von Willebrand's Disease, feat. Dr. David Abel

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Today we welcome Dr. David Abel, Assistant Professor in obstetrics and gynecology at the Oregon Health and Sciences University. Dr. Abel’s expertise and interest is in the most commonly encountered bleeding disorder for OB/GYNs: von Willebrand disease.

You can join the Foundation for Women and Girls' with Blood Disorders as a student, resident, or fellow for FREE and get access to their educational content by visiting this link.

Some light reading to accompany today’s podcast:

What is von Willebrand’s disease?

  • First described in 1926 by Erik von Willebrand, a Finnish pediatrician.

  • Most common inherited bleeding disorder, accounting for about 80 to 85% of all bleeding disorders.

  • Prevalence about 1 in 10,000, though possibly as high as 1 to 2% of the general population.

    • With respect to women with heavy menstrual bleeding, the prevalence appears be greater, ranging from 5 to 24%. 

  • Von Willebrand Factor is a large glycoprotein encoded by a gene on chromosome 12 that is synthesized in endothelial cells and megakaryocytes, the hematopoietic cells that produces platelets.

    • It is assembled from identical subunits into strings of subunits that vary in size and are referred to as multimers.

    • Two main functions:

      • Needed for normal adhesion of platelets to sites of injured endothelium

      • Serves as a carrier for Factor VIII, which also protects vWF from proteolysis

        • When vascular injury occurs, this multimeric protein uncoils which results in platelet adhesion, activation and aggregation.

  • Three main types of disease:

    • Type I: A partial quantitative deficiency of both von Willebrand factor and Factor VIII. This reduction is usually mild to moderate. 

      • Most common, accounting for 70-80% of cases of vWD

    • Type II: Quantitative reduction in von Willebrand Factor, with subtypes noted as A, B, M and N.

      • Accounts for 10 to 30 percent of cases of vWD

      • Patients with Type 2B vWD may have a moderate to severe bleeding phenotype that may present with thrombocytopenia during pregnancy.

        • Though uncommon, when you go through your differential for thrombocytopenia during pregnancy, you can keep type 2B von Willebrand disease on your radar!

    • Type 3 Most severe, characterized by the virtual absence of von Willebrand factor. 

      • Least common type, accounting for only 1-5% of cases.

  • VWD is usually inherited in an autosomal dominant fashion

    • Baby generally has a 50% chance of inheriting this condition — obstetric/neonatal implications.

    • Rarely vWDz is inherited as an autosomal recessive condition, namely in type 3,  and some cases of type 2. 

 How do we establish a diagnosis of von Willebrand’s disease?

  • Most common bleeding symptoms: bruising, epistaxis, bleeding after injury, surgery or tooth extraction, postpartum bleeding, and menorrhagia (most commonly reported symptom).

    • In addition to mucocutaneous and soft tissue bleeding, joint and muscle bleeding can also occur.

    • Severity of bleeding is usually related to the degree of von Willebrand factor and Factor VIII deficiency. 

  • Initial work up typically consists of nonspecific tests such as a CBC, PT, PTT and fibrinogen which are helpful in excluding a clotting factor deficiency.

    • PTT may be normal in patients with von Willebrand’s.

    • If thrombocytopenia is detected, type 2B vWDz is in the differential.

  • Next step are tests that are specific for von Willebrand Disease, three:

    • von Willebrand factor antigen (vWF:Ag) measures the quantity of von Willebrand Factor protein in the plasma.

    • Factor VIII assay measures Factor VIII activity which is essentially a surrogate marker for the activity of von Willebrand factor.

    • von Willebrand factor activity a functional assay that measures the interaction between VWF and platelets.

      • Historically this was measured by the von Willebrand Factor ristocetin cofactor activity assay (VWF:RCo).

      • Consultation with hematology will be helpful with diagnostic testing and interpretation of results. 

Why does von Willebrand’s disease matter for us in OB/GYN?

  • Strong association between von Willebrand Disease and heavy menstrual bleeding.

    • Among women with heavy menstrual bleeding, von Willebrand Dz is found to be the etiology frequently, with a reported prevalence ranging from 5 to 20%. 

  • Many treatment options are available for women with von Willebrand disease and heavy menstrual bleeding, including hormonal and nonhormonal therapies.

    • Association of VWD with other gynecologic problems, including ovarian cysts, endometriosis, and leiomyomas is unclear. 

  • Prior to procedures as egg retrieval if IVF is planned, or invasive procedure during pregnancy such as CVS and amniocentesis, DDAVP or VWF concentrates can be administered immediately prior to these procedures (more on treatment later).

Antepartum and Intrapartum Management of vWD

  • Both von Willebrand Factor and Factor VIII levels increase during pregnancy, an increase that usually starts in the second trimester and peaks in the third trimester.

    • The increase in VWF and FVIII levels usually reduces the likelihood that our patients warrant treatment during the antepartum, intrapartum or even postpartum period.

    • If a patient was previously undiagnosed, the increase in levels during pregnancy may obscure the diagnosis.

      • In general, women with baseline levels of VWF and FVIII of >30 U/dL, suggesting type 1 VWD, usually have a high likelihood to achieve normal levels by the end of pregnancy.

    • In the case of the severe and uncommon type III vWDz, both VWF and FVIII levels do not increase during pregnancy.

  • Levels of vWF and FVIII fall rapidly after delivery.

    • Levels start to approach patient’s baseline by one week postpartum and fully reach baseline by three weeks postpartum. 

  • Potential complications of vwD during pregnancy include antepartum bleeding, postpartum hemorrhage and perineal hematoma which are all increased by 2–10-fold.

  • Importantly the risk of delayed postpartum hemorrhage (bleeding occurring after 24 hours post-delivery) is also increased.

    • 16-29% of women with VWD will have postpartum hemorrhage within the first 24 hours of delivery,

    • 20-29% of women will experience delayed postpartum bleeding.

    • Bleeding is frequently reported to occur more than 2 to 3 weeks postpartum.

  • Factor VIII and von Willebrand Factor ristocetin cofactor activity assay are checked early in pregnancy and again in the third trimester.

    • Consult hematology to decide if any additional testing is needed

  • Women with type I vwDz with Factor VIII and ristocetin cofactor activity levels less than 50 IU/dL, and no history of severe bleeding, do not require special treatment at the time of delivery.

    • They can often be cared for by the general obstetrician in a community setting if the provider is comfortable and hematology available if needed. 

  • If levels are less than 50 IU/dl, the patient is at risk of hemorrhagic complications including delayed postpartum hemorrhage. These patients require treatment usually close to delivery or after cord clamping.

    • The classic teaching is to administer DDAVP.

      • DDAVP causes release of VWF that has been stored in secretory granules within the endothelium, resulting in FVIII and VWF levels three to five times above basal levels within 30‐60 minutes.

      • Effective in patients with type 1 VWD with baseline VWF and FVIII levels higher than 10 IU/dL.

      • The recommended dose of DDAVP is 0.3 μg/kg IV given over 30 minutes or 300 μg given intranasally. 

        • Onset of action of DDAVP is approximately 15-30 minutes.

        • Usually given at the time of cord clamping, but because the peak effect is 1.5 to two hours after administration, it may be more beneficial if administered during the second stage of labor or immediately before cesarean delivery. 

      • Risks: water retention that can lead to hyponatremia and seizures.

        • Need fluid restriction to less than 1L in the 24 hours following DDAVP administration.  

        • However, fluid restriction after delivery can be very difficult, and is the reason why many experts do not use DDAVP as a first line treatment.

    • Alternative: plasma derived VWF concentrates.

      • Options:

        • Plasma derived VWF concentration that contains VWF alone without Factor VIII.

        • Recombinant VWF concentrate that contains only VWF without Factor VIII.

        • Plasma derived concentrate that contains both VWF and Factor VIII.

          • The decision regarding which one of these to use will depend upon levels of both VWF and Factor VIII, what is available in your hospital and input from hematology.

Regional anesthesia

  • No consensus on levels that are safe for regional anesthesia, but if levels are greater than 50 IU/dL and assuming a normal platelet count, regional anesthesia is usually considered reasonable.

  • Recent ASH guidelines recommend VWF activity levels should be maintained at 50 IU/dL while the epidural is in place and for at least 6 hours after removal. 

Mode of Delivery

  • Fetal status unknown in most cases —> given AD inheritance and 50% risk, best to avoid procedures such as a fetal scalp electrode.

  • Operative delivery is discouraged due to the potential risk of intracranial hemorrhage - cesarean delivery preferred to operative vaginal delivery. 

  • The pediatrician should be made aware of the mother’s status and male circumcision should be postponed until the baby’s VWDz status can be determined.  

    • Sending cord blood at the time of delivery for a VonWill panel is recommended to determine the status of the newborn.

Postpartum Care

  • High risk of both primary and delayed postpartum hemorrhage. Perineal hematomas can be seen.

  • VWF and Factor VIII levels can significantly decrease postpartum, with a return to baseline within 7-21 days postpartum.

    • These levels are typically checked in the immediate postpartum period and then periodically.

    • Hematology consultation will be valuable to help work out these details.

    • NSAIDS should be avoided in the postpartum period. 

  • ASH guidelines recommend the use of oral tranexamic acid in the postpartum period.

    • Administration of one mg intravenously can be administered prophylactically immediately after delivery and continued PO for 10-14 days postpartum.

Imitators of Pre-Eclampsia

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Each of the conditions we’ll discuss today could be an episode all its own, so this will be way too brief to cover these topics in detail! But it’s important to keep a broad diagnostic mind open, especially if you feel the picture doesn’t totally add up. 

Reading: Sibai: Imitators of Severe Pre-Eclampsia (2007)

Previous podcasts: Hypertension and Pregnancy Trio (3/2019)

Diagnosing Pre-Eclampsia:

  • Pre-eclampsia is a syndrome - a recognizable complex of symptoms and physical findings that indicate a specific condition, but for which a cause isn’t necessarily understood. 

  • We need to think about the symptoms and signs of pre-eclampsia and determine how they overlap with other diseases!

    • What else might tie together: 

      • Hypertension

      • Neurologic changes

      • Pulmonary edema

      • LFT abnormalities and RUQ pain

      • Thrombocytopenia

      • Acute kidney injury

  • Some potential examples:

    • Acute hepatitis or cirrhotic liver disease

    • Lupus

    • Meningitis

    • TTP / HUS

    • Drug reactions or overdoses

    • Malignant hypertension (i.e., pheochromocytoma, renal artery stenosis)

    • Heart failure or heart attack

      • You can probably think of more if you try!

  • Let’s focus this broad differential on three primary significant culprits today: Acute Fatty Liver of Pregnancy (AFLP); Thrombotic Thrombocytopenic Purpura (TTP) / Hemolytic Uremic Syndrome (HUS); and a Lupus (SLE) Flare

Acute Fatty Liver of Pregnancy

  • Exactly what it sounds like -- acute fatty infiltration of the liver, typically in the 3rd trimester, leading to fulminant hepatic failure.

    • Appears to be related to defects in fatty acid metabolism -- 20% of AFLP associated with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency of the fetus. 

  • Incidence: 1 in 7k-20k pregnancies.

  • Risk factors:

    • Fetal LCHAD deficiency: fetal homozygosity renders it incapable of processing fatty acids, and mother (typically heterozygous) has decreased function to keep up -- thus the infiltration.

    • Prior history of AFLP

    • Multiple gestation

    • Preeclampsia / HELLP syndrome (so they can even be co-existent!)

    • Male fetal sex

    • Low BMI (<20)

    • Nulliparity

  • Typical presentation:

    • 3rd trimester: most common after 30 weeks

    • Often nonspecific symptoms: nausea/vomiting, abdominal pain, malaise, headache, anorexia

    • Frequently with hypertension +/- proteinuria 

      • Reported co-existent HELLP in 20-40% of cases

    • Hypoglycemia is frequent on laboratories - from impaired hepatic gluconeogenesis

      • Additionally can see signs of acute liver failure -- jaundice, ascites, encephalopathy, DIC. 

    • Renal failure upwards of 90% of cases.

  • Diagnosis:

    • Typically a clinical diagnosis -- biopsy can be performed to demonstrate fatty infiltration, but rarely performed.

    • Swansea criteria:

      • Ranges pending on reading from 6-9 positive signs. 

        • Most typically need 6 (in my experience)

      • Supposed to be done in patients without HELLP syndrome/preeclampsia, limiting utility.

    • Imaging can be performed, but is also of limited utility in diagnosis

Swansea Criteria (UpToDate)

  • Treatment of AFLP:

  • Supportive with critical care expertise! 

  • Have ongoing monitoring for:

    • MELD score (Model for End-Stage Liver Disease) - high MELD > 30 associated with increased risk of maternal complications

    • Hypoglycemia: typically need infusion of dextrose-containing fluids

    • Coagulopathy

  • Delivery!

    • Labor induction is reasonable if can be reasonable accomplished within 24 hours, and disease not rapidly progressing.

    • Cesarean delivery outright should be considered otherwise.

    • Betamethasone administration for FLM given, but shouldn’t delay delivery.

    • Magnesium as indicated for suspected preeclampsia and/or for CP prophylaxis. 

  • Postpartum:

    • Mortality in AFLP is attributable to hemorrhage, liver failure, and kidney injury.

    • AFLP will often resolve within 7-10 days after delivery

    • Hemorrhagic pancreatitis is a potential and fatal complication known to be associated with AFLP - follow lipase

    • Liver transplantation may need to be considered in those with persistent fulminant hepatic failure (though this is rare). 

    • LCHAD deficiency testing should be pursued in infants.

      • LCHAD deficiency in newborns can be life-threatening!

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)

  • Related but different diseases characterized by microangiopathic hemolysis, thrombocytopenia, acute renal failure, neurologic abnormalities, and fever.

  • TTP - caused by deficiency in ADAMST13, a protein involved in regulating blood-clotting by cleaving von Willebrand factor from endothelial surfaces, and at the sites of vascular injury.

    • Can be familial or acquired

    • Characterized by marked thrombocytopenia - platelets frequently <20k

  • HUS - can be caused by a variety of insults, but commonly Shiga-toxin from certain bacterial organisms as well as with abnormalities in complement system regulation. 

    • Renal failure is the dominating feature of HUS and tends to be particularly severe. 

  • Presentation:

    • Also tends to be vague: abdominal pain, nausea/vomiting, headache, vision changes, confusion, fever

    • May also include bleeding: epistaxis, GI bleeding, petechia/purpura, hematuria (particularly in HUS)

    • Can present with or without hypertension

  • Diagnosis:

    • Involve your hematology colleagues if there’s suspicion!

    • Early-onset preeclampsia may raise suspicion: 20-26ish week range, but can occur at any point

  • Treatment:

    • Plasma exchange: helps to remove large multimers of von Willebrand factor and autoantibodies against ADAMST13. 

    • Steroids - help to calm autoimmune response

    • Splenectomy - helps to avoid sequestration of platelets 

    • Platelet transfusion should be avoided - may contribute to increased microvascular thrombus formation

  • Delivery:

    • Not indicated immediately! PLEX and other therapies can be given opportunity to work

    • However, serial / frequent therapy is often indicated to continue pregnancy and prevent relapse

Systemic Lupus Erythematosus / Antiphospholipid Antibody Syndrome

  • SLE is an autoimmune disorder with varying symptomatology but can result in significant end-organ damage

    • 30-40% of SLE patients have antiphospholipid antibodies

    • Only 1% of patients will have antiphospholipid antibody syndrome - a disorder that is characterized by microangiopathy affecting multiple organ systems, and with particularly high pregnancy risks

  • Diagnosis:

    • Classically SLE diagnosis requires at least 4 / 11 American College of Rheumatology criteria;

    • However, in 2019 the ACR and European League Against Rheumatism came up with a combined criteria based on a points system:

ACR / ELAR Combined Diagnostic Criteria for SLE (2019)

  • APLAS diagnostic criteria we’ve previously reviewed in our RPL episode:

  • One of two clinical criteria:

    • a) Vascular thrombosis 

    • b) Pregnancy morbidity, defined as:

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

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

      • 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 

    • a) Lupus anticoagulant present in plasma on 2 or more occasions at least 12 weeks apart or 

    • b) 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  

    • c) 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 

  • Fortunately, many patients with SLE will come into pregnancy with an established diagnosis.

    • To determine if they’re having a flare to distinguish from preeclampsia, you’ll often use a serum marker for rheumatologic disease, such as:

      • Hypocomplementemia (C3 / C4 levels)

      • Anti ds-DNA antibody levels

  • Symptoms are vague, as previously described with the clinical criteria for SLE diagnosis, and have overlap with preeclampsia! 

  • Treatment:

    • If known from outset of pregnancy -- these patients should definitely be on aspirin for preeclampsia prevention!

    • Steroids are often used in acute flares - prednisone

    • DMARDs - safe medications for pregnancy can include azathioprine, hydroxychloroquine, and encouraging data exists for immunomodulating antibodies (i.e., adalimumab / Humira)

    • APLAS - low molecular weight heparin for prevention of VTE and pregnancy morbidity

SIBAI 2009 (ref above)

SIBAI 2009 (ref above)

Prenatal Genetic Screening: An Update

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One of our very first podcasts covered prenatal genetic screening and testing. Since then, ACOG has updated the former PB 163 to the new PB 226. For today, we’ll cover some changes/updates and get more into diagnostic testing, which we didn’t cover in depth on our previous episode. Diagnostic testing info remains well-covered by PB 162.

How do you provide genetic counseling to a patient? 

  • Every pregnancy has a risk for genetic abnormality and review that this risk increases with increasing age

    • Average rate is 1/150 live births. There is also risk based on family history. 

      • Review family history of birth defects, genetic diagnoses in the family, etc. prior to discussion

    •  Risk of abnormalities based on age:

  • Review options for genetic screening for patients.

    • All types of genetic screening is limited, and all genetic screening tests detect fewer abnormalities than diagnostic tests with microarray. Diagnostic tests include CVS and amniocentesis.

  • Screening and diagnostic testing should be discussed and offered to all patients early in pregnancy regardless of maternal age or baseline risk

What are the available tests?

  • Preimplantation genetic testing/screening 

    • PGT-A (also called PGS previously) - preimplantation genetic testing for aneuploidies 

      • Biopsy of an embryo at the blastocyst stage, usually around day 5-6 of development 

      • Cells are taken from the outer layer of cells (trophectoderm) that will eventually become the placenta 

      • PGT-A just screens for aneuploidy, and the idea is to increase the chances of live birth by screening for embryos that have aneuploidy.

    • PGT-M - preimplantation genetic testing for monogenetic/single gene mutations

      • Same as above in terms of how the cells are gotten, but in this case, tests are done for monogenic disease or single gene mutations 

      • Can be used to choose embryos that do not have a genetic disease, like screening for embryos that do not have Huntington’s or cystic fibrosis 

      • Disease and mutation must be known beforehand — this is a highly targeted screening.

    • PGT-SR - preimplantation genetic testing for structural rearrangements 

      • Useful when there are parental structural chromosomal abnormalities.

      • Detects things like translocation, inversion, deletions, insertions, etc.

    • With PGT, because the cells biopsied are destined to become placenta, other forms of pregnancy genetic screening should still be offered due to risk of mosiacism - that is, different genetic material in different cell lines.

  • Screening and Testing During Pregnancy 

    • Discuss that many screening tests are sensitive for T21, but may have less sensitivity for other chromosomal disorders. 

    • Review these tests cannot detect other genetic abnormalities like point mutations, deletions, translocations, etc. 

    • Types of screening tests: 

      • NIPT (cell free DNA) – test any time around 9-10 weeks to term. 99% detection rate for trisomy 21. It has the highest DR of all tests and lowest false positive rate, but also may detect maternal aneuploidy or disease. Highest sensitivity and specificity. Does NOT test for open neural tube defects.

        • Someone with a screen positive serum analyte test may choose cfDNA for follow up if they want to avoid a diagnostic test, but they should be informed that it is still a screening test, meaning it can still fail to identify some chromosomal abnormalities and may delay definitive testing if positive.

      • Integrated screen – two tests. First is at 10w-13w6d. Then 15-22w. DR for T21 is 96%, but you need two samples and no first trimester results. Method: NT + PAPP-A in first trimester, then quad screen (hCG, AFP, uE3, inhibin A)

      • Sequential – 10w-13w6d, then 15-22 w. 95% DR for T21. Still need two samples, with first trimester NT + BHCG, PAPP-A and +/- AFP. Then quad screen.

      • Quad screen – 15w-22w. 81% DR for T21. It’s a one-time test, but also has lower DR than integrated

      • Other options with lower detection rates: first trimester screen (NT+PAPP-A, bHCG, AFP), Serum integrated (Integrated just without NT), NT alone

ACOG PB 226

Diagnostic Testing

  • The gold standard for detecting genetic abnormalities and should be offered after abnormal genetic screening tests.

  • Chorionic villi sampling – done between 10-13 weeks. 

    • Get placental villi transabdominally or transcervically. 

    • Pregnancy loss rate 1/500. Limb reduction defect is super low, around 6/10,000. 

    • Can cause spotting/bleeding. Also the tissue is placental, so there is still possibility of mosaicism (ie. placenta doesn’t have abnormalities, but fetus does). 

      • Because of this, sometimes after CVS can still recommend amnio.

  • Amniocentesis – done between 15-20 weeks usually, but can be done any time later too. 

    • Reason not to do too early: amnion and chorion not fused, increasing anomalies/loss rate.

    • Rate of loss is about 1:300 – 1:750 depending on studies. 

    • Other complications include spotting or loss of fluid. 

    • Cells are from sloughed off fetal skin cells, so can actually get fetal DNA.

  • Type of tests that can be sent from diagnostic testing - a question you might get: what are you sending it for? 

    • Karyotype

      • Detects aneuploidies, like trisomies, 45X, 47 XXY.

      • Need culturable cells, so takes longer (7-10 days).

      • Cannot usually be done on dead tissue (ie. stillbirth), because the cells likely won’t grow 

    • Microarray

      • Can find major aneuploidies and submicroscopic changes that you can’t see just with karyotype.

      • Can’t detect balanced translocations and triploidy.

      • Can be done on cultured cells or uncultured tissue.

      • Can also be done on copy number variants If done on uncultured cells.

      • Can be fast turn-around (3-7 days).

    • FISH

      • Uses probes for specific chromosomes or chromosomal regions (ie, can detect T21 but also can detect 22q11.2 deletion).

      • Can be done on uncultured cells, so can get results in as few as 2 days.

      • Good to use if someone screens positive for T21 or other aneuploidy on serum analytes or cfDNA and you want a quick results before you get the full karyotype/microarray results

      • Often start with FISH, then reflex to microarray if normal, or karyotype if abnormal (to confirm).

COVID-19 Update #3: Treating the Pregnant Patient

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Prevention of COVID-19: More Updates on Vaccination

  • Vaccination is the #1 thing folks can do to protect themselves and their fetuses!

  • Since our last podcast, ACOG, SMFM, ASRM, ACNM, AABM (just to name a few) have all endorsed COVID-19 vaccination at any time for folks trying to conceive, who are pregnant, or postpartum and lactating!

  • SMFM has released consensus guidance for healthcare providers regarding vaccine counseling:

    • Check out our previous episodes (#1 and #2) on vaccine effectiveness

    • We at CREOGs Over Coffee wholeheartedly recommend vaccination, especially with this stronger data regarding safety in reproduction, pregnancy, and lactation.

COVID and Pregnancy: What Options Are Available for Treatment?

We’re going to address the following major questions today:

  • Does patient merit inpatient admission?

  • If they can stay outpatient, does the patient qualify for any therapy?

  • If they need to be inpatient, when to start therapeutics and what options are available? 

  • When is delivery indicated for maternal benefit?

Decision to Admit:

COVID can be broken into asymptomatic disease, then mild, moderate, severe, and critical disease:

  • Mild

    • Flu-like symptoms: fever, cough, myalgias

    • Anosmia

    • No dyspnea, shortness of breath, or abnormal chest imaging (if performed)

  • Moderate:

    • Symptomatic dyspnea/shortness of breath, but able to maintain SpO2 > 94% on room air

    • Evidence of pneumonia on imaging

    • Refractory fever (>39C) to acetaminophen

  • Severe:

    • Respiratory rate > 30

    • SpO2 < 94% on room air (so any O2 requirement!)

    • PaO2 / FiO2 < 300 

    • More than 50% lung area involvement of disease on imaging

  • Critical:

    • Multiorgan failure or dysfunction, shock

    • Respiratory failure requiring high flow nasal cannula or mechanical ventilation

  • Patients with mild disease or no symptoms can be safely monitored outpatient, with a 10-day self quarantine from positive test or onset of symptoms in accordance with CDC guidelines. 

  • Patients with moderate disease will often require hospitalization in pregnancy, owing to risk of progression. However, this is an individualized decision, and non-pregnant folks might more typically stay outpatient in this scenario.

    • If patients remain outpatient, SMFM recommends ongoing check-ins from patients to their prenatal care providers to assess symptoms and ensure there is no concern for disease progression.

    • Also recommend a follow up visit (either in-person or via telemedicine) at least once within 2 weeks of diagnosis.

    • Necessary and indicated medical care should not be avoided due to a positive COVID status!

  • Patients with severe or critical disease, obviously, will merit inpatient admission. 

  • Patients with mild-moderate disease with other comorbidities may also be considered for hospitalization (i.e., patients with hypertension, diabetes, other maternal medical conditions), as these patients appear to be more prone to acute decompensation. 

Inpatient Care: Protocols and Hospital Disposition

  • Vital signs and fetal monitoring as indicated when fetal intervention would be considered.

  • ICU level of care should be considered with:

    • Rapidly increasing oxygen needs to maintain SpO2 >95%

    • Hypotension (MAP < 65) despite some measure of fluid resuscitation.

      • Owing to risk of pulmonary edema, SMFM recommends an initial 500-1000cc bolus of crystalloid to assess response, and conservative fluid management unless clearly hypovolemic.

    • Need for mechanical ventilation or intubation - 

      • Intubation is recommended if O2 requirements are >15L by NC or mask, >40-50L by high-flow NC, >60% FiO2 by Venturi mask, or altered mental status with inability to protect airway. 

    • Need for other end-organ support (i.e., hemodialysis)

  • Prone positioning is possible in pregnancy! 

    • Proning in COVID (and other causes of acute respiratory distress syndrome) is well-studied

      • It is hypothesized to decrease ventilation-perfusion mismatch by bringing more blood to the more open anterior lung fields (rather than the often atelectasis-affected lower posterior lung).

    • Padding and support devices may need to be used for appropriate support in pregnancy.

    • In non-intubated patients, lateral-decubitus or full-prone positioning is also permissible and can help improve oxygenation.

  • Thromboprophylaxis is generally recommended in at least hospitalized patients, given critical illness increases hypercoagulability risk further in pregnancy.

    • Prophylaxis is generally not recommended after discharge, unless other specific comorbidities exist.

      • SMFM offers use of a risk scale, the IMPROVE Risk Score, as well as deferring to clinical expertise to guide use of pharmacologic prophylaxis once discharged from the hospital.

  • Extracorporeal membrane oxygenation (ECMO)

    • Allows for oxygenation of the lungs (VV ecmo) and possibly combining with pumping action (VA ecmo) in patients with severe ARDS refractory to other methods of therapy. 

      • It gets even more complicated than this, but that’s the basics!

    • ECMO is a significant intervention with its own set of morbidities and risks, and should be reserved for significant, severe cases of pregnancy where it may be helpful and delivery may not/cannot be considered at that present moment (i.e., previable or periviable gestation). 

    • These conversations are often very individualized by institution, so we’ll hold off on further discussion from here! 


Therapeutics and Indications

  • Outpatient:

    • Monoclonal antibody therapy (i.e., Regeneron)

      • FDA Emergency Use Authorization indicated for patients over age 12 who have mild-to-moderate COVID-19, weigh at least 40kg, and are at high risk of progression to severe disease or hospitalization. The criteria are:

        • BMI > 35

        • Chronic kidney disease

        • Diabetes

        • Immunosuppresive therapy 

      • Data is limited on their use in pregnancy, but other monoclonal antibodies are generally well-tolerated with no fetal effects. Thus, they can be used in appropriate pregnant patients. 

  • Inpatient:

    • Dexamethasone

      • Associated with decreased risk of mortality in those requiring mechanical ventilation

      • Also has small decrease in mortality for those requiring oxygen generally

        • (RECOVERY Trial)

      • Recommended dosing: 6mg IV or PO daily x 10 days.

        • NOT recommended in those who do not require oxygen

      • Dexamethasone does cross the placenta measurably: it is the alternative steroid to betamethasone for fetal lung maturity!

        • FLM dosing: 6mg IM q12h x 4 doses

        • Thus, it is appropriate to use in appropriate pregnant patients; FLM dosing should be given for the first 48h of therapy. 

    • Remdesivir

      • Associated with decreased duration of disease in patients requiring oxygen therapy (ACTT-1 Trial)

      • Recommended if SpO2 < 94% on mechanical ventilation or ECMO

      • No fetal toxicity is known, and can be used on an emergency / compassionate use basis.

When to deliver the hospitalized patient:

  • SMFM recommends that in patients with refractory hypoxemia, delivery at/after 32 weeks is reasonable if it will allow for further care optimization given:

    • Low risk of neonatal mortality at 32 weeks (0.2%) and

    • Overall low risk of major morbidity (8.7% at 32 weeks). 

      • This also logistically is often more appropriate - controlled delivery is certainly more preferable to chaos! 

  • In those who are critically ill, decision for delivery is certainly individualized.

    • Mechanical ventilation alone is not an indication for delivery.

    • Proning, ECMO, and other ventilator methods should be considered especially under 30-32 weeks. 

2nd and 3rd Trimester Bleeding

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  • Placenta previa - when the placenta partially or totally covers the internal cervical os. Defined as edge of placenta <10 mm from internal cervical os 

    • Occurs approximately 4/1000 births, but varies world wide. Increased risk associated with history of previous placenta previa, previous C-section, and multiple gestation 

    • Approximately 90% of placenta previa identified on ultrasound <20 weeks → resolve before delivery 

    • Painless vaginal bleeding can occur up to 90% of persistent cases 

    • 10-20% of women present with uterine contractions, pain, and bleeding 

    • Why we care: can lead to catastrophic bleeding, need for transfusion, and delivery. Can lead to stillbirth  

  • Placenta accreta spectrum 

  • Vasa previa 

    • What it is: when fetal vessels run within the membranes over the internal os of the cervix 

    • Very rare. Has been quoted 1/2500 deliveries 

    • Painless bleeding usually 

    • Two types: 

      • Velamentous cord insertion and fetal vessels that run freely within the amniotic membranes overlying the cervix or in close proximity of it (2 cm from os); usually pregnancies with low lying placenta or resolved placenta previas are at risk 

      • Succenturiate lobe or multilobe placenta and fetal vessels connectin both lobes course over or in close proximity of cervix (2 cm from os)   

    • Other risks: IVF 

    • Why we care: increased risk of fetal hemorrhage, exsanguination, and death 

  • Placental abruption

    • What it is: Separation of the placenta from the inner wall of the uterus before birth 

    • Usually painful bleeding 

    • Incidence: 2-10/1000 births in the US 

    • Risk factors: hx of fabruption, cocaine use, tobacco use, hypertension, uterine abnormalities (ie. fibroids, bicornuate uterus) 

    • Why we care: can lead to catastrophic bleeding, need for transfusion, and delivery. Can lead to stillbirth. 

  • Uterine rupture 

    • What it is: significant uterine disruption. Usually will occur along a previous uterine scar 

    • Very painful bleeding (pain is usually more significant than bleeding) 

    • Risk factors: previous uterine rupture, previous uterine scar, especially if a fundal or vertical scar (ie. cesarean delivery, myomectomy), induction, labor 

    • Why we care: very high incidence of morbidity and mortality for both mom and baby 

  • Less dangerous causes:

    • Labor - “bloody show” with labor

    • Cervicitis 

      • Can be caused by infection (ie. BV, candida infection, trichomonas, chlamydia, gonorrhea) 

    • Cervical polyp 

    • Vaginal laceration 

Doing a Workup for Bleeding in the 2nd and 3rd Trimester

  • History 

    • How much bleeding? (soaking through clothes? Passing clots?)

      • Passing tissue? 

      • Remember: just because someone has light bleeding does not mean that they don’t have something life-threatening for them or their fetus   

    • Is there pain? 

    • How long has the bleeding been happening? 

  • Exam 

    • After your physical exam, do an abdominal and pelvic exam 

      • Lift the sheet: how fast is the patient bleeding? 

      • Abdominal exam: is there tenderness to palpation anywhere? Over the uterus? How pregnant does the patient appear to be (if no records?) 

        • Patients with rupture will be very tender to palpation 

        • Less likely to be tender to palpation with something like placenta or vasa previa 

      • Start with a speculum exam - if passing tissue, that should be sent to pathology 

        • Look for vaginal laceration, neoplasms, discharge, evidence of cervicitis, cervical polyps, fibroids, ectropion 

        • Send testing for cervicitis and vaginitis (ie. wet mount, as well as chlamydia/gonorrhea) 

      • Do not do a digital cervical exam without confirming where the placenta is located!

  • Labs and Imaging 

    • Pregnancy test if not confirmed (just a urine pregnancy test!) 

    • Type and screen, CBC, coagulation profile

    • Putting the baby on the monitor 

      • Consider doing so if the fetus is viable 

      • Sometimes, the only way to tell if someone is abrupting or rupturing their uterus (other than having abdominal pain) is seeing non-reassuring fetal heart tracing 

      • Watch contraction pattern - can discern if someone is contracting with bleeding or now. Also, there may be evidence of abruption on monitor (small amplitude, frequent contractions) 

    • Ultrasound 

      • Usually, transabdominal is enough, but if you think that there is a placenta previa, placenta accreta, or vasa previa, you should do a transvaginal ultrasound 

      • Color and pulsed Doppler should be used to help in diagnosis 

      • Remember that placental abruption is a clinical diagnosis: you may not always see a blood clot or an area that appears “abrupted” on the placenta

      • Usually, placenta previa, placenta accreta, and vasa previa are diagnosed at the mid-trimester ultrasound and will require clinical follow-up 

Management 

  • Depending on the amount of bleeding: 

    • Vital signs 

    • Two large bore IVs 

    • Resuscitation - fluids vs. blood products

  • If there is less bleeding and you think you have more time:

    • Blood type and Rh status - administer Rhogam if it is indicated 

    • Management otherwise depends on reason for bleeding - will discuss briefly some of the more dangerous things 

  • Placenta previa:

    • Usually will trigger an admission for monitoring 

    • If preterm, usually recommend steroids, and if <32 weeks, can discuss magnesium for CP prophylaxis 

    • Pending the stability of mom and fetus, may require emergent delivery via cesarean section 

    • Certain locations may have a “threshold” for prolonged admission - ie. three strikes = three bleeds and admission for the rest of pregnancy 

    • If otherwise stable, can usually be delivered between 36w0d - 37w6d via c-section

    • Usually can have vaginal delivery if >2 cm from os, but some institutions may discuss if >1 cm 

  • Placenta accreta spectrum:

    • Will usually also trigger an admission for monitoring, and can also lead to emergent delivery + hysterectomy pending stability 

    • Steroids and mag if indicated 

    • If stable, recommend delivery between 34w0d-35w6d, and usually this will be done at tertiary care center with multi-disciplinary team 

  • Vasa previa:

    • There is usually a lower threshold for bleeding and contraction in vasa previa because the bleeding could come from the fetus 

    • While an adult human has 5-6L of blood, a fetus has much less. A term fetus+placenta can have up to 500mL of blood (baby may have 250-300cc). Usually describe to patients in measurements of a soda can (355 mL). 

    • For this reason, many places will hospitalize vasa previa between 28-34w0d and monitor 

    • Recommend delivery between 34w0d-37w0d pending stability of mom and baby