Congenital malformations of the uterus are not rare; they affect as much as 7% of women. When I was studying to be a nurse, I wanted to know more about the causes, effects, and nursing implications of these malformations, also known as "müllerian anomalies," and so researched the topic for a paper.
My interest was professional (I liked OB nursing) and personal, since I had found out the difficult way that I had a uterine anomaly, myself. These anomalies tend to be like buried WWII artillery shells . . . you don't know about them until something tragic—usually pregnancy loss—happens. A few might be discovered before a woman attempts pregnancy, but most of the time, painful menstrual periods are the only clue.
And who doesn't bitch about cramps from time to time?
In the interest of plunking one more anchovy onto the pizza that is DK4, and in the spirit of knowledge, I am subjecting you to this paper, minus the footnotes. If you read on, you even get to see my x-rayed innards, before and after surgery to correct the problem.
Among my support community for people who have this anomaly, the recent, undead "criminalizing miscarriage" issue sparked a lot of jokes about jail time, muttered darkly. And what would Michelle Bachman think of a woman unable to produce children as easily as she did?
Normal and abnormal Müllerian tract development in the human embryo: a review
In the world of infertility research, women with Müllerian anomalies—congenital defects of the vagina and/or cervix, uterus, Fallopian tubes and related structures—make up possibly 3.2% of the population, which may pose problems with conceiving and carrying a pregnancy to term in a significant subset of those women. A registered nurse will encounter patients with uterine anomalies more than once in his or her career. This review is my attempt to clarify the hormonal and physical events that lead to proper formation of the uterus, and the stages at which Müllerian formation can go awry. I will also review two of the systems used to classify Müllerian anomalies, and touch on the question of heritability and syndromes.
My interest is personal; I suffered 5 miscarriages, early and late in gestation, before giving birth to a term infant. I had a complete failure of the Müllerian duct septum to resorb (hysterosalpingogram at left, showing bifid uterine cavity), which should have happened when I was a 20-week fetus, and it took much research and corrective surgery before I could have my son.
Because of the lack of information and support available for someone like me, I started an on-line support group devoted to uterine anomalies in the year 2000. They were a small group of women—and a few anxious fathers, too—eager for information and generous with their support as I got through surgeries, miscarriage, and finally had my baby. Now they number over [3,500] members, and are there for sufferers and health professionals seeking information and support. And this paper is written for future nurses interested in understanding the origins and implications of a birth defect that may strike as many as 7 in 100 women.
Discussing the genesis of Müllerian duct anomalies will touch upon basic embryology, hormones, genetics, teratogens, and reproductive implications in later life.
First comes a review of normal Müllerian tract development in the embryo.
Müllerian tract development in the embryo
In the human embryo, two tracts form side by side, the Wolffian (mesonephric) and the Müllerian (paramesonephric) tracts (Fig. 2), which each consist of two parallel tubules. The Wolffian go on to form the prostate, seminal vesicles and vas deferens in the male, and may persist in the female as nonfunctional tubes running parallel to the ovaries, oviducts, and broad ligaments and as Skene’s glands, but otherwise waste away in the absence of high enough levels of testosterone, otherwise produced by a male embryo’s testes.
In the male, at about 8–10 weeks of gestation, he secretes anti-Müllerian hormone (AMH, also known as Müllerian inhibiting substance) from Sertoli cells in the gonads, and the Müllerian tracts recede, except to form the utricle, or nonfunctioning homologue of the uterus, in the prostate and a few other vestigial, poorly understood structures. Rarely, whenever the testes fail to secrete AMH, the Müllerian tract persists and forms a small, rudimentary uterus behind the urinary bladder, often with the testicles in place where ovaries might have been suspended in a female.
Because a female embryo lacks testis and Sertoli cells, AMH is never secreted, and the Mullerian ducts do persist and develop into normal reproductive anatomy, while the Wolffian ducts dissolve away in the absence of enough testosterone. However, the Wolffian ducts do persist long enough to form a kind of template or scaffolding for the Müllerian ducts to grow along, and that is why uterine and kidney anomalies are frequently associated—e.g. if one kidney fails to form, there may be an abnormality on that side of a Fallopian tube and hemiuterus. I will discuss that more in the section about uterine anomalies.
In normal development, portions of the Müllerian ducts go on to fuse and form a Y-shaped tube called the “uterovaginal primordium,” or “UVP.” The caudad UVP goes on to form the upper vagina, cervix, uterine fundus, while the cephalad portion remains widely separated and forms the oviducts, or Fallopian tubes. What causes the fusion? According to some researchers, no one really knows the molecular basis for fusion (Simpson, 1999), although the aforementioned anatomical influence of the Wolffian ducts in encouraging elongation and approximation of the Müllerian ducts is well known.
From gestational week 10 to 20, roughly, the fused part of the UVP has a double-lumen tube as it develops. At the cephalad end of the fused portion, the medial septum expands laterally to widen the fundus, while the lower uterine segment remains narrow.
Around twenty weeks, a single uterine cavity which normally appears like an inverted triangle, apex terminating at the internal cervical os, begins to take shape as the midline septum dissolves away. The septum dissolves under the control of chemicals. According to a study done by Lee, et al., Bcl-2 is a protein responsible for protecting fetal myometrium from apoptosis, or controlled cell death, and has been found present in the outer myometrial walls but absent from fetal uterine septa (Lee, 1998). Without the protein present, that midline septum disappears by apoptosis throughout the length of the uterus, cervix and upper vagina, leaving only a single lumen. Everything now configured properly (right), it remains for the uterus only to grow in size and undergo glandular maturation from hormones secreted at puberty. If everything has developed normally, that is.
When tubes go bad: classifying congenital uterine defects
With two tubes fusing in a caudo-cephalic direction, then unifying, then fusing inferiorly with the invagination of the urogenital sinus to form the lower portion of the vagina, a lot of things have to happen rather seamlessly, not to mention symmetrically, in order to form a textbook set of internal female organs. For environmental and sometimes genetic reasons, it does not always happen properly. And because over half of these anomalies never declare themselves and are only incidental findings during a c-section or hysterectomy, there has not been much of a concerted effort to classify them. According to Hurst, et al., various systems have included symmetric defects versus asymmetric defects, vertical versus lateral fusion defects, agenesis and others (Hurst, et al. as cited in Verkauf, 91). But the most widely accepted classification system was instituted in 1979 by the American Fertility Society (below), and classifies anomalies by both the embryological stage when failure happened as well as the clinical manifestations (AFS, 1988).
The American Fertility Society classification of Müllerian anomalies
Category I: agenesis and hypoplasia
Referring to the AFS chart above, we see that Category I covers agenesis or hypoplasia of various segments of the uterus, cervix, tubes, and any combination. For example, one member of my support group had a fairly normal Mullerian tract except for a 2-mm thick membrane in place of a cervix. Thanks to artificial insemination, abdominal cerclage (a purse stitch around the lower segment of the uterus, deep to the uterine arteries), she has had two near-term infants, the last time we heard from her. Most women suffering from agenesis or extreme hypoplasia, however, have severe fertility problems, simply by lacking sufficient tissue to support a growing pregnancy. Category I sufferers generally have normal hormonal cycles, however.
There is a subset of women who have been told that they have an “infantile” uterus and to expect fertility problems, but if the endometrial cavity meets a certain minimum length and the endometrium itself exceeds 5mm in thickness, it is probably sufficient to support a pregnancy. Sometimes the small uterine size is due to hypopituitary problems, not a Müllerian anomaly per se. Hypopituitarism is easily remedied by the use of injectible gonadotropins and menotropins to induce ovulation. I know a handful of women with primary amenorrhea who have had great success carrying to term, including two women who each delivered twins at 35 weeks. The uterus grows adequately under stimulation from luteal and placental hormones. The term “infantile uterus” is falling into disuse.
Category II: Unicornuate uterus
Category II covers uterus unicornis (left) with or without an anlage, or primordial bud, on the opposite side, the anlage in turn with or without canalization or communication with the well-developed hemiuterus. The type without an anlage on the opposite side results from a complete degeneration or failure to appear of that particular Mullerian duct (Moore, 161)
The type with a canalized, communicating rudimentary horn used to get classified as an asymmetrical bicornuate uterus, and is represented in the category chart above. A few interesting things about this type of uterus with anlage is that a canalized primordial bud with endometrium is capable of supporting a pregnancy, usually only up to about 20 weeks gestational age, at which point it ruptures , causing a genuine emergency. A hemihysterectomy is sometimes done to prevent that possibility, taking the bud and leaving the well developed horn.
"I like to think of my womb as a cozy place to rent—with a granny unit attached" —Arkansas woman with a unicornuate uterus and rudimentary horn
According to the Hurst review, unicornuate uterus is uncommon, comprising only about 5% of anomalies, and has a rather higher pregnancy wastage rate of ~36%. Almost all of patients presenting with “UU” have some kind of major renal anomaly, described below. (Hurst, et al. as cited in Verkauf, 95-97)
For reasons somewhat unclear, women with unicornuate uteri seem to suffer from greater subfertility than women with the other anomalies, possibly because of a high prevalence of endometriosis.
Asymmetrical defects such as unicornuate uterus are also associated commonly with unilateral agenesis of a kidney, because of the close association with Wolffian development. Failure of the Wolffian duct on one side often leads to a unicornuate uterus. Furthermore, the ovary contralateral to the functional horn may be suspended in its proper place or it might be located at the costal margin on the flank. In one case, an acquaintance was told that she had a “streak” ovary, although it did produce follicles.
Category III: Uterus didelphys
Category III, uterus didelphys (right), happens to about 1 in 2,000 women (Hurst, et al., as cited in Verkauf, 97). It is often described as a “duplication” of the Mullerian tract, but a true duplication (two separate vaginas, cervices and uterine fundi, each with two cornua and two tubes) is rare and borne of faulty twinning, not just faulty Müllerian tract development. Uterus didelphys is simply a top-to-bottom split of one Mullerian tract. Kidney anomalies are strongly associated with uterus didelphys, too. 75% have a longitudinal vaginal septum that reaches the introitus that may cause dyspareunia or confound attempts to use a tampon.
"I thought to myself, `Oh my God. It's Friday night, and I've just found another bodily orifice!'" —a friend with uterus didelphys who discovered that she had two vaginal openings one night during college
Because of the vaginal septum, uterus didelphys is one of the Mullerian anomalies most frequently diagnosed independent of pregnancy, miscarriage or birth. The vaginal septum and dual cervices are sometimes (and sometimes not) noticed during a routine pelvic exam. The septum is often lysed surgically, and is frequently obliterated by a normal vaginal delivery.
One of the rarest of uterine anomalies, uterus didelphys is also one of the most problematic, with a miscarriage and live birth rate somewhere around 47%, similar to that of unicornuate uterus (Raga, 1997). And as with any uterine anomaly, certain things apply across the board, however: abnormal fetal lie and breech births are very common; external version is dangerous and should not be attempted, and induction—especially with Cytotec—is dangerous to use in a uterus that does not contract in a predictable way.
One example of the unpredictability of uterus didelphys is when a twin is carried in each hemiuterus. In those cases, each pregnancy is regarded as a separate entity, and the twins may be born hours, days or weeks apart, unlike twins in a more integrated uterus. (Tyagi, 2001)
Category IV: Bicornuate uterus
Category IV, uterus bicornis, (left) is one of the more common defects, and as with categories II and III, comes from a failure of the Mullerian ducts to unite to form unified uterine and sometimes cervical segments. It is classified according to whether or not the fundal division comes down to the cervix or not. Some researchers have further divided the bicornuate uterus into “bicollis” (two cervices) or “unicollis” (just one) . On some imaging studies, such as hysterosalpingogram (HSG), the bicornuate uterus is indistinguishable from a septate uterus.
A few features definitely distinguish the bicornuate uterus, Category IV from the septate uterus, which belongs in Category V:
1. A muscular, adequately vascularized septum with a healthy endometrium separates the two uterine horns
2. An external division of the uterine horns is visible during a laparotomy or laparoscopy and some of the newer imaging methods, such as MRI. The depth of the external fundal groove in the bicornuate uterus must exceed 1.5 cm.
A common external appearance of a partially bicornuate uterus is “heart-shaped,” as many women have heard following a delivery by c-section.
About 10% of bicornuate owners have accompanying urinary tract anomalies (Hurst, et al. as cited in Verkauf, 101)
"My husband calls me his `concept wife.' You know like those cars with three headlights or gull-wing doors. My exciting design is a double-horned uterus. It's the latest thing." —a Georgia woman on her bicornuate uterus
Fortunately, a bicornuate uterus does not pose many problems with conception or carrying to term, although the statistics for live term births is not as good as with a normally shaped uterus, and when a study does show it as having problems, it is usually because no distinction has been made between bicornuate and septate uteri, the latter of which does produce a lot of spontaneous abortions. Breech presentation is the most common complication with a bicornuate uterus. A friend of mine carried fraternal twins to 34 weeks in only the left horn of her completely bicornuate uterus, and is now pregnant with baby number four—this time in her unused right horn. Her story, if not exactly common, is not quite rare.
The uterus has amazing elasticity and capability for hypertrophy during pregnancy, and my friend and her twins are living proof of that. But where one thing is wrong in the Mullerian tract, it is quite likely that something else did not develop correctly elsewhere in the tract, and that is where the problems start. Moving on, we come to the most problematic category—my own.
Category V: Septate uterus
Unlike the preceding three categories, Category V, uterus septus (lright, an example of complete septate uterus) is the result of proper Mullerian fusion, but faulty resorption; the inner partition has either totally or partially failed to disappear midway between the female fetus’ conception and birth. Going back to Lee et al., the midline septum in the embryonal uterus lacks the protein Bcl-2, which protects other parts of the uterus from apoptosis (Lee, 1998). When the septum is retained, it is reasonable to hypothesize that a genetic factor may account for oversynthesis of Bcl-2, and its presence in the septum, which then fails to resorb.
Outwardly, the uterus septus looks normal—or near-normal, with either a domed fundus, or an external fundal groove of less than 1.5 cm in depth permissible within the classification, giving the outer fundus at times a flat or slightly dented appearance. Uterus septus makes up over half of all uterine anomalies. 20%, according to Hurst, et al., have urinary anomalies.
The septate uterus, however, has arguably the worst track record of any of the malformation for producing viable infants, with subseptate uteri (example at left) doing better than completely septate uteri. Completely septate uteri have had, in some studies, a pregnancy wastage rate of from 67 to 90%, although the live birth rate rose as high as 62% in one longitudinal sample of over 3,000 women (Raga, 1997). The variability in figures depends in large part upon the study subjects, and whether they came from the population at large or from a pool of women suffering pregnancy complications.
It is not just the length of the septum but the type of tissue (muscle versus fibrous), vascularity, and the quality of the overlying endometrium that influences pregnancy outcomes. Most miscarriages happen early in a septate uterus when the conceptus has implanted on the septum itself, and found the blood supply lacking. There have also been studies showing that septal endometrium lacks sufficient progesterone (P2) receptors, and so will not have the proper decidual response of pregnancy, either. And yet another histological study indicates that septal endometrium does not respond right to estradiol during the follicular phase (Fedele, 1996), which would mean that it did not build up well enough to form a proper deciduum. In any case, it causes a lot of spontaneous abortions.
As one of my physicians stated, there is a high probability of something else being wrong when there is one uterine anomaly present (Gary Berger, M.D.: personal interview, March 20, 2001). Depending on the sources, 20-25% of all uterine anomalies carry the risk of cervical incompetence, either due to the higher pressures on the tightly closed collagen of the cervix, and/or simple defect in cervical formation, whether in collagen content or on a gross level. In any case, pregnant women with septate uteri—or any other anomaly—run a greater risk of second-trimester miscarriage and premature labor than the normal population. Again, a complete uterus septus has the worst outcomes, in part because it does not stretch normally, causing incompetent cervix, abruption, preterm labor and more (Raga, 1997).
Referring again to the first image, my own HSG (right), there was no way to tell if the image represented a bicornuate or septate uterus—not without seeing the outer contour of the uterus. And indeed I received an initial misdiagnosis, and was told to keep trying to conceive. Instead I pursued further imaging studies and corrective surgery.
At this point, a reader might ask “So what?” Well, the importance of proper diagnosis is that women can get the proper treatment that, as late as 1993, was not available. Hurst et al. wrote in 1993 that deciding on a treatment and pregnancy prognosis for bicornuate was “frustrating” because traditionally, bicornuate and septate uteri had been lumped together as “bicornuate” or “double uterus.”(Verkauf, 1993) Failing to distinguish between the types, physicians prescribed watchful waiting for a lot of women with a septum, who then lost a lot of pregnancies. Conversely, a lot of women with bicornuate uteri were overtreated with what used to be state of the art: Tompkins or Jones metroplasties through a laparotomy, which carried all the risks of major abdominal surgery: adhesions, infection, deep vein thrombosis, infertility, rupture during pregnancy and so forth.
These days, with proper diagnostic techniques, including MRI or laparoscopy, a patient with a bicornuate uterus is treated with watchful waiting, and a woman with a septate uterus is treated with a simple endoscopic lysis of the septum, as I was (open metroplasties are reserved now for only the thickest of septa, or other complicating factors, such as leiomyomata) (Rock, 1987). Thus corrected, a formerly completely septate uterus (left) has a pregnancy and miscarriage rate approaching that of a normal uterus.
Category VI: Arcuate uterus
Category VI is known as uterus arcuatus, (right) or an arcuate uterus, and it refers to the slight fundal filling defect visible on an HSG, or to an outward groove in the dome of the fundus and a slight “heart-shaped” appearance. The etiology is either a failure of the Mullerian ducts to fuse or to completely do away with the septum, or both, but only to a slight degree. There is no reliable documentation of trouble associated with an arcuate uterus and it is considered a variation of normal. This is theoretically the kind of uterus I have, after two metroplasties (Fig. 10), but it is true only if you ignore the intact septum in the lower uterine segment that the resectoscope somehow missed twice.
Category VII DES or T-shaped uterus
Category VII deformities—a T-shaped uterus (refer to final category in the chart above)—are predominantly, although not totally, caused by a pregnant mother’s having taken diethylstilbestrol (DES) in the event of “threatened miscarriage,” i.e. uterine bleeding. DES was prescribed off-label and then through FDA approval in an attempt to halt miscarriages from 1941 until 1971, when it was found to be a teratogen (and it failed to change the miscarriage rate as well). About 69% of female offspring of mothers who took DES had abnormal uterine cavities that took on a T shape, with or without dilated cornua (that variation is visible on the chart as well). The uteri also tended to be hypoplastic and prone to cervical incompetence and accompanying loss of the fetus at midterm. DES daughters also suffer from histological abnormalities of the cervix and vagina and are susceptible to cervical and vaginal cancer at an early age.
Pregnancy outcomes are, predictably, not as good as those of a woman with a normal uterus. In DES daughters, miscarriage rates rise to 38% (normal baseline is 20%) and term births only come to 34% of pregnancies. As with all Müllerian anomalies, ectopic pregnancies are much more common in the DES uterus (Kaufman, 1980).
There are experimental surgeries to open up the small T-shaped cavity by carving at the sides of the endometrial cavity, quite similar to the hysteroscopic surgery done to lyse a uterine septum, but the surgery is not yet widely performed. Cerclage is another remedy to head off preterm birth.
Heritability and other causes
Although substances such as DES and thalidomide are proven teratogens affecting Müllerian formation, there is increasing evidence of heritability, too. Sometimes, the two may intersect, as has been shown in studies of Viet Nam and Gulf War veterans’ offspring, and a tenuous link to radiation.
Some syndromes involving Müllerian anomalies cluster in families, although incidence in siblings of an isolated defect is very low—only 2.7% (Elias, 1984). According to Simpson, “familial aggregates of the most common disorders of mullerian differentiation in females [ . . . ] are best explained on the basis of polygenic/multifactorial inheritance. No information exists on the number and chromosomal location of responsible genes.” (Simpson,1999). Polygenic inheritance means that a group of genes all affect the expression of a trait. Since it is less probable that a large group of necessary genes will all turn up at the same time and cause the defect, that explains why only 2.7% of siblings in the study above shared the defect. The term multifactorial refers to other influences upon the Müllerian development, such as the development of the Wolffian ducts, ingestion of teratogens, and other accidents that could influence reproductive organs at a critical time.
As for the syndrome aspect, there are a number of syndromes involving Müllerian anomalies. For example Hand-Foot-Genital syndrome is an autosomal dominant syndrome in which a person has stubby thumbs and big toes, crooked little fingers and a whole raft of urogenital problems: bicornuate uterus and vaginal septum in the females, hypospadias in the males and various kidney and ureter anomalies in both sexes (Stern, 1970). There are other syndromes involving Müllerian anomalies, ear and eye formation and deformities of the appendicular skeleton, but nothing so clear-cut and highly heritable as Hand-Foot-Genital syndrome.
Müllerian anomalies and you
So what implications do Müllerian anomalies have on nursing practice? To begin with, as many as four percent of all women have some type of uterine anomaly, so chances are that an RN will encounter more than one such patient. And even if she never has trouble conceiving, that patient may well have a breech birth, cervical incompetence, catastrophic uterine rupture, an abruption, an ineffective labor or other form of dystocia, or a preterm birth. She has a greater chance of presenting with an ectopic pregnancy. Chances are good that she has only one kidney, or is more likely to suffer from UTIs or pyelonephritis. Her menstrual periods are often very painful, she has a much higher incidence of endometriosis, and certain procedures, such as fitting an IUD, induction of labor, or external version of a fetus, could be fatal. And if she is a DES daughter or has uterus didelphys, she may be at greater risk of certain kinds of uterine, cervical and vaginal cancers.
A woman with a known uterine anomaly may approach you with apprehension about her prospects of conceiving and carrying to term, or with worries about the well-being of her fetus. An acquaintance with the various disorders will help you to help her more effectively.
Here is a practical FAQ about uterine anomalies for people who need to learn more about diagnosis and treatment options.
References
AFS. (1988) The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, müllerian anomalies and intrauterine adhesions. Ferti.l Steril, 49(6), 944–55.
Elias, S., Simpson, J. L., Carson, S. A., Malinak, L. R., Buttram, V. C., Jr. (1984). Genetics studies in incomplete müllerian fusion. Obstetrics and Gynecology, 63(3), 276–9.
Kaufman, R. H., Adam, E., Binder, G. L., Gerthoffer, E. (1980). Upper genital tract changes and pregnancy outcome in offspring exposed in utero to diethylstilbestrol. American Journal of Obstetrical Gynecology, 137(3): 299–308.
Lee, D. M., Osathanondh, R., Yeh, J. (1998). Localization of Bcl-2 in the human fetal müllerian tract. Fertil Steril, 70(1), 135–40.
Moore, Keith L. (1977). Before we are born: Basic embryology and birth defects. Philadelphia: W. B. Saunders Company
Raga, .F, Bauset, C., Remohi, J., et al. (1997). Reproductive impact of congenital Müllerian anomalies. Human Reproduction, 12(10), 2277–81.
Rock, J.A. (2003). Surgery for anomalies of the mullerian ducts. In J. D. Tompson & J.A. Rock, (Eds.), TeLind's Operative Gynecology. (9th ed., p. 705). Philadelphia, Pa: JB Lippincott Williams & Wilkins.
Simpson, J. L. (1999). Genetics of the female reproductive ducts. American Journal of Medical Genetics, 89(4), 224–39.
Tyagi, A., Minocha, B., Prateek, S. (2001). Delayed delivery of second twin in uterus didelphys. International Journal of Gynaecology and Obstetrics, 73(3), 259–60.
Verkauf, Barry S. (1993). Congenital malformations of the female reproductive tract and their treatment. Norwalk, CT: Appleton & Lange
Williams, P.L.; Wendell-Smith, C. P.; & Treadgold, S. (1969). Basic human Embryology. Philadelphia: J.B. Lippincott Company