Mullerian Anomalies

Today we are rejoined by Dr. Emily Seidler of the Division of Reproductive Endocrinology and Infertility at Beth Israel Deaconess and Boston IVF, as well as Margie Thorsen, a PGY-1 at Brown & Women and Infants, to talk through congenital uterine anomalies (CUAs), also known as Mullerian anomllies.

CUAs can cause pelvic pain, AUB/dysmenorrhea, recurrent pregnancy loss (RPL), and/or preterm deliver, or can be asymptomatic . They are often found during an evaluation for primary amenorrhea and infertility. On their own, CUAs are associated with skeletal and renal abnormalities (20-30% of women with CUAs have concomitant renal anomalies), and can also be associated with inguinal hernias. Due to these generally being asymptomatic, true prevalence is hard to estimate; but it’s estimated around 5-6% amongst all women. This increases to 8-10% in infertile women, 12-15% in women with history of SAB, and 20-25% in women with both infertility and prior history of SAB.

Frequency of types of CUAs in affected women, in decreasing order:

• Septate (most common)

• Bicornuate

• Unicornuate

• Didelphys

• Agenesis 

“Arcuate” uteri, which refers to an up to 1cm “dip” i the fundal contour of the cavity, is considered a normal variant.

Embryology of Mullerian Structures

• Wolffian ducts = mesonephric =  “male” (need Y chromosome🡪 SRY gene🡪 AMH).

• Mullerian ducts = paramesonephric = “female” (default, no AMH means Wolfiann ducts regress).

  • Includes the UTERUS, TUBES, CERVIX & UPPER VAGINA

    • Ovaries are totally separate (urogenital ridge)

• Mullerian ducts start to elongate caudally at ~6 wks GA.

  • By 12 wks GA, the caudal portion of Mullerian ducts fuse to form the early uterus and vagina.

    • Initially, Mullerian ducts are like 2 solid cylinders laying side by side. Later, each cylinder undergoes canalization, and then fuses (like putting your elbows together and then slowly bringing the arms together until your wrists join).

  • By 20 wks GA, septum absorption is complete.

    • Top part forms the fallopian tubes and fimbria

    • Bottom part becomes the uterus and upper vagina

The Mullerian Anomalies

• Genetics are not well understood; mostly thought to be polygenic/multifactorial. For affected patients, karyotype is usually normal 46, XX.

• 3 main types: agenesis/hypoplasia, lateral fusion defects, vertical fusion defects.

• Agenesis or hypoplasia

  • Classic test question involves complete agenesis of uterus/cervix/upper vagina termed MRKH syndrome, presenting as primary amenorrhea with otherwise normal pubertal development.

    • On exam: overall look totally normal; pelvic exam = “blind pouch” + shortened vagina; normal breasts, normal pubic & axillary hair.

    • Exams may try to confuse this presentation with androgen insensitivity syndrome (AIS).

      • Key labs to differentiate: karyotype is 46,XX, total T is female range in MRKH, whereas 46, XY and elevated T in AIS.

    • Treatment: dilators to become sexually active; can have biologic children later in life with the use of a GC (ovaries/eggs are normal!)

• Lateral fusion defects

  • i.e., your two arms don’t come together “elbows to hands” normally

  • Longitudinal vaginal/uterine septum, bicornuate, didelphys, etc.

    • Can have 2 cervices = “bicollis.”

    • If abnormal/absent uterine horn, that side’s tube will also be affected.

      • Same concept with renal abnormalities (abnormal uterine side = abnormal renal side).

    • Treatment depends on the anomaly, symptoms,  and patient’s goals.

      • Generally with infertility patients with a septum, will be resected,

      • If not associated with infertility and not surgically corrected, just helpful to know going into pregnancy (SABs, preterm labor/delivery, etc.).

• Vertical fusion defects

  • Leads to a TRANSVERSE vaginal septum, partial vaginal agenesis, and/or cervical agenesis.

• Miscellaneous uterine anomalies include those related to in-utero exposure to diethylstilbestrol (DES).

  • Moms were ironically given it to prevent pregnancy loss from 1950s-1971

  • Female babies born with classic uterine anomalies: T shaped uterine cavity, hypoplastic uterus, endometrial cavity adhesions.

Diagnostics for Suspected Anomalies

• 2D ultrasound = initial imaging modality of choice, as it is widely available, noninvasive, relatively inexpensive, and can also look at renal system.

  • 3D sonohysterogram especially helpful if available.

• MRI only necessary if ultrasound isn’t definitive; can be helpful for surgical planning.

• HSG might make the initial diagnosis (infertility patient eval.) but this only evaluates the uterine CAVITY, not the fundus!

  • I.e., an HSG with 2 “bunny ears” could be a large uterine septum (normal fundus) or a bicornuate or didelphys (heart-shaped fundus).

Treating Infertility

Today we are thrilled to have Dr. Emily Seidler of the Division of Reproductive Endocrinology and Infertility at Beth Israel Deaconess and Boston IVF, come help us revisit Infertility with a discussion on treatment. We start out with definitions of fecundity versus fecundability, meaning:

• Fecundity: Fertility; the ability to conceive and produce offspring, vs.

• Fecundability = probability of getting pregnant in a single menstrual cycle.

For the first six months of attempted conception, 80% of couples will succeed. After one year, this jumps to about 85%, leaving a 15% rate of infertility overall based on the definitions we reviewed in our prior infertility episode.

Patients/couples should be initially counseled on lifestyle modification to improve fertility:

• Stop smoking.

• Reducing excessive alcohol/caffeine consumption.

• Weight loss to target normal BMI.

• Appropriately timing intercourse just before/around time of ovulation.

  • Use of OPKs starting around CD10

• Once health and lifestyle is (reasonably) optimized, treatment may still be needed and varies depending on cause of subfertility/infertility.

We then started to talk about the specific causes of infertility. The first and most broad is ovulatory dysfunction. Ovulatory dysfunction is broken into major categories by the World Health Organization (WHO):

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Contemporary OB/GYN

• WHO class 1: hypogonadotropic hypogonadal anovulation (5-10%)

  • Common causes of this include anorexia, over-exercising, or Kallman’s and Sheehan’s syndromes.

  • These women need extensive nutritional support and hormonal support for bone and heart health.

  • To conceive, this group of patients will need injectable gonadotropins.

• WHO class 2 = Normogonadatropic normoestrogenic (70-85%)

  • The most common example in this group is PCOS.

  • Treatment should focus on optimizing health (weight loss, improve/control insulin resistance, etc.) then ovulation induction with timed intercourse.

  • Letrozole is first line ovulation induction agent with PCOS.

    • NEJM 2014 comparing Clomiphene and Letrozole for PCOS.

      • Showed LTZ was associated with higher ovulation rates and higher live brith rates.

    • Clomiphene can also be used if can’t use letrozole or patient doesn’t respond to letrozole.

    • Clomiphene & Letrozole have different mechanisms of action but similar end result:

      • Clomid works at the level the brain as a SERM to inhibit negative feedback of estrogen on GnRH and FSH production/release.

      • Letrozole works at the level of the ovary and is an aromatase inhibitor, thus reducing the amount of estrogen available and pushing more production of FSH.

        • Both trick the brain into thinking estrogen is low, so FSH goes up.

• WHO class 3 = hypergonadotropic hypoestrogenic anovulation (10-25%)

  • Classically described as primary ovarian insufficiency (POI)

  • Some can go through treatment with their own eggs, but often FSH is very elevated and AMH/AFC are very low- these patients generally need IVF donor eggs to conceive.

Next, we moved beyond ovulation to other causes of infertility.

Tubal factor:

• I.e., both tubes are blocked.

• Treatment is IVF, as this is only way to bypass the tubes in this case.

• If hydrosalpinx, consider removing prior to treatment (these reduce pregnancy rate by 50% after embryo transfer when left in situ).

Male factor:

• If sperm is present but in low counts (generally under ~4 mil total motile sperm), IVF with ICSI is helpful

  • ICSI = intracytoplasmic sperm injection.

    • One sperm injected into each egg under the microscope

• If azospermic but male factor is an obstructive cause (i.e., cystic fibrosis patients with congenital absence of vas deferens), can surgically obtain sperm with TESE (testicular sperm extraction).

• If azospermic and non-obstructive (i.e., patient isn’t making sperm), need donor sperm for conception.

Uterine factor:

• This is generally not an independent cause of infertility or reason, in isolation, for surgical intervention.

• However, when uterine factors that affect the cavity are found in an infertility evaluation, these are typically corrected prior to treatment.

  • Submucosal fibroids and endometrial polyps can be removed hysteroscopically .

  • Uterine septum or intracavitary adhesions can be resected hysteroscopically with cold scissors or with energy.

Unexplained infertility:

• Testing all normal but unable to conceive after 6-12 mos; includes age-related subfertility.

  • Treatment is empiric (“cover the bases” approach).

    • Can start with medicated IUI with Clomiphene or Letrozole

    • If unable to conceive after 3-4 cycles, move on to IVF.

• IVF can involve a fresh embryo transfer on day 3 or day 5, or frozen embryo transfers (always day 5).

• Prenatal genetic testing for aneuploidy (PGT-A) is an adjunct to treatment (formerly called PGS).

  • This involves a trophectoderm biopsy at the blastocyst stage

    • Trophectoderm becomes the placenta; inner cell mass becomes the fetus.

  • Embryos generally are then frozen and biopsy samples are tested to determine chromosomal status 

    • Used as a selection tool to transfer a single euploid embryo

      • Theoretically increases pregnancy rate to 60-70% and decreases miscarriage rate to 10%

      • However, recent studies (i.e., STAR trial) haven’t shown huge benefit to PGT-A over standard morphologic criteria for embryo evaluation.

Same sex couples/single patients:

• Same sex female couples have options various therapies vs. traditional IVF

  • TDI = therapeutic donor insemination.

    • simply timing insemination with one partner’s menstrual cycle and using donor sperm.

    • Can also utilize ovulation induction techniques (i.e., letrozole/clomiphene).

  • Partner-assisted Reproduction (PAR), aka reciprocal IVF = using one partner’s eggs for conception, but the other partner carries the pregnancy.

    • Ovarian stimulation and egg retrieval on one partner.

    • Create embryos with donor sperm.

    • Transfer the embryo(s) into the other partner’s uterus.

  • Traditional IVF particularly if one partner is unable to conceive using TDI.

• Same sex male couples require donor egg + gestational carrier.

  • Gestational carrier: just carrying the pregnancy.

    • Donor egg from a different woman; embryos created with one of the male partner’s sperm,

    • Traditional surrogacy typically refers to using the carrying woman’s egg, as well as her uterus. This has become very complicated legally and ethically and thus is not used with frequency.

#MedEd: Applying into REI

Nick and Fei and joined by Dr. Andrey Dolinko, who will be a reproductive endocrinology and infertility fellow at the University of Pennsylvania next year. He talks to us about what to expect in residency and his tips for success in matching in REI. 

Recurrent Pregnancy Loss

Today we discuss a fortunately uncommon problem, but a difficult one to workup appropriately. Recurrent pregnancy loss is defined the American Society of Reproductive Medicine (ASRM) as two or more failed clinical pregnancies; though ideally a threshold of three or more is utilized for research purposes. It is estimated that less than 5% of women will experience 2 consecutive miscarriages, and less than 1% will experience three or more consecutive miscarriages. That said, the live birth rates are still excellent overall for women experiencing recurrent miscarriages:

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ASRM

Let’s review the most common causes of RPL.

Unexplained: About 50-75% of couples with RPL have no explanation, but the below should be evaluated and ruled out.

Cytogenetic: These are abnormalities in chromosome number or structure. This accounts for at least 50% of early pregnancy loss!

• Aneuploidy: risk of aneuploidy increases with increasing number of miscarriages.

• Chromosomal rearrangements: 3-5% of couples with RPL have a major chromosomal rearrangement (vs. 0.7% in general population).

Cytogetnetic abnormalities can be evaluated by karyotyping to review for balanced reciprocal translocations. Preimplantation genetic screening can be used if other genetic causes are identified.

Antiphospholipid syndrome (APLS): 5-15% of patients with RPL may have APLS. The diagnosis of APLS is challenging to make, and requires the following criteria:

One of two clinical criteria:

1. Vascular thrombosis 

2. Pregnancy morbidity, defined as:

   1. One or more unexplained deaths of morphologically normal fetus after 10 weeks of gestation by ultrasound or direct examination of fetus.

   2. One or more premature births of morphologically normal neonate before 34 weeks because eclampsia or severe pre-eclampsia or recognized features of placental insufficiency.

   3. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation with maternal anatomic or hormonal abnormlaities and paternal and maternal chromosomal causes excluded.

And one of the following laboratory criteria 

1. Lupus anticoagulant present in plasma on 2 or more occasions at least 12 weeks apart or 

2. Anticardiolipin antibody IgG or IgM isotype in serum or plasma present in medium or high titer on 2 or more occasions at least 12 weeks apart, or  

3. Anti-B2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >99th%ile), present on two or more occasions at least 12 weeks apart 

If your patient is found to have APLAS, treatment is with heparin and aspirin.

Anatomic:

• Uterine: congenital uterine anomalies are present in 10-15% of women with RPL, vs 7% of the general population. Additionally uterine leiomyoma, polyps, or adhesions can also be at play. Saline sonohysterogram or hysterosalpingogram can be used to evaluate the cavity.

Hormonal or metabolic 

• Poorly controlled DM - associated with early and late pregnancy loss; several studies have linked high hemoglobin A1c values early in pregnancy (>8%) to increased frequency of miscarriages and congenital malformation.

• PCOS - mechanism unknown, but miscarriage rate is as high as 20-40%.

• Thyroid antibodies and disease - some studies have reported an increased rate of fetal loss in women with high serum thyroid antibody concentrations; also related to unexplained infertility and implantation failure.

• Hyperprolactinemia - may be associated with RPL through alterations in the HPO axis.

• Thrombophilia - association between hereditary thrombophilia and fetal loss have been suggested, but prospective cohort studies have failed to confirm this 

Psychologic 

• There was a nonrandomized trial that looked at cohorts of couples with 3 or more consecutive pregnancy losses and no other identifiable etiology. These were divided into “standard care” vs “tender-loving care” or TLC group, consisting of psychologic support with weekly medical and ultrasonographic exams and instructions to avoid heavy work, travel, and sex. There was a 36% livebirth rate in the control group and 85% in the TLC group! 

Personal habits: There is no clear association between RPL and obesity, smoky, alcohol use, and caffeine consumption. That said, these may have some dose-dependent effect.

An Initial Infertility Evaluation

Infertility is a problem with many social, economic, and psychological ramifications for patients presenting to an OB-GYN’s office, so it’s important to be able to start this work up with confidence. We’re here today to help!

We know somewhere between 82-92% of couples will conceive within 12 months of regular, unprotected intercourse; of those that don’t conceive in the first year, an additional 5-15% of couples will achieve conception within 24 months. So the odds of success are high, but may take some time. The frequency of infertility does climb with age, though: 7.3-9.1% among 15-34 year olds; 25% of 35-39 year olds; and 30% of 40-44 year olds. Infertility is defined based on these incidences:

• 12 months of regular, unprotected intercourse without conception in women under age 35, or

• 6 months of regular, unprotected intercourse in women over age 35.

These time frames are also the indication for our workup. Ideally, the first infertility visit should involve both partners; up to 26% of all infertility is provably male-factor in origin, and 6% of infertility may be related to coital problems! A history & physical for both partners can suggest where the workup will be most beneficial:

Female: 

• PMH & PSH (ie. history of cancer, previous treatment? Ovarian surgery, uterine surgery?) 

• Menstrual history

• History of any previous pregnancies 

• Social history: extensive smoking, drug use, etc.

• Exam should focus on features of hyperandrogegism (i.e., PCOS), hyperinsulinism (i.e., uncontrolled DM or metabolic syndrome) or thyroid dysfunction, as well as assuring anatomy is present.

Male: 

• History of testicular trauma, cancer, exposure to cytotoxic drugs 

• History of previous children? 

From couple:

• Regularity & timing of intercourse.

• Sometimes it’s as simple as… are they having intercourse when patient is ovulating? Is he ejaculating within the vagina? 

When considering a laboratory & imaging workup, cost can be a challenging factor. Sometimes insurances require certain tests, or a certain sequence of tests, in order for coverage to be assured. Others don’t cover this testing at all, and thus it’s up to you to make the appropriate decisions to work out the reason for infertility in a couple. Testing ideally includes the following:

• Semen analysis - for assessing male factor 

• Some assessment of ovarian reserve 

  • Day three FSH and estradiol level 

  • Anti-Mullerian hormone

  • Antral follicle count 

    • Early cycle count of antral follicles; done on day 3 of cycle. What is normal is different at each institution, but can be 3-8 per ovary.

• Assessment of uterine cavity with hysterosalpingogram or sonohysterogram 

  • Can test tube patency as well, though with sonohyst, if there is spilling of fluid, that only confirms that at least 1 tube is patent.

• TSH, A1c, PRL.

In deciding on your workup, keep in mind the most common causes of infertility: a semen analysis will almost always be indicated! These all add up to >100% because some couples will have multiple reasons.

1. Unexplained: 28% 

2. Male factor (ie. hypogonadism, post-testicular defects, seminiferous tubule dysfunction) = 26% 

3. Ovulatory dysfunction: 21% 

4. Tubal damage: 14% 

5. Endometriosis: 6% 

6. Coital problems: 6%