My patient with lupus wants to get pregnant- what should the nephrologist know?

Written by: Cristina Popa, MD, Anoushka Krishnan FRACP

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Systemic lupus erythematosus (SLE) affects young women of childbearing age and has significant implications for pregnancy- for both the mother and the fetus. Given that most nephrologists will come across a scenario wherein a young lupus patient wishes to conceive a child, it is essential to have some basic concepts on the outcomes of lupus on pregnancy and vice versa, preconception counseling, and medication regimens that are safe in pregnancy. While some of these topics have been touched upon in the blog on Pregnancy and Transplantation, we will deep dive into lupus and pregnancy in this section.

Let us start by discussing maternal and fetal outcomes in patients with lupus. Perhaps the greatest risk for the mother is lupus flares, which can result in declining (or loss of) kidney function and a significant risk of pre-eclampsia. A systematic review looking at 37 studies, including 1,842 women with active (defined as presence of proteinuria 500 mg/24 hours and/or active urine sediment with or without an elevation in serum creatinine, at time of conception; lupus nephritis flare during pregnancy or a new diagnosis of lupus nephritis during pregnancy) and quiescent lupus nephritis, demonstrated that a systemic lupus flare was not uncommon and occurred in up to 26% of pregnancies. Active lupus nephritis occurred in 16.1% of pregnancies, hypertension was seen in 16.1%, pre-eclampsia in 7.6%, and eclampsia or stroke in 1%. Women with active LN had a higher risk of adverse outcomes. These are all major issues that should be discussed with the mother, emphasizing the need for preconception counseling. Additionally, maternal mortality is nearly 20-fold higher in women with lupus, with a 3-7 fold higher risk of thrombosis and infections. Notably, patients with class 3 or 4 SLE tend to be at higher risk of lupus nephritis (LN) flare and hypertensive complications.

There are several risks to the fetus as well, particularly in patients with active lupus nephritis. Risks include a higher need for cesarean section, spontaneous abortion (16%), higher risk of premature delivery (35%), stillbirth (3.6%), neonatal death (2.5%), and intra-uterine growth restriction (12%). There is also a small risk of neonatal lupus erythematosus (NLE), wherein maternal auto-antibodies cross the placenta and cause symptoms. The incidence rate is estimated at 5-10%, mostly in pregnancies exposed to anti-Ro and anti-La antibodies. The most severe manifestation is congenital heart block (1-2%), requiring early diagnosis and intervention, otherwise resulting in up to 20% perinatal mortality. Congenital heart block typically manifests between 18-24 weeks of pregnancy (when immunoglobulins can cross the placenta), and most surviving children will usually require a pacemaker at an early age. Other manifestations of NLE usually resolve within 3-6 months of birth (coinciding with the half-life of auto-antibodies).

How might women with quiescent disease fare? A large prospective study including patients in the United States and Canada evaluating 385 women at low risk of complications (quiescent disease, no lupus nephritis or active systemic disease {uPCR <1000 mg/g, serum creatinine <1.2 mg/dl, prednisolone use <20 mg}, follow-up in specialist centers, on hydroxychloroquine) demonstrated that severe flares mostly occurred in the second (2.5%) and third trimesters (3%). Nearly 81% had uncomplicated pregnancies. Of those who did have complications, risk factors included ethnicity (non-white or Hispanic), lupus anti-coagulant positive, and those on anti-hypertensive agents. Adverse outcomes, including fetal or neonatal death, preeclampsia or hypertension, in this group were high at 58%.

These data may suggest that women with well-managed lupus do not necessarily have a bad outcome. If pregnancy is planned, the disease is quiescent, the patient is on appropriate pharmacological therapy, and the risk of adverse outcomes can be reduced under close specialist surveillance. Nevertheless, the high-risk nature of this population warrants close supervision and the involvement of a multidisciplinary team.

The conundrum of symptoms: is this a flare or just typical pregnancy symptoms?

Clinicians face a real challenge distinguishing symptoms of an SLE flare in pregnancy because the many physiological signs and symptoms of pregnancy overlap with the clinical features of a lupus flare (Figure 1). Fortunately, most of the time, flares of SLE activity in pregnancy are not severe. In most studies, skin, joint, and constitutional symptoms are the most commonly reported. SLE activity scores were adapted to differentiate between SLE activity and pregnancy.

Figure 1. Common manifestations in lupus and pregnancy (created with BioRender.com)

SLE is associated with a higher risk of flares during pregnancy and a higher risk of preeclampsia. Preeclampsia and lupus activity may have common clinical features, often challenging the differentiation between said entities (Table 1). A kidney biopsy may be advised, but know it is associated with a higher complication rate and a higher bleeding risk, particularly at 23-26 weeks of gestation. The 2019 UK guideline recommends biopsy in the first and early second pregnancy trimesters only if the histological diagnosis is likely to change management (class 1C).

Table 1. Differential diagnostics in SLE flare vs Preeclampsia: laboratory findings (Clowse WE, 2007, Zeisler H, et al, 2016, Dijkstra DJ et al, 2022)

Anti-phospholipid antibody syndrome and pregnancy: a dreaded combination

Up to 40% of patients with lupus have antiphospholipid syndrome (APS). Pregnancy complications in obstetric APS (OAPS) include unexplained, recurrent, early pregnancy loss (before ten weeks gestation), fetal death, or premature birth due to severe preeclampsia, eclampsia, and intrauterine growth restriction. Anti-b2-glycoprotein antibodies, lupus anticoagulant (LAC), and anti-cardiolipin antibodies should be tested. The presence of LAC conveys the greatest risk of adverse outcomes in pregnant women with or without SLE. Other risk factors include younger age and a history of prior thrombotic events. Treating OAPS early improved pregnancy outcomes; in a European registry study of 1000 women with OAPS, 45% received recommended OAPS treatment, and subsequently, nearly 85% had a good live-birth rate.

Preconception planning:

Pre-conception counseling is a pivotal parts of ensuring safe pregnancy for both mother and baby. Clinicians should aim to work with their patients to optimize disease control and work towards the shared goal of a safe pregnancy and healthy baby.

SLE's systemic activity must be evaluated clinically and biochemically, as a recent lupus nephritis flare is a risk factor for recurrence. Ideally, kidney function should be stable, on a safe medical regimen, and without evidence of a flare for at least six months before conception.

Antepartum care must be provided in a multi-disciplinary setting involving obstetricians and nephrologists/ rheumatologists. Expectant mothers should be monitored on a monthly basis (and more frequently if at higher risk). Serial fetal ultrasounds should be performed to evaluate growth.

Pharmacotherapy in pregnancy:

Appropriate pharamco-therapy is also crucial to avoid the associated risks of fetal malformations and miscarriages.

Immunosuppressants: Immunosuppressive drugs safe to use in pregnancy include corticosteroids and azathioprine.

Tacrolimus has been used on occasion, although we lack well-controlled studies on safety in pregnant women. Tacrolimus is considered safe to be used in pregnancy, with a small risk of neonatal hyperkalemia and renal dysfunction, and these parameters should be monitored in the newborn. Any of these three agents may also be used to treat a flare in pregnancy.

Hydroxychloroquine should be continued throughout pregnancy or initiated if there are no contraindications.

Immunosuppressive agents that are unsafe in pregnancy include mycophenolate (risk of miscarriage, first-trimester pregnancy loss, malformations like cleft lip and cleft palate), cyclophosphamide (severe birth defects) and methotrexate (risk of miscarriage and possible birth defects).

Rituximab lacks adequate safety data. EULAR guidelines suggest that while sound data is unavailable for rituximab, registry data have not shown an increased risk of congenital malformations. While it may be considered for use in early pregnancy, its use in late pregnancy can result in severe B-cell depletion in the neonate. The American College of Rheumatology conditionally recommends its use in life/ organ threatening disease. The use of belimumab is also not recommended in pregnancy.

Intravenous immunoglobulins (IVIG) may be used in a flare of LN refractory to other therapies but can be associated with a risk of kidney insufficiency.

In the relatively rare but important scenario of a severe life-threatening flare whereby treatment typically involves teratogenic therapy, shared decision-making should be undertaken with the clinical team and the patient and the patient’s family to discuss the option of termination of pregnancy.

Figure 2. Lupus flare - treatment (created with BioRender.com)

Anti-hypertensive agents: This has already been discussed in detail in our ‘Hypertension in Pregnancy’ segment, but labetalol, nifedipine, and methyldopa are generally safe bets. ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are avoided in the second and third trimesters of pregnancy as they are associated with severe birth defects (oligohydramnios, renal failure, and pulmonary hypoplasia, amongst others). Some evidence suggests that using an ACEi in the first trimester may not be associated with significant anomalies or adverse outcomes. So if your patient is dependable and has reliable menstrual cycles, it may be an idea to continue the ACEi or ARB until she falls pregnant and then cease it (to achieve the maximal anti-proteinuric effect).

ACEi, such as enalapril or captopril, are considered safe during lactation, more on a common practice ground. In a little study, both drugs have been shown to be relatively safe when breastfeeding, with minimal amounts secreted into breast milk. It may be associated with a small risk of neonatal hypotension, and monitoring is recommended.

Anticoagulation: If deep vein thrombosis prophylaxis is required, either unfractionated heparin or low molecular weight heparin may be used. Warfarin is contraindicated in pregnancy due to the risk of fetal birth malformations, spontaneous abortion, perinatal bleeding, and risk of fatal hemorrhage to the fetus in utero (it can cross the placental barrier). Data is limited on direct-acting oral anticoagulants in pregnancy and should therefore be avoided until robust evidence is available. As pregnancy is a pro-coagulant state, low-dose aspirin and therapeutic anticoagulation are advised for all patients with a history of anti-phospholipid (APS) antibody syndrome and a history of the thrombotic events (characterized by venous, arterial, and/or small vessel thrombosis with persistently positive anti-phospholipid antibodies). Treatment is advised throughout pregnancy and 6-12 weeks post-partum. Low-dose aspirin and prophylactically dosed anti-coagulation are recommended for women with known obstetric APS. Close surveillance may be considered in those with APS antibodies who do not meet the criteria for APS, or either low-dose aspirin or anti-coagulation may be used. Prophylactic anticoagulation should also be considered in pregnant women with nephrotic syndrome in the absence of APS antibodies (figure 2). Low-dose aspirin is recommended for all pregnant women with SLE at the beginning of the first trimester.

Lupus remains a tricky condition to manage, and given the population it affects, a working knowledge of how to manage fertility and pregnancy around this challenging condition is important. A shared decision-making process with the treating team and the patient incorporating the patient’s core values and preferences is the key to ensuring optimal maternal and fetal outcomes.

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Primary Glomerulonephritis and Pregnancy

Written by : Priyadarshini John DM

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The incidence of primary glomerulonephritis ranges between 0.2/100,000/year and 2.5/100,000/year. Pregnancy can take a toll on the kidney or vice versa. There is sparse literature about pregnancy counseling and managing primary glomerulonephritis during pregnancy.

Disease activity is the most important factor that affects maternal and fetal outcomes, and therefore control of the active disease should be undertaken prior to conception. This study which studied outcome of pregnancy in chronic kidney disease including chronic glomerulonephritis reported stable renal function in 79% of pregnant women, out of which 20% of the women had a 25% decline in renal function postpartum and 10% progressed to end-stage renal disease by six months postpartum, which probably undermines the importance of contributing factors like presence of HTN, amount of proteinuria and etiology of renal dysfunction at the time of conception. Fetal outcomes in terms of birth weight and gestational period were better in women with renal dysfunction without proteinuria than in women with proteinuria.

Control of proteinuria prior to embarking on pregnancy is of utmost priority, and evidence stems from outcomes of pregnancies in lupus. It is recommended to achieve complete remission of proteinuria for at least 3 to 6 months prior to pregnancy.

For glomerular diseases that mandate treatment with RAS inhibitors, these drugs can safely be used before pregnancy and are not considered teratogenic in the first trimester. Nevertheless, the best practice is to stop RAS inhibitors prior to conception.

Cyclophosphamide and Mycophenolate mofetil should be discontinued six weeks prior to planning pregnancy and it is recommended to wait for at least a year after rituximab.

Chronic hypertension is also common in patients with CKD and GN.The strict control of blood pressure is critical in pregnant women with glomerulonephritis, as severe hypertension in the first trimester is associated with adverse pregnancy outcomes. Methyldopa, extended-release dihydropyridine calcium channel blockers, and hydralazine are preferred antihypertensive drugs during pregnancy.Beta blockers labetalol are also first line. Labetalol crosses the placenta and can cause neonatal bradycardia and hypoglycemia. RAS inhibitors cause congenital cardiac abnormalities like atrial and ventricular septal defects, patent ductus arteriosus, pulmonary hypoplasia in the fetus, and oligohydramnios. For a comprehensive review about hypertension in pregnancy check here.

However, patients with glomerulonephritis may also experience difficulty getting pregnant or difficulties during their pregnancy.

Infertility in glomerulonephritis is secondary to disease processes of advanced chronic kidney disease, which causes hypothalamic pituitary dysfunction and impaired ovulation. In chronic kidney disease, there is defective pulsatile release of Gonadotropin releasing hormone(GnRH) and hence decreased release of Follicular stimulating hormone(FSH) and luteinizing hormone(LH) from pituitary.(Figure 1)

Figure 1 Hypothalamic-Pituitary axis in Normal Vs ESKD

Pharmacological therapy like cyclophosphamide can sometimes put women at risk for infertility. Oral cyclophosphamide and older age put women at risk for gonadal failure. It is emphasized that intense hemodialysis or transplantation might improve fertility.

Superimposed preeclampsia can develop on chronic hypertension, and patients with CKD are at particularly higher risk of preeclampsia compared to the general population. Worsening proteinuria and blood pressure after 20 weeks of gestational age should prompt evaluation for preeclampsia. Diagnosis of preeclampsia can be ruled out if sFlt1/PlGF ratio<38, but again the utility of these markers in underlying chronic kidney disease or glomerulonephritis is unclear. Kate et al studied the utility of markers of preeclampsia like serum sFLT1, PIGF in a spectrum of chronic kidney disease patients and inferred that cut off of these markers are similar to those who do not have chronic kidney disease population.Until these assays are validated in CKD for commercial purpose, high resistance patterns and low-velocity waveforms in uterine and umbilical arteries can differentiate chronic kidney disease (normal flow waves) from preeclampsia (high resistance flows with a pulsatility index >1.4) as suggested by Piccoli et al.

Despite best efforts, some patients may develop worsening renal function or proteinuria or de novo AKI or proteinuria that may necessitate renal biopsy.Indications for renal biopsy in pregnancy include rapid deterioration of renal function and de novo nephrotic syndrome. Renal biopsy should be considered, especially when diagnosing the underlying pathology will change the management of the patient and cannot wait until the delivery time.Complications of Kidney biopsy like the need for renal artery embolization, blood transfusion, preterm delivery, or fetal death occur in around 2% of pregnant women and were more common after 23 weeks of gestational age and during the postpartum period.

Medications:Prenatal supplementation of folic acid 5 mg, oral/IV iron, Vit D, and calcium are recommended.Calcium and low-dose aspirin (75-100mg/day) are known to reduce the risk of preeclampsia in high-risk women.Erythropoietin stimulating agents are safe to be used in pregnancy and help reduce the need for blood transfusion. Anticoagulation and thromboprophylaxis should be considered in women with albumin less than 2.5mg/dl. Treatment with low molecular weight heparin is deemed safe during pregnancy. Warfarin crosses the placenta and causes fetal loss and skeletal and central nervous system defects. Thromboprophylaxis is usually held before delivery and reinitiated at the earliest and continued until six weeks postpartum as the risk of thrombosis increases during the postpartum period.

Immunosuppression:Corticosteroids are the mainstay of therapy in many glomerular diseases and are considered safe to use in pregnancy. The placenta acts as a barrier and inactivates maternal cortisol by 11-beta-hydroxysteroid dehydrogenase type 2 on syncytiotrophoblasts, and low-doses do not cause thymic hyperplasia and adrenal suppression. Betamethasone and dexamethasone bypass this step, and fetal levels will be around 30% of maternal levels and hence used to accelerate fetal lung maturation. Adrenal suppression should be considered and treated during labor and delivery if a woman is on more than 20mg of steroids for greater than three weeks within six months prior to delivery.

Azathioprine in doses <2 mg/kg/day is safe to use in pregnancy as the fetal liver lacks inosinate pyrophosphorylase, essential in conversion to the active metabolite. Increased risk of congenital malformations, prematurity, and perinatal mortality is seen with azathioprine. Still, these adverse effects were not confirmed by the National Transplantation Pregnancy Registry.

Evidence regarding the safety of calcineurin inhibitors comes from their use in transplantation. These drugs can aggravate maternal hypertension. Dosages of CNI should be regularly monitored and adjusted due to the increased volume of distribution.

Rituximab safety is not well documented. Though there is some reassuring data about the usage of rituximab during pregnancy, it is recommended to delay pregnancy for at least 6-12 months after exposure to rituximab.

Cyclophosphamide and Mycophenolate are potential teratogens. Mycophenolate, a purine biosynthesis inhibitor, causes cleft lip and palate microtia with atresia of the external auditory canals, micrognathia, and hypertelorism. Cyclophosphamide causes calvarial defects, abnormalities of the ear, craniofacial structure, limb, and visceral organs, and developmental delay.

Table 1. Summary of immunosuppression in pregnancy

Glomerular disease-specific outcomes in pregnancy:There is meager data about pregnancy outcomes in minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. Few of the oldest studies by Jungers et al and Barcelo et al reported fair maternal and fetal outcomes if hypertension and proteinuria are well controlled. Proteinuria in the first trimester of idiopathic membranous nephropathy is associated with worsening nephrotic syndrome, gestational hypertension, renal dysfunction, fetal loss, and prematurity.

Pregnancy has minimal effect on IgA nephropathy as long as the renal function is preserved, and pregnancy did not have a significant impact on disease progression over a period of 4 years when compared to the non-pregnant population. Proteinuria at the time of conception is an independent risk factor for the postnatal decline in renal function. Shimizu et al in study concluded that renal function at the time of conception has a significant impact over a period of five years or thereafter. They observed that women who had eGFR <45 ml/min/m2 had progressed to CKD stage 4 during pregnancy and reached stage 5 within five years postpartum. Perinatal death in 3%, premature delivery in 10%, HTN in 21%, and 8.5% had superimposed preeclampsia are some of the Maternal and fetal outcomes in IgA nephropathy

Literature regarding pregnancy in Anti GBM disease is sparse. Significant maternal morbidity in the form of infections, preeclampsia, and need for renal replacement therapy are seen, and IUGR, prematurity, fetal demise, and congenital malformations contribute to fetal morbidity. Anti-GBM antibodies cross the placenta, which is detectable in the blood of neonates without renal or pulmonary disease.

Pregnancy in ANCA vasculitis is rare, unlike SLE. Active vasculitis at the time of conception might result in spontaneous abortions and deterioration of renal function. Relapse during pregnancy is seen in 18% and postnatal flare in 21.3% of patients. Vasculitis Clinical Research Consortium Patient Contact Registry looked into the pregnancies before and after vasculitis and concluded that there is an increased risk of fetal demise and preterm delivery in women who conceived after vasculitis. Case reports of neonatal vasculitis are secondary to transplacental passage of anti-MPO and anti-PR3 antibodies.

Conclusions:

• Women with glomerulonephritis can plan conception after discussing it with a multidisciplinary team of obstetricians, nephrologists, and pediatricians.

• Safe maternal and fetal outcomes depend on renal function, which includes control of HTN and proteinuria

• Timely maternal and fetal monitoring is the key to optimal outcomes.

Figure 2. Holistic approach to women with glomerulonephritis who wish to get pregnant.

Reviewed by : Amy Yau MD, Sophia Ambruso MD, Silvi Shah MD

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.

Thrombotic microangiopathy in pregnancy: it's more than just a "classic triad"

Written by: Priya Yenebere, DO MS (@PriRenalAKI)

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Thrombotic microangiopathy (TMA) is a pathological process of thrombotic occlusion of systemic microvasculature, resulting in end-organ ischemia and infarction. Classically, we know this by a familiar triad: consumptive thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and acute kidney injury. TMA is characterized by the formation of fibrin-rich platelet clots in glomerular capillaries and arterioles. TMA can present either during pregnancy or in the postpartum period whereby early recognition is necessary as it impacts the health of both mother and newborn. While the differential for TMA is long in pregnancy, there are select diagnoses that must be considered, which we will discuss below.

1. Preeclampsia

2. Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome

3. Acute fatty liver of pregnancy (AFLP)

4. Complement-mediated HUS (also known as atypical HUS [aHUS])

5. Thrombotic thrombocytopenic purpura (TTP)

(Adapted from Scully and Goel)

Preeclampsia

We discuss preeclampsia in a separate review, please visit here for more information.

HELLP

Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome is a serious, pregnancy-specific disorder characterized by the classic triad of increased transaminases, reduced platelet counts, and hemolysis. There have been accounts of partial or incomplete forms, where only one of two parts of the triad are present. Overall, this syndrome occurs in approximately 0.5 to 0.9% of all pregnancies but is seen in up to 10 to 20% of severe preeclampsia cases which can result in increased maternal and perinatal morbidity and mortality. While cardiopulmonary complications are already high in severe preeclampsia, they double to 12% in patients with HELLP syndrome.

Classically, this is seen during the third trimester with peak frequency between gestational weeks 27 through 37 but can also occur in the postpartum period, coupled with other morbidities. A large prospective cohort study of 442 pregnancies found that 30% of HELLP syndrome cases occurred postpartum, which were associated with an increased risk of serious maternal morbidity including disseminated intravascular coagulation (DIC), placental abruption, and acute renal failure. Overall maternal mortality was 1.1% in this study.

HELLP should be considered in the setting of epigastric or right upper quadrant pain and elevated AST or ALT levels (alkaline phosphatase levels are usually increased in normal pregnancy physiology). Hemolysis usually presents in the form of microangiopathic hemolytic anemia with red cell fragmentation (schistocytes) or contracted red cells with spicules (burr cells) on peripheral smear. Red cell destruction leads to increased serum lactate dehydrogenase (LDH) levels and decreased haptoglobin levels. Thrombocytopenia is a consumptive process, as activated platelets adhere to damaged vascular endothelial cells.

While there are different HELLP severity classifications (Table 1), these predict the risk for hemorrhagic complications rather than drive treatment plans. Hemorrhagic complications are higher in platelet counts less than 40 x 109/L. Similar to pre-eclampsia, the definitive treatment of HELLP is the delivery of the fetus. However, gestational age is very important when making this decision. Prompt delivery is most acceptable for gestational age greater than 37 weeks in the setting of HELLP syndrome. Management may also include immediate hospitalization, seizure prophylaxis with magnesium sulfate, and corticosteroids for gestational weeks 25 through 34 to minimize the risk of infant respiratory distress syndrome.

(from Haram et al.)

Acute fatty liver of pregnancy (AFLP)

There is noticeable overlap between HELLP syndrome and AFLP. AFLP is a rare but life-threatening cause of liver failure, multiorgan involvement, and coagulopathy affecting about 2 to 3 thousand patients annually. Although rare, it is considered the most common cause of acute liver failure in pregnancy - more common than hepatitis and drug-induced etiologies. AFLP occurs during the third trimester with nonspecific symptoms of malaise, anorexia, nausea and vomiting. More worrisome symptoms such as right upper quadrant pain and jaundice can be observed. Usually, there is no associated hypertension or proteinuria, but metabolic acidosis, acute liver failure, and low-grade DIC identified laboratory studies can be observed (see below for evaluation of AFLP). It is thought that AFLP is caused by mitochondrial dysfunction during the oxidation process of fatty acids. Delivery is the definitive treatment for AFLP. Interestingly, as the patient is severely coagulopathic, vaginal delivery is preferred over cesarean. AFLP improves within weeks of delivery, but may recur in subsequent pregnancies, although very rare.

(Nelson et al.)

Complement-mediated HUS (CM-HUS or C-HUS) or atypical HUS (aHUS)

CM-HUS (also known as atypical HUS) is a dysregulation disorder of the alternative complement pathway whereby complement protein mutations lead to an overactive complement cascade and eventual endothelial cell injury. Major complement gene mutations include factor H, factor I, membrane cofactor protein, factor B, complement component 3 (C3), and thrombomodulin. Similar complement gene mutations are seen in patients with preeclampsia and HELLP syndrome, demonstrating overlap between TMA conditions in pregnancy. CM-HUS triggers include medications, infections, or systemic illness, and pregnancy is considered a frequent trigger for CM-HUS, where 20% of cases occur prior to delivery and 80% of cases occur in the postpartum setting.

Clinical features usually reveal the classic triad of anemia, thrombocytopenia, and decreased renal function, in addition to schistocytes on blood smear, low haptoglobin levels, and high lactate dehydrogenase levels. ADAMTS-13 levels may be decreased, but not to the degree seen in TTP. Initial treatment for CM-HUS is similar to TTP with plasma exchange, but eculizumab can also be part of the treatment strategy in severe cases. Eculizumab is a recombinant, humanized, monoclonal antibody that binds to C5 which prevents its cleavage to C5a and C5b, necessary players in the overstimulated complement cascade. Eculizumab is safe to give during pregnancy, and prompt initiation of the medication is encouraged while the workup is pending. The risk of relapse in subsequent pregnancies is about 25%, with the greatest risk occurring in patients with complement factor H and I mutations. There is no data on starting treatment for high-risk cases once pregnancy is confirmed, but it may be considered in certain cases.

Thrombotic thrombocytopenic purpura (TTP)

TTP is a systemic disorder of microvascular thrombosis that is due to an inherited or acquired severe deficiency of von Willebrand factor (vWF)-cleaving protease called ADAMTS-13 (a disintegrin-like and metalloprotease domain with thrombospondin type-1 motif, number 13). During pregnancy, there are increased levels of Von Willebrand factor which may remain elevated in the postpartum period. There is also a relative decrease in ADAMTS-13 levels, but they are still within the usual normal range. In pregnancy-associated TTP, an ADAMTS-13 level of < 10% supports this clinical diagnosis. The classic pentad of TTP is as follows: 1) thrombocytopenia 2) MAHA 3) acute renal failure 4) fever 5) neurological changes, but this pentad is neither sensitive nor specific. A clinical prediction tool, called the PLASMIC score, has been developed to determine the risk of a patient developing severe ADAMTS-13 deficiency, as it is rare to present with the complete pentad of symptoms. The scoring tool takes into account the platelet count, evidence of hemolysis, active cancer diagnosis, history of transplant (solid-organ or stem-cell), mean corpuscular volume (MCV), INR, and creatinine level - the higher the score, the higher the risk of severe ADAMTS-13 deficiency. This score is helpful as timely results of ADAMTS-13 activity testing may be unavailable.

There are many TTP triggers (ie malignancy, infection, or medication), pregnancy is a well-recognized trigger of TTP and is referred to as pregnancy-associated TTP or pregnancy-related TTP. While congenital and acquired TTP are associated with pregnancy-onset TTP, congenital TTP is often triggered by the first pregnancy and carries a maternal mortality rate of more than 90% if left untreated. Pregnancy-associated TTP accounts for approximately 5 to 10% of all TTP cases and can happen at any stage of pregnancy but is most frequently observed in the third trimester and postpartum period.

TTP treatment relies on prompt plasma exchange therapy at the time of diagnosis (Figure 1 below). This differs from previously discussed pregnancy-related TMAs where delivery is the definitive treatment.

(Scully, Thomas, et al.)

Although HELLP, AFLP, aHUS, and TTP share pathological features of TMA, they carry distinct clinical courses and triggering events. While many of them are rare, they remain life-threatening, with high maternal and fetal morbidity and mortality, and should always be on the differential for maternal hypertension.

(Adapted from Vijayan, Critical Care 2019)

Reviewed by: Amy Yau MD, Sophia Ambruso DO, and Silvi Shah MD, MS

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.