Keywords
COVID-19 - HELLP - pregnancy - overlapping conditions
During the current novel coronavirus disease 2019 (COVID-19) pandemic, clinicians
from every field are encountering novel findings. There have been reports of infectious
diseases mimicking hemolysis, elevated liver enzymes, and low platelets syndrome (HELLP)
in gravid patients.[1]
[2] However, our understanding of how severe acute respiratory syndrome-coronavirus-2
(SARS-CoV-2) affects these patients has not been elucidated. These findings can become
clinical conundrums when there is significant overlap with known, and serious, syndromes
in pregnancy. This case series describes two gravid patients who tested positive for
the novel coronavirus and had laboratory findings that mimicked HELLP.
HELLP is generally characterized by three diagnostic criteria: microangiopathic hemolysis
with schistocytes on peripheral blood smear, elevated liver enzymes, and thrombocytopenia.[3] While HELLP is typically associated with proteinuria and hypertension, representing
a severe form of preeclampsia, atypical presentations of HELLP have been described
in the literature.[4]
[5] Laboratory abnormalities commonly seen in COVID-19 patients include lymphopenia,
leukopenia, and elevated liver enzymes.[6] Additionally, studies of patients with severe disease have shown laboratory abnormalities
consistent with disseminated intravascular coagulation (DIC), including an elevated
D-dimer and evidence of microangiopathic hemolytic anemia.[6] In small studies of pregnant women with COVID-19, laboratory abnormalities were
similar and included elevated C-reactive protein (CRP), lymphopenia, and elevated
liver enzymes.[7]
Cases
The first patient was a 41-year-old G9P8008, with no previous medical history, who
was admitted for suspected COVID-19 pneumonia at 22 weeks of gestational age. Consistent
with other cases already reported in the literature, the patient decided to seek medical
care on COVID-19 at day 7 and reported 1 week of worsening fever, cough, and chest
pain, and had no obstetrical complaints. Her physical exam was remarkable for mild
respiratory distress with mild crackles appreciated bilaterally on lung examination.
Chest X-ray was performed with an abdominal shield, which showed diffuse hazy and
patchy opacities of the bilateral lungs with a basilar and peripheral predominance.
The constellation of these findings was highly suspicious for atypical/viral pneumonia
(COVID-19). She was normotensive with a blood pressure range of 92 to 106/50 to 64.
Urinalysis on admission was unremarkable with +1 protein. Nasopharyngeal testing performed
on the day of admission for the novel coronavirus was subsequently positive. Given
the fact that the patient was previable, a bedside transabdominal ultrasound was not
performed and there is no estimated fetal weight documented in chart. The decision
of not performing a bedside ultrasound was in attempt to limit provider's prolonged
exposure time to patients with suspected COVID-19 infection. Bedside Doppler examinations
were performed and a positive fetal heart rate of 150 beats per minute (bpm) was documented.
A fetal heart rate check was performed daily. She received hydroxychloroquine, azithromycin,
and ceftriaxone. Her oxygen saturation remained between 88 to 92% on 100% nonrebreather.
A ventilator was not used at this time, and therefore, no FIO2 was documented. Arterial blood gas performed at that time showed the following findings:
pH, 7.430/PaCO2, 31/PaO2, 285/bicarb, 20.6/base excess of −2.8. On hospital day 5, COVID-19 day 12, she was
diagnosed with an intrauterine fetal demise (IUFD) during her daily fetal heart rate
check. Her laboratory work revealed hemolysis, worsening elevation of liver enzymes,
thrombocytopenia, and acute kidney injury (AKI; [Table 1]). The patient delivered spontaneously without any intervention. Placental findings
included diffuse perivillous fibrin deposition and maternal floor infarction.
Table 1
Summary of laboratory findings for cases 1 and 2
|
Case
|
Baseline laboratories
|
PPD 0
|
PPD 1
|
|
41-year-old woman
|
COVID-19 day 7: complete blood count: 21.3 > 10.8/31.3 < 216
Blood urea nitrogen/creatinine: 9/0.51
Aspartate aminotransferase/alanine aminotransferase: 89/29
Lactate dehydrogenase: 296
C-reactive protein: 24
Prothrombin time/partial thromboplastin time: 12.6/36.7 < 1.19
D-Dimer: 0.54
|
COVID-19 day 12: complete blood count: 25.3 > 12.7/87.4 < 48
Blood urea nitrogen/creatinine: 42/1.49
Aminotransferase/alanine aminotransferase: 192/88
Lactate dehydrogenase: 1,366
C-reactive protein: 8.4
Prothrombin time/partial thromboplastin time: 14.4/31.5 < 1.35
Fibrinogen: 185
D-Dimer: >35.2
Urinalysis: +1 protein
|
COVID-19 day 13: complete blood count:51.3 > 10.6/32.8 < 41
Blood urea nitrogen/creatinine: 97/6.35
Aminotransferase/alanine aminotransferase: 172/204
Lactate dehydrogenase: 5,540
|
|
31-year-old woman
|
1st prenatal visit (October 2019):
Complete blood count: 6.8 > 13.5/40.2 < 212
|
COVID-19 day 7: Complete blood count: 5.6 > 14.8/44.2 < 24
Peripheral smear: platelets decreased, slight schistocytes, bands
Basic metabolic panel:
137/3.5/100/28/6/0.5 < 116
Aspartate aminotransferase/alanine aminotransferase: 43/17
Prothrombin time/partial thromboplastin time: 12/32.4 < 1
Fibrinogen: 97
Urinalysis: +1 protein
|
COVID-19 day 8: Complete blood count: 11.36 > 10.2/30.2 < 110
Fibrinogen: 181
Procalcitonin: 0.12
Lactate: 2.7
|
Abbreviations: COVID-19, novel coronavirus disease 2019; PPD, postpartum day.
Following delivery, the patient was transferred to the intensive care unit (ICU) with
an oxygen saturation of 70% and required immediate intubation. Arterial blood sampling
at this time resulted in a PaO2:FiO2 ratio of 164 consistent with adult respiratory distress syndrome (ARDS).[8] Due to a low suspicion of preeclampsia with severe features or HELLP syndrome, the
patient was not started on magnesium sulfate for seizure prophylaxis. The patient
remained intubated with acute respiratory failure, ARDS, acute renal failure, and
sepsis. Hemodialysis was started for anuria. She received ceftriaxone for 4 days for
presumed bacterial superinfection, 5 days of azithromycin, 3 days of hydroxychloroquine,
and two doses of tocilizumab. Computed tomography (CT) scan of the head showed an
acute/subacute small- to moderate-sized right-middle cerebral artery vascular territory
infarct and small left middle cerebral artery vascular territory infarct.
The second patient was a 31-year-old G2P1001 who presented to the emergency department
at 29 6/7 weeks of gestational age with decreased fetal movement. She reported a 1-week history
of cough and fever to 102°F and like the first case sought medical attention on COVID-19
disease day 7. The physical exam was unremarkable. Urinalysis was noted to have +1
protein. Her blood pressure ranged from 115 to 133/77 to 89. Fetal heart rate monitoring
was nonreassuring, and a biophysical profile for fetal assessment was 2/8 (two for
a normal maximum vertical pocket). Emergent cesarean delivery was performed at which
time, significant bleeding was noted. Platelets obtained during the cesarean section
indicated 24,000/µL. Intraoperatively, the patient was transfused two units of fresh
frozen plasma (FFP) and two units of super-packed platelets. Postoperatively, a nasopharyngeal
SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) test was performed and was
found to be positive, 7 hours following her emergent cesarean delivery. Pathological
examination of the placenta included acute and chronic (predominantly chronic) villitis,
intervillositis (predominantly chronic), and perivillous fibrin deposition likely
representing severe placental hemorrhage consistent with disseminated intravascular
coagulation (DIC). CT of the chest from postoperative day 1 revealed subtle peripheral
opacities in the lower lobes.
Shortly after delivery, the neonate was intubated and transferred to the neonatal
ICU (NICU). Initial laboratory findings revealed an elevated white blood cell count
(28.06 cells/µL) and a normal platelet count (224,000/µL). Chest X-ray showed diffuse
ground-glass appearance throughout both lung fields. On the second day of life, the
neonate's white blood cell count normalized and CRP was found to be within normal
limits. However, significant transaminitis was noted with aspartate aminotransferase/alanine
aminotransferase of 362/321 U/L. Interestingly, the neonate's platelets down trended
and reached a nadir of 66,000/µL on day 6 of life and ultimately, the fetus was confirmed
to be positive for SARS-CoV-2.
The postoperative course for patient 2 was complicated by acute blood loss anemia
([Table 1]) and she was transfused two units of packed red blood cells. The patient's platelets
up trended postoperatively ([Table 1]) and her COVID-19 symptoms remained mild. She never required medical treatment for
COVID-19 symptoms or supplemental oxygen. The patient was discharged on postoperative
day 4.
Discussion
HELLP complicates 0.5 to 1% of pregnancies and approximately 20% of HELLP occurs with
severe preeclampsia.[9] AKI is commonly associated with HELLP, complicating 7 to 15% of cases. HELLP is
widely considered to be a severe form of preeclampsia, yet up to 15 to 20% patients
do not have antecedent signs or symptoms of preeclampsia.[10] The syndrome is progressive in nature. The pathophysiology of HELLP is not entirely
clear and there are several theories that try to isolate the trigger for this disease
spectrum. The pathophysiological process of HELLP presents with endothelial damage
resulting from platelet activation, leading to platelet aggregation. HELLP may also
be associated with DIC, and in fact, some investigators believe that DIC is the primary
process.[9] Seventy percent of HELLP cases develop in the third trimester, while 30% develop
within 48 hours of postpartum; delivery is considered first-line treatment. The additional
use of magnesium sulfate for the prevention of progression to eclampsia is recommended,
as well as the treatment of elevated blood pressure with antihypertensives.[9]
Much of the research on COVID-19 and its effects on pregnant patients and unborn fetuses
is currently under investigation. Reports already exist of elevated liver enzymes,
thrombocytopenia, DIC, cardiomyopathy, AKI, and ARDS in the general population.[11]
[12]
[13]
[14] Pregnant patients are likely to present with similar signs and symptoms, and many,
if not all, of the same laboratory abnormalities as the general population.[7]
[15]
[16] Research on the immediate and long-term maternal and fetal effects is still limited.
Although the similarities between COVID-19 and HELLP are evident ([Table 2]), it is essential to focus on some of the clinical criteria that could help the
obstetrician differentiate between the two. The first is the presence or absence of
an elevated blood pressure. In up to 20% of HELLP cases, mild-to-severe range blood
pressures will be evident, compared with patients with COVID-19, who have normal to
low blood pressures, depending on the severity of the disease. The presence of a fever,
leukocytosis, respiratory distress, and hypoxia will increase the suspicion of COVID-19.
Proteinuria, in the context of AKI should be monitored and treated, but is unlikely
to clarify the diagnosis. D-dimer has been used widely as an initial screening parameter
for COVID-19, yet its sensitivity in pregnancy is known to be low.[7] Although van der Pol et al have set a useful D-dimer parameter in pregnancy to help
rule out pulmonary embolism using the pregnancy-adapted YEARS diagnostic algorithm,[17]
[18] further studies are needed to determine its role in pregnancies affected by COVID-19.
With that said, chest X-ray or CT is of benefit, since the presence of “ground glass
appearance,” or “patchy infiltrates'' can help differentiate COVID-19 from pulmonary
edema that could rarely be evident in patients with HELLP.[19]
[20]
Table 2
Comparison of HELLP syndrome and COVID-19
|
HELLP syndrome
|
COVID-19
|
|
Clinical manifestations
|
Nausea, vomiting, diarrhea, malaise, abdominal pain, midepigastric pain, headache,
jaundice, visual changes, ± elevated blood pressure
|
Diarrhea, malaise, headache, cough, fevers, tachypnea, hypoxia
|
|
Laboratory findings
|
Hemolysis, transaminitis, elevated LDH, elevated BUN/creatinine, thrombocytopenia, ± proteinuria
|
Hemolysis, transaminitis, elevated LDH, elevated BUN/creatinine, thrombocytopenia,
elevated D-dimer
|
|
Complications
|
DIC, liver infarction, renal failure, pulmonary edema
|
Cardiopulmonary arrest, ARDS, septic shock, renal failure, cardiomyopathy, DIC
|
|
Treatment
|
Delivery
|
Investigational. currently in our institution the regimen is: azithromycin, cephalosporins
and hydroxychloroquine
|
Abbreviations: ARDS, adult respiratory distress syndrome; BUN, blood urea nitrogen;
COVID-19, novel coronavirus disease 2019; DIC, disseminated intravascular coagulation;
HELLP, hemolysis, elevated liver enzymes, and low platelets syndrome; LDH, lactate
dehydrogenase.
Furthermore, early chest imaging could be a useful tool to differentiate the diseases
if laboratory abnormalities present later in disease progression. Early documentation
of a respiratory infectious process could help avoid confusion once changes indicating
HELLP occur. The final clue will likely present only after delivery. While HELLP will
begin to resolve 24 to 72 hours of postpartum, the COVID-19 course is likely to be
unrelated to the timing of delivery; yet more research is needed to clarify these
outcomes.
Similarly, in centers where rapid viral testing is possible, our case series supports
the practice of early testing of pregnant patients regardless of disease severity.
Early documentation of a positive COVID-19 test could help the obstetrician be on
high alert and foster collaboration with a multidisciplinary team, including intensivists,
neonatologists, and maternal-fetal medicine specialists for close monitoring and possible
need for intubation and early delivery. Anticipatory testing can also help in clarifying
the etiology of clinical and laboratory changes indicating HELLP, if gradual progression
occurs.
Conclusion
In conclusion, the differential diagnosis of HELLP should be considered in women with
COVID-19 to avoid iatrogenic preterm delivery, delay in treatment, and complications
of both undiagnosed and untreated HELLP and COVID-19.
