalence of M}ullerian anomalies, and specifically unicornuate uterus, while at the same time attempting to minimize selection biases. In one such study, the uteri of 679 women with normal reproductive outcomes were evaluated with laparoscopy or laparotomy before tubal ligation and then by follow-up hysterosalpingography 5 months after sterilization (10). The incidence of congenital uterine anomalies was 3.2%. As might be expected, the prevalence is higher among women with adverse reproductive outcomes. For example, the incidence of M}ullerian anomalies among women with recurrent first trimester miscarriage and late first/early second trimester miscarriage was 5%–10% and >25%, respectively (9). In an attempt to remove the numerous biases associated with incidence data, Nahum’s meta-analysis examined 22 studies of fertile but otherwise unselected patients undergoing universal uterine screening, whether by routine uterine evaluation at the time of hysteroscopic tubal
Pregnancy outcomes in unicornuate uteri
Vol. 91, No. 5, May 2009
TABLE 1 Pregnancy outcomes in unicornuate uteri: Studies from 1953 to the present.
Study
Source of data
(32)
Literaturereview 1930–51/ Camp Lejeune, NC
(33)
General Jewish Hospital, Jerusalem Wilford Hall Medical Center
(34) (35) (36) (31) (4) (37)
East Bay Fertility Obstetrics/ Gynecology, Berkeley, CA Norfolk General/Johns Hopkins Hospital,1969–81 Carmel Hospital, Haifa Israel Literature review University of Milan
Population under study
Diagnostic modality
Patients, n
Cases from literature/ general obstetric population Camp Lejeune Recurrent abortion
HSG/cesarean
4
HSG/cesarean
1
Premature labor/ malpresentation Case reports of patients
Uterine exploration at delivery/HSG HSG/cesarean
1
Infertile or recurrent loss
Cesarean/HSG
5
Recurrent loss NA Primary infertility
HSG/laparoscopy NA Hystero-salpingogram þ LSC or LAP HSG
(30), intervention Serlin Maternity Hospital, bias Tel Aviv 1962–86
Known congenital uterine anomalies evaluated for r/o cervical incompetence (38) University of Pennsylvania, Referred patients with 1980–88 known anomalies (3) Johns Hopkins, 1950–90 Gynecology and infertility patients (18) Westeinde Hospital, Infertility/sterilization/ Netherlands, 1981–89 recurrent abortion/ incidental (LSC/LAP) (39) University of Alicante, Hospital obstetric / Spain gynecologic population Infertility patients/recurrent (40), intervention Tampere University abortion/cesarean Hospital, Finland, bias; IVF/horn section/LAP 1962–95 removal (15) Institute of Infertility-Valencia, Sterilization patients Spain and infertile women (41) Rabin Medical Center, Israel Abdominal pain (42) Alexandra Hospital, Greece Abdominal pain Patient with history of (22) MFM Thomas Jefferson/ uterine anomaly Pennsylvania Hospital 1995–2004 (7) Akdeniz Medical School, Abdominal pain/infertility/ recurrent loss Turkey (43) Baskent University, Turkey Patient with perimenopausal bleeding Total
5
1 31 19 7
HSG or hysteroscope
5
HSG/H/s/LSC or LAP
23
HSG/Laparoscopy/ HSG and LSC
45
HSG/ultrasound/ cesarean/LAP/LSC LAP or LSC þ HSG or H/s
23 42
HSG and LAP or LSC
8
LSC LAP Three-dimensional ultrasound/HSG/H/s
1 1 12
HSG þ LSC or LAP
55
LAP
1 290
Note: HSG ¼ hysterosalpingogram; LSC ¼ laparoscopy; LAP laparotomy; NA ¼ not available. Reichman. Pregnancy outcomes in unicornuate uteri. Fertil Steril 2009.
occlusion, sterilization, or intrauterine assessment after delivery, and analyzed these results collectively. His conclusion was that uterine malformations affect one in 594 women (8). Moreover, Nahum performed a meta-analysis of seven studies involving uterine assessment in infertility patients, Fertility and Sterility
either by hysterosalpingography or hysteroscopy in addition to laparoscopy. He thus concluded that 3.5% of infertile women possess a congenital uterine malformation, suggesting that uterine anomalies are 21 times more prevalent among infertile women than among those with normal fertility. Using weighted analysis of these findings, 0.5% of the general population, or one in 201 women, is affected by 1889
TABLE 1 Abortions first Preterm Term Intrauterine Ectopics, trimester/second deliveries, deliveries, fetal demise, Live Conceiving, n Pregnancies, n n (%) trimester, n (%) n (%) n (%) n (%) births, n (%) 4
5
0
0/0
0
5
NA
4
1
2
0
0/2
0
0
2
0
1
1
0
0/0
0
1
NA
1
4
8
0
1/0
3
5
NA
7
5
13
0
4/0; 3
1
4
1
5
1 NA 13
3 60 29
0 NA 1
3/0 29 15/2
0 10 3
0 NA 8
0 NA NA
0 24 11
NA
12
NA
0/1
3
8
NA
NA
5
5
0
1/0
1
3
0
4
20
36
1
11/2
3
19
NA
21
23
45
0
10/7
8
20
0
28
21
55
1
10/2
9
33
2
40
36
93
20
13/2
10
48
1
57
NA
16
0
6/1
4
5
NA
7
1 1 NA
2 3 12
1 1 NA
0 1/1 NA
1 0 2
0 0 NA
0 0 10
1 0 NA
38
65
3
9/10
28
15
NA
19
1
3
0
0/1
0
3
0
3
175
468
28 (6.0)
84 (17.9)/30 (6.4)
16 (3.4)
232 (49.6)
a congenital uterine anomaly (8). Various other studies have contended that unicornuate uteri constitute roughly 5% of the constellation of uterine malformations (11). By then using this apportionment of uterine anomalies among the major subtypes, and based on Nahum’s data for the incidence of congenital anomalies in the general population, we conclude that the frequency of this specific anomaly in the general population is approximately one in 4020 women. 1890
Reichman et al.
86 (18.4)
177 (37.8)
GENETICS M€ullerian anomalies are most typically noted as de novo congenital occurrences. Familial aggregates of such conditions, however, have been reported. The low frequency of affected relatives, however, is more consistent with a multifactorial, polygenic cause rather than with genetic inheritance (12). However, Nahum argues that ‘‘relatives of women with uterine defects are at higher risk for similar M} ullerian
Pregnancy outcomes in unicornuate uteri
Vol. 91, No. 5, May 2009
malformations’’ (8). Familial studies are challenging given that many of the women with these anomalies have no symptoms and can, as described above, have normal reproductive histories. HOX genes play a role in determining positional identity along the axis of the developing paramesonephric duct. HOX genes are a family of regulatory genes that encode transcription factors and are essential during embryonic development: Hoxa9 is expressed at high levels in areas that will ultimately become the fallopian tube; Hoxa10 is predominantly expressed in the developing uterus; Hoxa11 is expressed in the primordia of the lower uterine segment and cervix (13). Mutations in these genes in mice have been shown to result in reproductive anomalies (14). No doubt, countless other genes are involved in the process of M} ullerian development, and more work must be done to elucidate whether any one gene, or family of genes, directly correlates with uterine anatomy. COMPLICATIONS The challenge faced by patients with unicornuate uterus has long been thought to be pregnancy maintenance rather than impaired fertility. Patients with this anomaly have higher frequencies of spontaneous abortions in the first and second trimester, preterm labor, and abnormal fetal presentations (15). The assisted reproductive technology data, however, suggest that clinical pregnancy rates are reduced by 33% in patients with unicornuate uterus, perhaps contradicting such previous statements (16). In fact, Raga et al. reported an infertility rate of 23.7% for their patient population with unicornuate uterus (15). Explanations for decreased fertility might include diminished uterine muscle mass or absent uterine vasculature, which might diminish nutrition for the developing fetus (7). Although the mechanisms for reduced fertility in such patients have not been elucidated, the data certainly suggest that fertility is indeed impaired in these patients; more work, however, must be done to minimize confounding factors that may cloud the validity of such claims. One of the best described elements of unicornuate uterus that leads to gynecologic and obstetrical complications is the rudimentary uterine horn present in the types A1a and A1b anomalies. A small cavity within such a space may be home to functional endometrium. Gynecological problems usually include endometriosis, hematometra, hematosalpinx, and pelvic pain (17). Retrograde menstruation and metaplastic conversion of omnipotential mesothelium to functional endometrium have been hypothesized as causes of endometriosis in such cases (18). Pelvic pain is often the presenting symptom, the investigation of which will often lead to the discovery of the M} ullerian anomaly. Moreover, the rudimentary uterine horn has long been known as a liability for ectopic pregnancy. This uterine appendage can be a site of implantation that results in horn gestation. This seems straightforward in patients with type A1a malformations, whose horn cavities are in direct comFertility and Sterility
munication with the primary uterine cavity. It seems more miraculous that such a gestation could result in the A1b malformation, in which the rudimentary horn cavity is without communication to the primary uterine cavity. Transperitoneal migration of sperm is a frequent occurrence in human reproduction, and has been well established in the literature (19). This phenomenon no doubt must occur, given the plentitude of cases in the literature regarding pregnancies in A1b uterine horns. In Fedele et al.’s aforementioned study examining the link between unicornuate uterus and urinary tract abnormalities, five of the 49 patients included in the study presented with acute abdomen for ruptured rudimentary horn containing ectopic pregnancy (6). The remaining 44 in that study presented with either infertility or pelvic pain. Rupture is such a risk because most individuals are asymptomatic and there exists no communication with the vagina. For this reason, many practitioners advocate prophylactic removal of the rudimentary horn to reduce dysmenorrhea, prevent endometriosis caused by retrograde menstrual effluent, and avoid horn gestation (20, 21). Even in women in whom the uterine horn is asymptomatic, if it contains endometrium (as diagnosed on ultrasound or MRI), then it should removed laparoscopically so as to avoid retrograde menses, endometriosis, and adhesions. Beyond rudimentary horn complications, however, are those obstetrical problems that plague the unicornuate uterus itself. Unicornuate uterus has been implicated in IUGR, miscarriage, malpresentation of the fetus, preterm labor, and cervical incompetence (1). In fact, it has been reported that unicornuate uterus has the highest rate of cervical shortening, and the highest rate of spontaneous preterm birth when the cervix is shortened, of all uterine anomalies (22). Akar et al., in their 10-year retrospective study regarding pregnancy outcomes in patients presenting with infertility, recurrent pregnancy loss, or chronic pain, concluded that the reproductive performance of women with this type of uterus was poor, with a live-birth rate of only 29.2%, prematurity rate of 44%, miscarriage rate of 29%, and ectopic pregnancy rate of 4% (7). Moreover, ‘‘preterm delivery, fetal growth restriction, perinatal death and caesarean section delivery rates were 43%, 10%, 36.9% and 33.8% respectively’’ (7). Several researchers have theorized on the root cause of such poor obstetrical outcomes. Three main etiologies have been suggested to explain such outcomes: diminished muscle mass, abnormal uterine blood flow, and cervical incompetence. In patients with unicornuate uterus, gestational capacity is jeopardized by the presence of only half the full complement of uterine musculature (3). Not only are the walls of congenitally abnormal uteri thinner than normal, but their myometrium diminishes in thickness as gestation advances, causing inconsistencies over different aspects of the uterus (23, 24). This diminished muscle mass is thought to play an important role in both second trimester abortion and premature delivery (7). It has even been claimed that a high maternal serum alphafetoprotein in the absence of a structural abnormality or multiple pregnancy warrants careful inspection of uterine wall contour and thickness, as it has been shown that a thin uterine wall leads to elevated levels of 1891
121/275 (44.0%) 139/190 (73.2%) 175/351 (49.9%) 73/363 (20.1%) 15/143 (10.5%) 130/351 (37.0%) 67/276 (24.3%) 27/278 (9.7%) 8/291 (2.7%) 3/3 1/1 3/3 0/3 0/3 19/65 0/3 9/65 0/3 10/65 0/3 3/65 0/3 15/65 38/55 19/65 28/65
0/3 1/1 0/3 0/3 2/12 0/3 10/12 2/3 1/3 1/3 1/3 5/16 0/2 1/1 7/16 1/2 4/16 1/2 0/2 7/16 0/2 6/16 1/16 0/2 0/16 1/2 33/55 21/23 40/55 9/55 2/55 12/55 10/55 2/55 1/55 20/45 23/45 28/45 8/45 0/45 13/36 17/45 11/36 10/45 2/36 7/45 1/36 0/45 19/36 20/23 21/36 3/36
3/5 5/5 4/5 1/5 0/5 1/5 1/5 0/5 0/5
Reichman et al.
0/1 0/1 0/1 0/1 0/5 0/5 0/5 0/5
Reichman. Pregnancy outcomes in unicornuate uteri. Fertil Steril 2009.
0/3 8/29 1/1 13/19 0/3 24/60 11/29 0/3 10/60 3/29 0/3 3/3 29/60 17/29 3/3 15/29 0/3 2/29 0/3 1/29 4/13 5/5 5/13 1/13 1/13 1/8 7/13 1/8 0/8 0/8 0/13 5/8 4/5 7/8 3/8 1/1 1/1 1/1 0/1
0/2 1/1 0/2 0/2 2/2 2/2 0/2 2/2 0/2 5/5 4/4 4/5 0/5
Term deliveries Conception rate Live births Preterm deliveries Intrauterine fetal demise Spontaneous abortion First trimester TAB Second trimester TAB Ectopic
Total (%) (43) (7) (22) (40) (15) (41) (42) (39) (18) (3) (30) (38) (37) (4) (32) (33) (34) (35) (36) (31)
Rates of various pregnancy outcomes in unicornuate uteri from various studies.
TABLE 2 1892
maternal serum alphafetoprotein in the maternal blood stream and peritoneal cavity (17, 25). Diminished muscle mass, however, serves as a purely theoretical explanation of those obstetrical phenomena seen with unicornuate uteri, and further research must be done to establish a causal link between uterine muscle mass and adverse outcome, should one exist. Another postulated etiology for the adverse obstetrical outcomes reported in unicornuate uteri is the anomalous vasculature supplying the uterus. Disturbance in the uterine blood flow, caused by an absent or abnormal uterine or ovarian artery, could explain growth restriction or spontaneous abortion. This poor vascularity would result in impaired fetal nutrition, diminished fetal size, and higher incidence of first trimester abortion from compromised uteroplacental blood flow (3). Burchell et al. performed radiographic maps of the vascular configuration of uteri removed at hysterectomy and subsequently correlated those results with the reproductive histories of the patients in their study (26). Their work showed that patients with anomalous ascending uterine arteries had more abortions and growth-restricted infants as compared with those patients with normal vasculature. This body of work serves as possibly promising evidence that an absent uterine artery on one side could play a large role in the complexities of unicornuate pregnancy. Lastly, the cervix is often believed to be at least a part of the difficulty in maintaining a viable pregnancy in the unicornuate uterus. According to Roddick et al., cervical incompetence is caused by an abnormal ratio of muscle fibers to connective tissue in the uterine cervix (27). Should there exist a greater proportion of muscle fibers with a resultant loss of connective tissue in women with congenital uterine anomalies, a predisposition to cervical weakness would result (28). Added to this predisposition is believed to be the asymmetric downward force exerted by an anomalous uterus and the markedly increased pressure during pregnancy. Gestational cervical incompetence might then be initiated by hormonally induced relaxation of a congenitally hypermuscular cervix (29). Cervical cerclage has been attempted in many patients with unicornuate uterus, often with impressive results. Golan et al. suggested that cerclage placement be considered in all patients with uterine malformations, although in their study the number of patients with unicornuate uterus was too small to draw conclusions (30). Ambramovici et al., in a similar study, placed cerclages in women with uterine anomalies and no evidence of cervical incompetence. The spontaneous abortion rate decreased from 88% to 0, and the term delivery rate increased from 0 to 87% after placement of cerclage (31). Neither study, however, was randomized, and both lacked appropriate controls. Although several studies have suggested a benefit to routine placement of cervical cerclage early in pregnancy, none have been randomized and nearly all have lacked controls, making them subject to numerous biases. As will be revealed in our review of the existing studies, it seems unlikely that cervical incompetence plays as large a role in recurrent abortion as has been argued for, given that the bulk of pregnancy losses in unicornuate uteri occur
Pregnancy outcomes in unicornuate uteri
Vol. 91, No. 5, May 2009
during the first trimester. Various other researchers have proposed biochemical explanations to adverse outcomes as opposed to morphologic abnormalities. Blum, for example, studied eight women with second trimester losses and found that half of the study population with uterine anomalies had significantly diminished levels of serum cystine aminopeptidase, an enzyme that neutralizes oxytocin (28). DISCUSSION Our review revealed 20 studies of varying size and design that had commented on pregnancy outcomes in patients with unicornuate uteri. These studies ranged in date from 1953 to 2006 and from a sample size of one to 55 patients. In compiling our data, we excluded any patients who were accounted for elsewhere in a previous study. Several of the sources used were more or less complete than others; for instance, one study might cite numbers for ectopic pregnancy and intrauterine fetal demise, and another might not report figures for either. Rather than simply presume that these numbers were zero, we instead excluded these studies when calculating our outcome rates, modifying the denominator accordingly for that series of data. Moreover, we made note of any study in which an obvious bias, most notably intervention bias, was introduced. These studies were excluded entirely when calculating outcome rates. Having done so, we hope to present the most thorough and complete data possible, while at the same time reporting the most accurate assessment of pregnancy outcomes, excluding those data points or studies that were in any way equivocal. In total, we examined 290 women with unicornuate uterus reported in the literature. Of those patients, 175 conceived to carry a total of 468 pregnancies. Table 1 presents those studies found in the literature with varying degrees of information on pregnancy outcomes in patients with unicornuate uteri. In Table 2, we calculate the rates of various pregnancy outcomes after having excluded either biased or uncertain data. In sum, 2.7% of pregnancies were ectopic, 24.3% ended in first trimester abortion, and 9.7% ended in second trimester abortion. In another 3% of cases, the term of abortion was not specified. Another 20.1% resulted in preterm delivery, whereas 44.0% resulted in term births. Lastly, 10.5% ended in intrauterine fetal demise within the third trimester. In total, there was a live-birth rate of 49.9%, roughly half of the 351 pregnancies used to quantify that outcome. CONCLUSIONS In this review, we examined what is known regarding pregnancy in a specific type of uterine anomaly, compiling a comprehensive review of the literature on unicornuate uteri. Our intent was both academic and practical, seeking better understanding of the poorly understood process of unicornuate pregnancies as well as devising a set of statistics that could be used in the counseling of women confronting potentially worrisome pregnancies. Embryologically, unicornuate uterus can result either from incomplete development of one paraFertility and Sterility
mesonephric duct or from urogenital ridge anomalies in which coincident renal and ovarian variants are also found. Although many women go undetected with this condition, our best estimate using the incidence data in the literature is that unicornuate uterus occurs in 1:4020 in the general population; the anomaly, however, is significantly more common in infertile women, as in women with repeated poor outcomes. Although the genetics of uterine development has not been completely revealed, unicornuate uterus exhibits a multifactorial inheritance pattern, with no clear genetic link established. Many theories have been put forth as explanations of the adverse outcomes associated with unicornuate uterus, the three most common being diminished muscle mass, abnormal uterine blood flow, and cervical incompetence. Our review revealed 2.7% ectopic pregnancy, 24.3% first trimester abortion, 9.7% second trimester abortion, 20.1% preterm delivery, and 10.5% intrauterine fetal demise. Finally, we found a 49.9% live-birth rate. We hope that this review might allow clinicians to better assist patients with known anomalies in negotiating the unique anatomy and physiology of their conditions. It is important to keep in mind that such anomalies confer the need not only for additional gynecologic and obstetrical attention but also increased vigilance for renal abnormalities and gynecologic symptoms. Rudimentary uterine horn removal has become the accepted surgical approach for dysmenorrhea, ectopic pregnancy, and retrograde menstruation in such patients. Asymptomatic rudimentary horns that contain endometrium should also be removed. To our knowledge, this represents the largest and most thorough outcome review of pregnancies in patients with unicornuate uterus, and we hope it will serve as a valuable tool for counseling these patients with regard to their expected outcomes. It is important to keep in mind, of course, that the numbers presented herein represent a certain worst-case scenario, given that the patients presented in this review were predominantly brought to clinical attention by either infertility or poor outcomes. As mentioned above, many others no doubt escape detection with normal pregnancies and good outcomes and thus would skew our data favorably toward more reassuring endpoints. We hope, however, that knowing these outcomes, clinicians might be better able to counsel women on making decisions in regards to their current and future pregnancies.
REFERENCES 1. Cohen A, Chhibber G. Obstetric complications of congenital anomalies of the paramesonephric ducts. Semin Reprod Endocrinol 1986;4:59–65. 2. Engmann L, Schmidt D, Nulsen J, Maier D, Benadiva C. An unusual anatomic variation of a unicornuate uterus with normal external uterine morphology. Fertil Steril 2004;824:950–3. 3. Moutos D, Damewood M, Schlaff W, Rock J. A comparison of the reproductive outcome between women with a unicornuate uterus and women with a didelphic uterus. Fertil Steril 1992;58:88–93. 4. Buttram V, Gibbons W. Mullerian anomalies: a proposed classification (an analysis of 144 cases). Fertil Steril 1979;32:40–6.
1893
5. American Fertility Society. The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, Mullerian anomalies and intrauterine adhesions. Fertil Steril 1988;49:944–55. 6. Fedele L, Bianchi S, Agnoli B, Tozzi L, Vignali M. Urinary tract anomalies associated with unicornuate uterus. J Urol 1996;155:847–8. 7. Akar M, Bayar D, Yildiz S, Ozel M, Yilmaz Z. Reproductive outcome of women with unicornuate uterus. Aust N Z J Obstet Gynaecol 2005;45: 148–50. 8. Nahum G. Uterine anomalies: how common are they, and what is their distribution among subtypes? J Reprod Med 1998;43:877–87. 9. Acien P. Incidence of mullerian defects in fertile and infertile women. Hum Reprod 1997;12:1372–6. 10. Simon C, Martinez L, Pardo F, Tortajada M, Pellicer A. Mullerian defects in women with normal reproductive outcome. Fertil Steril 1991;56: 1192–3. 11. Lin P, Bhatnagar K, Nettleton GS, Nakajima S. Female genital anomalies affecting reproduction. Fertil Steril 2002;78:899–915. 12. Elias S, Simpson JL, Carson SA, Malinak LR, Buttram VC Jr. Genetic studies in incomplete mullerian fusion. Obstet Gynecol 1984;63:276. 13. Taylor HS. The role of Hox genes in the development and function of the female reproductive tract. Semin Reprod Endocrinol 2000;18:81–9. 14. Taylor H, Du H. Molecular regulation of mullerian development by Hox genes. Ann N Y Acad Sci 2004;1034:152–65. 15. Raga F, Bauset C, Remohi J, Bonilla-Musoles F, Simon C, Pellicer A. Reproductive impact of congenital mullerian anomalies. Hum Reprod 1997;12:2277–81. 16. Lavergne N, Aristizabal J, Zarka V, Erny R, Hedon B. Uterine anomalies and in-vitro fertilization: what are the results? Eur J Obstet Gynecol Reprod Biol 1996;68:29–34. 17. Jayasinghe Y, Rane A, Stalewski H, Grover S. The presentation and early diagnosis of the rudimentary uterine horn. Obstet Gynecol 2005;105: 1456–67. 18. Donderwinkel P, Dorr J, Willemsen W. The unicornuate uterus: clinical implications. Eur J Obstet Gynecol Reprod Biol 1992;47:135–9. 19. Nahum G, Stanislaw H, McMahon C. Preventing ectopic pregnancies: how often does transperitoneal transmigration of sperm occur in effecting human pregnancy? Br J Obstet Gynaecol 2004;111:706–14. 20. Canis M, Wattiez J, Pouly L, Mage G, Manhes H, Bruhat M. Laparoscopic management of unicornuate uterus with rudimentary horn and unilateral extensive endometriosis: case report. Hum Reprod 1990;819–20. 21. Nezhat F, Nezhat C, Bess O, Nezhat CH. Laparoscopic amputation of noncommunicating rudimentary horn after hystcroscopic diagnosis: a case study. Surg Laparosc Eudosc 1994;155–6. 22. Airoldi J, Berghella V, Sehdev H, Ludmir J. Transvaginal ultrasonography of the cervix to predict preterm birth in women with uterine anomalies. Obstet Gynecol 2005;106:553–6. 23. Nahum G. Uterine anomalies, induction of labor, and uterine rupture. Obstet Gynecol 2005;5:1150–2. 24. Achiron R, Tadmor O, Kamar R, Aboulafia Y, Diamant Y. Prerupture ultrasound diagnosis of interstitial and rudimentary uterine horn pregnancy in the second trimester: a report of two cases. J Reprod Med 1992;37:89–92.
1894
Reichman et al.
25. Zaidi J, Carr J. Rupture of pregnant rudimentary uterine horn with fetal salvage. Acta Obstet Gynecol Scand 1994;73:359–60. 26. Burchell C, Creed F, Rasoulpour M, Whitcomb M. Vascular anatomy of human uterus and pregnancy wastage. Br J Obstet Gynaecol 1978;85: 698. 27. Roddick J, Buckingham J, Danforth D. The muscular cervix—a cause of incompetency in pregnancy. Obstet Gynecol 1961;17:562. 28. Blum M. Comparative study of serum C.A.P. activity during pregnancy in malformed and normal uterus. J Perinat Med 1978;6:165. 29. Nwosu C, Soffronaff C, Bolton C. A new look at the etiology of cervical incompetence. Int J Gynaecol Obstet 1975;13:201. 30. Golan A, Langer R, Wexler S, Segev E, Niv D, David M. Cervical cerclage—its role in the pregnant anomalous uterus. Int J Fertil Womens Med 1990;35:164–70. 31. Ambramovici H, Faktor J, Pascal B. Congenital uterine malformations as indication for cervical suture in habitual abortion and premature delivery. Int J Fertil Womens Med 1983;28:161–4. 32. Baker W, Roy R, Bancroft C, McGaughey H, Dickman N, Tucker G. Congenital anomalies of the uterus associated with pregnancy: an analysis of one hundred eighteen cases from the literature with a report of nine additional cases. Am J Obstet Gynecol 1953;66:580–97. 33. Wajntraub G, Milwidsky A, Weiss D. Prevention of premature delivery in a unicornuate uterus by cervical cerclage. Acta Obstet Gynaecol Scand 1975;54:497–8. 34. Green L, Harris R. Uterine anomalies: frequency of diagnosis and associated obstetric complications. Obstet Gynecol 1976;47:427–9. 35. Beernink F, Beernink H, Chinn A. Uterus unicornis with uterus solidaris. Obstet Gynecol 1976;47:651–3. 36. 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. 37. Fedele L, Zamberletti D, Vercellini P, Dorta M, Candiani G. Reproductive performance of women with unicornuate uterus. Fertil Steril 1987;47:416–9. 38. Ludmir J, Samuels P, Brooks S, Mennuti M. Pregnancy outcome of patients with uncorrected uterine anomalies managed in a high-risk obstetric setting. Obstet Gynecol 1990;75:906–9. 39. Acien P. Reproductive performance of women with uterine malformations. Hum Reprod 1993;8:122–6. 40. Heinonen P. Unicornuate uterus and rudimentary horn. Fertil Steril 1997;68:224–30. 41. Dicker D, Nitke S, Shoenfeld A, Fish B, Meizner I, Ben-Rafael Z. Laparoscopic management of rudimentary horn pregnancy. Hum Reprod 1998;13:2643–4. 42. Daskalakis G, Pilalis A, Lykeridou K. Antsaklis. Rupture of noncommunicating rudimentary uterine horn pregnancy. Obstet Gynecol 2002;100: 1108–10. 43. Haydardedeoglu B, Simsek E, Kilicdag EB, Tarim E, Aslan E, Bagis T. A case of unicornuate uterus with ipsilateral ovarian and renal agenesis. Fertil Steril 2006;85(3):750e1–4. 44. Emans J, Laufer MR, Goldstein DP. Pediatric and adolescent gynecology. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2005.
Pregnancy outcomes in unicornuate uteri
Vol. 91, No. 5, May 2009