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).

Chronic Pelvic Pain

Today we welcome Dr. Eva Reina, who is a current PGY-3 at Brown/Women and Infants. Eva shares with us some information on one of the most clinically challenging topics in office gynecology: chronic pelvic pain.

In terms of the initial evaluation, using the PPUBS framework can be useful:

• Pain: typical “can you describe your pain?”

• Periods: a thorough menstrual history, which should always be part of your GYN history taking.

• Urinary symptoms: timeline of symptoms with respect to urination, as well as triggers for any symptoms related to urination.

• Bowels: constipation and diarrhea, depending on pattern, can relay problems such as IBS, IBD, or other functional GI disorders.

• Sexual function: describing not only the nature of dyspareunia, but the timing and length of pain symptoms.

After history taking, a physical examination is the next important step. Particularly with the pelvic exam, starting with a single digit may be revelatory. Deep infiltrating endometriosis may be suggested by particular point tenderness. Bimanual examination can help to assess uterine size or concerns for adenomyosis. Speculum exam may not reveal much in the way of pain, but allows for testing for infectious etiologies.

We then discuss some of the mechanisms of chronic pelvic pain development:

Central Sensitization: Most patients with chronic pelvic pain do have multiple pain generators and may even be centrally sensitized: that is, amping up of a stimulus leading to a state of constant reactivity. This lowers the threshold of a stimulus to cause pain and also may maintain pain even after the initial insult has been removed. For instance, in population-based studies vulvodynia, IC, endo, IBS, migraines are commonly found together.

Cross-Talk:

• The top-down phenomenon. The patient who has low back pain, migraines, fibromyalgia, and has now been referred to your office with chronic pelvic pain. 

• The bottom-up phenomenon. 30 year old female who has “always had painful periods.” Stopped OCPs 5 years ago in order to achieve pregnancy. Presenting to your office for urinary symptoms (pain with bladder filling, urgency, frequency). 

• Pelvic Organ Cross-Sensitization: Convergence of sensory input from the pelvic viscera, their associated striated sphincters, muscular components of the pelvic floor, lower abdominal wall, the muscular perineum and its corresponding cutaneous components. 

Afferent information from the major pelvic organs (e.g. bladder, bowels, and uterus) is conducted through the hypogastric, splanchnic, pelvic, and pudendal nerves to cell bodies in thoracolumbar and lumbosacral dorsal root ganglia. At first, these signals go up to the brain (central nervous system), and an efferent signal comes back down (e.g. reflexically removing your hand from a hot stove). 

Over time, if one doesn’t remove the noxious stimulus, the body thinks there must be nobody home to hear the fire alarm, let’s try the neighbor’s house. So, long-term, noxious afferent stimulation from an irritated pelvic organ (peripheral to central) leads to that sensory input traveling back down to the peripheral nervous system to pass the message along to a nearby pelvic organ that was not previously affected. This neurogenic “inflammation” via the central to peripheral pathway may even produce functional changes in the uninsulted organ with little evidence of an organic etiology (e.g. IBS, IC/PBS, vulvodynia). 

Where do the muscles come in? 

• It is helpful to think of muscular spasm as a reactive phenomenon. If you uncover pelvic or abdominal wall myalgia, be sure to treat other primary pain generators BEFORE pelvic floor PT. If you don’t remove the stimulus, the patient is unlikely to make sustained forward progress in PT. 

• Pelvic floor PT is hard to come by (shortage of well-trained providers) and it is uncomfortable both physically and mentally for patients. Thus it is difficult to motivate patients to return to pelvic floor PT after a previous failure of therapy. 

Sepsis

In today’s podcast, we try to provide an update on sepsis for OB/GYN’s. It’s a long one but hopefully full of lots of good information for your practice and knowledge.

Sepsis definitions have changed recently, put forth in 2016 the Third International Consensus Conference for the Definitions of Sepsis and Septic Shock Task Force. These marked a major departure from previous iterations, which were defined by the “SIRS” or “Systemic Inflammatory Response Syndrome” criteria. This also ushered in a new scoring system for sepsis evaluation, known as the Sequential Organ Failure Assessment tool, and a quick bedside version known as qSOFA.

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Common obstetric and gynecologic etiologies include urinary tract infections and pyelonephritis; chorioamnionitis/endometritis; wound infections and necrotizing fasciitis; septic abortions; toxic shock syndrome; and ruptured tuboovarian abscess. Non-obstetric or non-gynecologic causes should also be considered. Some of these more common etiologies include gastrointestinal causes, such as appendicitis, diverticulitis, or peritonitis; respiratory causes, such as influenza or pneumonia; and skin infections including cellulitis. 

In our hospital, we remember the primary interventions for sepsis using the acronym “BLAST”: Blood Cultures, Labs/Lactate, Antibiotics, Saline, Time.

B: Blood Cultures; L: Lactate/Laboratories

With the suspicion for sepsis, laboratory evaluation is essential. CBC, BMP, lactic acid, and blood cultures are often part of the initial workup.

Lactic acid production partially results from the shift of aerobic to anaerobic cellular metabolism, so it functions as a proxy marker of poor tissue perfusion. In sepsis, higher lactic acid levels have been associated with worsened outcomes. Surviving Sepsis Campaign guidelines do recommend guiding resuscitation to lactate normalization.  The SMFM consensus statement does recommend lactate measurement for suspected sepsis in pregnancy.

Blood cultures are important to obtain upfront, prior to the initiation of antibiotic therapy. Even with an initial antibiotic exposure, blood cultures can become useless. Two sets of peripheral blood cultures, with each set consisting of aerobic and anaerobic cultures, are recommended (13). If an infection site is suspected and can be easily accessed for culture in a timely manner, cultures are recommended prior to antibiotic initiation.  

In obstetric patients, the most common causes of sepsis include septic abortion, chorioamnionitis and postpartum endometritis, urinary tract infections, pneumonia, and gastrointestial origins such as appendicitis.

A: Antibiotics

Empiric antimicrobial therapy should be broad in coverage, but also directed towards the most likely source, if one is known. The SMFM consensus statement, the Surviving Sepsis Campaign, and the SEP-1 core measure promote administration of appropriate antibiotic therapy within three hours of presentation. Mortality risk in septic shock appears time-dependent with respect to antibiotic therapy based on observational data.

Combination or “double coverage” therapy for critically ill or neutropenic patients (using two antibiotics to cover the same spectrum of pathogen) is not recommended. However, one notable exception is a source of sepsis more commonly encountered by gynecologists: toxic shock syndrome (TSS).

TSS results from the production of noxious exotoxins by Streptococcus and is described with retained objects, such as tampons, in the vagina. The antibiotic therapy of choice in this case is a combination of penicillin and clindamycin, as clindamycin acts as a transcription inhibitor to the production of bacterial exotoxins.

S: Saline

Crystalloid fluid is the choice for initial resuscitation in severe sepsis or septic shock. The landmark trial on early-goal directed therapy (EGDT), published by Rivers in 2001, randomized patients to standard therapy versus targeted fluid therapy with placement of both central venous and arterial lines, with strict goals for mean arterial pressure (MAP), central venous pressure (CVP,) venous oxygen saturation, hematocrit, and urine output. Fluid administered prior to randomization in both arms was 20-30 cc/kg over 30 minutes. This has ultimately become the standard of care for initial fluid resuscitation.

In pregnancy, this may be overly aggressive, and predispose patients to pulmonary edema; thus, the SMFM consensus statement on sepsis in pregnancy recommends an initial bolus of 1-2 L. Frequent reevaluation of volume status should be performed.

T: Time

The SEP-1 core measure from CMS is predicated on two major time points, with time starting at the time of patient presentation with severe sepsis or septic shock. The SEP-1 bundle requirements at three hours and six hours are shown in Figure 2. The entirety of the “BLAST” protocol covers the initial, “three hour” time point.

The next marker is six hours, which states there should be a redrawn lactate if there was a diagnosis of severe sepsis or septic shock. There also should be a full physical examination, The reexamination can include central venous pressure measurement, central venous oxygen measurement, a bedside cardiovascular ultrasound, or a passive leg raise test as well. For obstetricians and gynecologists, likely the physical examination and passive leg raise are the most easily performed. This may not work in pregnancy due to aortocaval compression; thus, SMFM recommends continued bolus with small fluid volumes (250 - 500 cc) and close monitoring of vital signs to determine if patients are fluid responsive.

If patients in septic shock do not respond to fluid and are persistently hypotensive despite adequate fluid resuscitation, the SEP-1 core measure requires administration of vasopressors by the six hour mark. Norepinephrine is the primary choice in sepsis both in and out of pregnancy. Norepinephrine is associated with lower rates of arrhythmia and overall mortality compared with other vasopressors.

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We go into a lot more detail in the podcast on some additional points, but be sure to check out the SMFM Sepsis guideline for all the deep reading on this topic!

Long Acting Reversible Contraceptive Methods (LARC)

Today we review the classic topic of LARCs! We’ll spend our focus on the specifics of each method. However, in general LARCs are recommended by ACOG as the most effective form of reversible contraception. This is in large part due to their effectiveness independent of coitus and user motivation/adherence to the method. They also enjoy the highest continuation rate and user satisfaction of any method, along with their quality of being reversible with rapid return to fertility. There are also few contraindications to these methods — so what’s not to love?

We’ve put together a comparison table for your studying.

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(c) CREOGS over Coffee, 2019

Vulvovaginal Itching

Today we’re working up the classic GYN sick visit in vulvovaginal itching. We recommend The V Book by Elizabeth Stewart, MD, and though we haven’t read Dr. Jen Gunter’s The Vagina Bible yet, we’ve heard great things!

We start off the episode with a review of things that can cause itching, stratifying from benign to more worrisome. For benign causes, the primary culprit is vaginitis. Think yeast (Candida), bacterial vaginosis, or less commonly gonorrhea/chlamydia or trichomoniasis. Another benign cause is desquamative inflammatory vaginitis, that can be associated with large amounts of discharge. Genitourinary syndrome of menopause, or atrophic vagnitis, is another common cause in postmenopausal women.

Benign dermatoses of the vulva can include lichen planus, which manifests as a red or purplish raised rash, that can present as hypertrophic or ulcerative. It can further lead to lichen simplex chronicus, which is an area of thickened skin due to repeated excoriation. Lichen planus can also involve other areas of the body. Finally, benign dermatoses like eczema, contact dermatitis, or psoriasis can also affect the vulva.

More worrisome dermatoses can include lichen sclerosus. Generally benign, this is a chronic, progressive inflammatory mucocutaneous disease that peaks in prepubertal and in menopausal women. The skin becomes thin and parchment-paper or “cigarette paper”-like in consistency, whitening, and destruction of the architecture and narrowing of the vaginal introits. It can be worrisome, particularly in older women, because it can harbor vulvar intraepithelial neoplasia (VIN) or squamous vulvar cancer. Of course, both of those can also occur on their own, often in the context of HPV infection.

Another malignant dermatosis is extramammary Paget’s disease. In this case, the vulva have an eczematous appearance with slightly raised edges and a red background. This is rare, with the malignancy originating in the vulvar apocrine-gland-bearing skin cells.

Ok, so lots of things can cause this itching, but what should we do? Always start with a complete history and physical. Histories should have special focus on vulvar hygiene, as this is often the culprit. A physical exam should include all skin including the vulva, to rule out more significant dermatoses. With the vulva, we advise a “top down” systematic approach before proceeding with the speculum exam.

The gynecologists handy tool will be the wet mount. Vaginal pH should be < 4.5, and basic pHs may suggest infection or poor lactobacillus presence. Dropping 20% KOH solution on the slide will allow for better visualization of yeast, as well as allow for the performance of the whiff test. On microscopy, you should see plenty of squamous cells (large, squarish cells with small nucleus or no nucleus), compared to paranasal cells (small round cells with prominent nuclei). Sheets of squamous cells with paranasal cells suggests desquamative inflammatory vaginitis. Clue cells have stippled or fuzzy borders along squamous cells. Yeast often has the classic ‘budding pseudohyphae’ or ‘spaghetti and meatballs’ appearance.

Genital cultures may be helpful in identifying resistant or unusual organisms, such as Candida glabratta. If allergies are suspected, referral for patch testing may be worthwhile if avoidance isn’t feasible. Biopsy should be performed to rule out malignancy at ulcerating areas, with lichen sclerosus, or with other areas of concern.

With vulvar hygiene, go as simple as possible. As our mentor Dr. Crichton always says: if you wouldn’t put it in your eye, don’t put it on the vulva. Recommend cotton underwear during the day, no underwear at night; unscented detergents and soaps; only water on vulva; latex condoms and provide own lube with silicone lube; avoid panty liners every day, only during periods . Coconut oil makes for excellent personal moisturizer and lubricant.

If something is present, you should treat the condition. Infections should be treated with appropriate antimicrobials. Lichen planus should be given symptomatic treatment to stop itching. Lichen sclerosus often will need high potency steroids (i.e., clobetasol) to resolve. Malignancies will require excision with referral to oncology for true invasive cancers.