A Newborn with Thrombocytopenia, Cataracts, and Hepatosplenomegaly


http://www.nejm.org/doi/full/10.1056/NEJMcpc1706110?utm_medium=referral&utm_source=r360

A Newborn with Thrombocytopenia, Cataracts, and Hepatosplenomegaly


How common is the use of the rubella vaccine worldwide?

The acronym TORCH (toxoplasmosis, other [syphilis, varicella, parvovirus B19 infection, HIV infection], rubella, cytomegalovirus infection, and herpes simplex virus infection) is often used to identify possible congenital infections.

Clinical Pearls

Q: What are some of the clinical manifestations of the congenital rubella syndrome?

A: Cataracts, thrombocytopenia, bony abnormalities, and deafness are consistent with the congenital rubella syndrome.

Table 2. (10.1056/NEJMcpc1706110/T2) Manifestations of the Congenital Rubella Syndrome.

Q: How is the congenital rubella syndrome diagnosed?

A: Newborns with the congenital rubella syndrome shed rubella virus in the throat, nasopharynx, and urine. Because growth of the virus in cultured mammalian cell lines is relatively slow and cultivation and identification of the virus are labor-intensive, nucleic acid amplification tests have been developed to directly detect rubella virus RNA in clinical samples.

Morning Report Questions

Q: Can serologic testing also establish the diagnosis of the congenital rubella syndrome?

A: In addition to direct viral detection, evidence of the production of antibodies to rubella virus in an infant can be used to establish a diagnosis of the congenital rubella syndrome. Affected newborns produce IgM antibodies to rubella virus. These antibodies can usually be detected at birth with the use of a capture enzyme-linked immunosorbent assay; the level increases during the first 3 months of life and then declines over time. At birth, tests for IgG antibodies to rubella virus cannot be used to distinguish between transplacentally acquired maternal antibodies and antibodies produced by the neonate. However, another means of establishing a diagnosis of the congenital rubella syndrome is showing that the level of IgG antibodies to rubella virus does not substantially decrease during the first few months of life, as the maternal antibodies decay. Finally, IgG antibodies to rubella virus that are produced by infants with congenital infection are typically of low avidity; therefore, a diagnosis of the congenital rubella syndrome can be established by detecting low-avidity antibodies in the blood after the maternal antibodies have waned.

Q: How common is use of the rubella vaccine worldwide?

A: The estimated number of cases of the congenital rubella syndrome worldwide is still approximately 100,000 per year. Rubella and the congenital rubella syndrome have been eradicated from the Western hemisphere because of good vaccine coverage. Unfortunately, although rubella has been controlled in many countries in Europe, opposition to vaccination in some countries has prevented the elimination of rubella, and there is much work to be done. In contrast, routine vaccination against rubella has just begun in some Asian countries, including India, Thailand, China, Japan, and Indonesia. Coverage in Africa is spotty, but a few countries have introduced the vaccine. In Nigeria, vaccination is limited to private providers, and coverage is less than 10%. There is a campaign to introduce the combined measles–rubella vaccine throughout the world, and all regions have goals to eradicate both diseases.

Jakafi: First and only FDA-approved agent for myelofibrosis.


Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis—collectively known as myelofibrosis diseases.1

Identifying intermediate or high-risk myelofibrosis2-4

In order for a patient to be classified as having intermediate or high-risk myelofibrosis, he or she must have 1 or more of the following characteristics:

  • Age >65 years
  • Presence of constitutional symptoms
  • Hemoglobin <10 g/dL
  • White blood cell count >25 × 109/L
  • Blood blasts ≥1%
  • Platelet counts <100 × 109/L
  • Unfavorable karyotype*
  • Red cell transfusion dependence

Jakafi significantly reduces spleen volume and improves symptoms of myelofibrosis

In both phase III studies, a significantly higher proportion of patients receiving Jakafi achieved a ≥35% reduction in spleen volume vs those receiving placebo or best available therapy.1 Learn more about splenomegaly efficacy.

  • Superior reductions in spleen volume vs placebo1,5
    • 41.9% of patients receiving Jakafi achieved a ≥35% reduction in spleen volume at Week 24 vs 0.7% of patients receiving placebo (P < 0.0001)1,5
  • Superior reductions in spleen volume vs best available therapy1,6
    • 28.5% of patients receiving Jakafi achieved a ≥35% reduction in spleen volume at 48 weeks vs 0% of patients receiving best available therapy (P < 0.0001)1,6

Significantly more patients receiving Jakafi achieved a ≥50% improvement in symptoms vs those receiving placebo.1,5 Learn more about symptoms efficacy.

  • Superior improvements in symptoms vs placebo1,5
    • 45.9% of patients receiving Jakafi achieved a ≥50% improvement in Total Symptom Score (TSS) vs 5.3% of patients receiving placebo (P < 0.0001) at Week 241,5

Responses were seen in patients regardless of JAK2V617F mutational status.5

  • Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo5
  • Patients with myelofibrosis have dysregulated Janus kinase (JAK) signaling, regardless of the presence or absence of the JAK2V617F mutation7

Safety profile of Jakafi

Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. Serious bacterial, mycobacterial, fungal and viral infections may occur. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache.

Similar and low discontinuation rates were observed in both the Jakafi and placebo arms (11% and 10.6%, respectively).1

Dosing for Jakafi based on platelet counts1

Starting dose for Jakafi is based on platelet counts. Dosing should be modified based on

  • Patient response
  • The presence of thrombocytopenia
  • Organ impairment
  • Concomitant administration of CYP3A4 inhibitors
  • Anemia and neutropenia

*Unfavorable karyotype: complex karyotype or sole or two abnormalities that include +8, –7/7q-, i(17q), –5/5q-, 12p-, inv(3), or 11q23 rearrangement.

At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.1

Important Safety Information

  • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated
  • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary
  • Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi
  • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery
  • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache
  • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. Advise patients about early signs and symptoms of herpes zoster and to seek early treatment
  • Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate
  • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy
  • Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed

Source: http://www.jakafi.com

Do not forget about HELLP.


Summary

A 32-year-old female para 4 gravi 3, who was 21 weeks pregnant, presented to the emergency department (ED) with a 2-day history of abdominal pain, headache, blurred vision and vomiting. On arrival, she was agitated and confused with a blood pressure 162/106 mm Hg, pulse rate 107, respiratory rate 18, temperature 37 degrees Celsius, point of care blood glucose 6.2 and her Glasgow coma scale was 13/15 M6V4E3. Paramedics witnessed seizure-like activity lasting <1 min during transport. A diagnosis of eclampsia complicated by the HELLP syndrome (haemolysis, elevated liver enzymes, low platelets count) was made. She was commenced on magnesium and labetalol intravenously for blood pressure control. Initial blood test results were consistent with the HELLP syndrome. Recognition of the HELLP syndrome with prompt management of blood pressure and clotting abnormalities is essential in the ED setting. An aggressive multidisciplinary approach is a key to optimise the prognosis for mother and fetus.

Background

HELLP (haemolysis, elevated liver enzymes, low platelets count) syndrome is a multisystem disease that is characterised by microangiopathic haemolytic anaemia, hepatic dysfunction and thrombocytopenia. It was first described by Weinstein in 1982.1 It has a high maternal and perinatal morbidity and mortality. Its incidence is reported as 0.2%–0.6% of all pregnancies, and 10%–20% of women with co-morbid pre-eclampsia. HELLP usually begins during the third trimester, and usually in Caucasian women over the age of 25.2 Prompt recognition of HELLP syndrome and timely initiation of therapy are vital to ensure the best outcome for mother and fetus.

Case presentation

A 32-year-old female para 4 gravi 3, who was 21 weeks pregnant, presented to the emergency department (ED) with a 2-day history of abdominal pain, headache, blurred vision and vomiting. Her mother stated that earlier in the day she had an episode consistent with seizure-like activity. Medical and family history was unremarkable.

On arrival, she was agitated and confused with a blood pressure 162/106, pulse rate 107, respiratory rate 18, temperature 37 degrees Celsius, point of care blood glucose 6.2 and her Glasgow coma scale was 13/15 M6V4E3. Paramedics witnessed seizure-like activity lasting <1 min during transport. Primary survey revealed that her chest was clear, heart sounds normal and abdomen was soft and non-tender with a palpable uterus rising just below the umbilicus. She had no per vaginal bleeding. She was icteric and had evidence of tongue biting. A urine dipstick revealed protein 4+.

An initial working diagnosis of eclampsia complicated by the HELLP syndrome was made. She was commenced on magnesium and labetalol intravenously for blood pressure control. Initial blood test results were consistent with the HELLP syndrome (table 1).

View this table:

Table 1

Initial blood test results

She was transfused two pools of platelets and transferred to an obstetric centre. She was treated conservatively for 24 h; unfortunately she miscarried the following day. Day 1 post spontaneous abortion, the labetalol and magnesium were discontinued.

Discussion

HELLP syndrome is a multisystem disease that is characterised by microangiopathic haemolytic anaemia, hepatic dysfunction and thrombocytopenia. It was first described by Weinstein in 1982.1 It has a high maternal and perinatal morbidity and mortality. Its incidence is reported as 0.2%–0.6% of all pregnancies, and 10%–20% of women with co-morbid pre-eclampsia. HELLP usually begins during the third trimester, and usually in Caucasian women over the age of 25.2

The aetiology and pathogenesis of HELLP syndrome remains unclear. Van Beek et al postulate that abnormal placentation results in placental ischaemia and the production of a circulating toxin that causes endothelial cell injury.3 The injury is believed to cause vascular constriction within multiple organ systems, activation of the coagulation system, increased capillary permeability and platelet activation with platelet consumption in the microvasculature, all resulting in hypertension, proteinuria, oedema and thrombocytopaenia.

Prompt recognition of HELLP syndrome and timely initiation of therapy are vital to ensure the best outcome for mother and fetus. When the syndrome was first described, prompt delivery was recommended.4 Recent research suggests that morbidity and mortality do not increase when patients with HELLP are treated conservatively. Patients with HELLP syndrome may be eligible for conservative management if hypertension is controlled at less than 160/110 mm Hg, oliguria responds to fluid management and elevated liver function values are not associated with right upper quadrant or epigastric pain. One study found that pregnancy was prolonged by an average of 15 days when conservative management (i.e., bed rest, fluids and close observation) was used in patients who were at less than 32 weeks of gestation.4 Maternal morbidity was not increased. For infants, the prolongation of pregnancy translated into less time in the neonatal intensive care unit, a decreased incidence of necrotising enterocolitis and a decreased incidence of respiratory distress syndrome.4 Females treated conservatively should be managed in a tertiary care centre that has a neonatal intensive care unit and a perinatologist available for consultation. Patients with HELLP syndrome should be treated prophylactically with magnesium sulphate to prevent seizures, whether hypertension is present or not. A bolus of 4 to 6 g of magnesium sulphate as a 20 percent solution is given initially. This dose is followed by a maintenance infusion of 2 g per h. The infusion should be titrated to urine output and magnesium level. Patients should be observed for signs and symptoms of magnesium toxicity. If toxicity occurs, 10 to 20 ml of 10 percent calcium gluconate should be given intravenously.

Antihypertensive therapy should be initiated if blood pressure is consistently greater than 160/110 mm Hg despite the use of magnesium sulphate. This reduces the risk of maternal cerebral haemorrhage, placental abruption and seizure. The goal is to maintain diastolic blood pressure between 90 and 100 mm Hg. Patients who have had HELLP syndrome should be counselled that they have a 19 to 27 per cent risk of developing the syndrome in subsequent pregnancies. They also have up to a 43 per cent risk of developing preeclampsia in another pregnancy.5

Recognition of the HELLP syndrome with prompt management of blood pressure and clotting abnormalities is essential in the ED setting. An aggressive multidisciplinary approach is a key to optimise the prognosis for mother and fetus. This case report highlights the need for vigilance regarding HELLP recognition in the ED setting.

Learning points

  • ▶ HELLP syndrome is a multisystem disease that is characterised by microangiopathic haemolytic anaemia, hepatic dysfunction and thrombocytopenia.
  • ▶ An aggressive multidisciplinary approach is a key to optimise the prognosis for mother and fetus.
  • ▶ Recognition of the HELLP syndrome with prompt management of blood pressure and clotting abnormalities is essential in the ED setting.
  • Competing interests None.
  • Patient consent Obtained.

Footnotes

References

    1. Weinstein L

. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982;:15967.

[Medline][Web of Science]

    1. Sibai BM,
    2. Ramadan MK,
    3. Usta I,
    4. et al

. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet Gynecol 1993;:10006.

[Medline][Web of Science]

    1. Van Beck E,
    2. Peeters LL

. Pathogenesis of preeclampsia: a comprehensive model. Obstet Gynecol Surv 1998;:2339.

[CrossRef][Medline]

    1. Visser W,
    2. Wallenburg HC

. Temporising management of severe pre-eclampsia with and without the HELLP syndrome. Br J Obstet Gynaecol 1995;:1117.

[CrossRef][Medline]

    1. Sibai BM,
    2. Taslimi MM,
    3. el-Nazer A,
    4. et al

. Maternal-perinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia-eclampsia. Am J Obstet Gynecol 1986;:5019.

[Medline][Web of Science]

 

Source: BMJ