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)