COVID-19 and hemolysis, elevated liver enzymes and thrombocytopenia syndrome in pregnant women - association or causation?

Table 1 Published studies on coronavirus disease 2019 and hemolysis, elevated liver enzymes, and low platelet count syndrome

Ref.	Type of study	Age (yr), gestation (wk)	Number of patients	Main results	Conclusion
Mendoza et al[31], 2020	Case series		5 cases with severe PE and/or HELLP syndrome	Out of 8 cases with severe COVID-19, 5 developed PE, proteinuria, elevated liver enzymes and hypertension. One developed platelet less than 150000. However, only one patient had PE based on the uterine artery pulsatility index, sFlt-1/PlGF ratio and LDH	PE like clinical features can develop with severe COVID-19. It can be distinguished from true by PE by sFlt-1/PlGF, LDH and UtAPI measurement
Braga et al[32], 2020	Case report	31, 31	1	Multiple pregnancy (dichorionic twins) with PE and partial HELLP syndrome. Moderate COVID-19 with HRCT showing ground-glassing. Underwent caesarean delivery for HELLP syndrome. One of the foetus died on day 16 due to intracranial hemorrhage. Both women and other foetus survived	There is a possible synergism between the pathophysiology of COVID-19 and PE/HELLP syndrome
Federici et al[33], 2020	Case report	33, 23.5	1	Multigravida, severe COVID-19 with ARDS requiring mechanical ventilation develop features of PE and HELLP syndrome. The serum sFlt-1/PlGF ratio was normal. Pregnancy continued and laboratory abnormalities resolved spontaneously with removal of mechanical ventilation after 10 d and discharge on day 19. Mother delivered spontaneously a live foetus at 33.4 wk	Severe COVID-19 can mimic PE and HELLP syndrome. Pregnancy can be continued in absence of complications with strict surveillance
Ahmed et al[34], 2020	Case report	26, 37	1	Family history of PE, atypical HELLP syndrome with acute kidney injury. Vaginal delivery with induction Postpartum day 3, developed abdominal hematoma requiring laparotomy and blood transfusions. Moderate respiratory symptoms with foetus and mother survived	Severe SARS-CoV-2 infection may be a risk factor for hypertensive disorders of pregnancy
Ronnje et al[35], 2020	Case report	26, 32.6	1	Underwent emergency caesarean. Both mother and foetus survived	Possible association of HELLP syndrome and COVID-19 was proposed
Coronado-Arroyo et al[36], 2021	Case series	Mean: 29 yr, gestation 31 wk	14 out of 20 patients with severe PE including 5 with HELLP syndrome	One out of 5 women was multipara. Two were asymptomatic and remaining had mild severity COVID-19. Four required caesarean delivery and two had still-birth. No maternal mortality	SARS-CoV-2 infection, can predisposes pregnant female to a greater severity of PE, irrespective of the severity of respiratory symptoms
Norooznezhad et al[37], 2021	Case report	24, 29	1	Primigravida, emergency caesarean for HELLP syndrome. Ostelmavir, lopinavir/ritonavir, chloroquine and 0.5 gm/d of methylprednisolone was used. Moderate respiratory symptoms. Both foetus and mother survived	Association between COVID-19 and HELLP syndrome cannot be concluded but deliver and methylprednisolone caused improvement in the condition
Farahani et al[38], 2021	Case report	28, 38	1	Multigravida, vaginal delivery for HELLP syndrome. Postpartum developed seizure, lopinavir/ritonavir and dexamethasone was used for treatment. Moderate respiratory symptoms. Both mother and foetus survived	COVID-19 in pregnant women can resemble PE and with possible CNS involvement
Aydın et al[39], 2021	Observational retrospective study	Case 1: 22, 31 Case 2: 25, 28	167 pregnant with COVID-19. 20 patients had PE and two (1.2%) had HELLP syndrome.	Case 1: Pregnancy with IVF. Need invasive mechanical ventilation, underwent caesarean delivery for HELLP syndrome and postpartum developed arterial thrombosis. Case 2: Vaginal delivery with preterm foetus. Both patients survived	No significant difference was observed in adverse pregnancy outcomes such as PE, preterm birth, and foetal growth restriction, gestational diabetes mellitus and HELLP syndrome according to the gestational age
Vaezi et al[40], 2021	Case series	36, 28	24 patients, 1 with HELLP syndrome	Delivery by caesarean section, performed for HELLP syndrome, preterm foetus admitted to NICU. Both mother and foetus survived	-
Jering et al[41], 2021	Retrospective cohort study		406 446 women hospitalized for childbirth. Among women with HELLP syndrome, 989 (0.2%) were without COVID-19 and 33 (0.5%) with COVID-19	Unadjusted and adjusted OR for HELLP syndrome with COVID-19 was 2.10 (95%CI- 1.48-2.97) and 1.96 (1.36-2.81), P < 0.001	In large US cohort of women admitted for childbirth during the pandemic, patients with COVID-19 had higher risk of in-hospital mortality, pre-eclampsia, VTE and HELLP syndrome
Bhardwaj et al[42], 2022	Case report	33, 36	1	Underwent caesarean delivery. Both mother and foetus survived	COVID-19 and HELLP overlap and associations are puzzling to clinicians
Conde-Agudelo et al[6], 2022	Meta-analysis of observational studies		28 studies, 790954 patients including One study for HELLP syndrome	SARS-CoV-2 infection during pregnancy was associated with significant increase in the odd ratio of PE (1.58, 95%CI- 1.39-1.8), severe PE (1.76, 95%CI 1.18-2.63), eclampsia (1.97, 95%CI 1.01-3.84) and HELLP syndrome (2.76, 95%CI 1.48-2.97)	SARS-CoV-2 infection during pregnancy is associated with significantly higher odds of PE
Madaan et al[43], 2022	Case series	Case 1: 32, 34 Case 2: 29, 37 Case 3: 26, 39	3	All three cases had HELLP syndrome and ground glassing opacities on HRCT with RT-PCR positive for SARS-COV-2. Case 1: Severe COVID-19, mother survived, baby still born by caesarean section. Case 2: Patient developed eclampsia and required mechanical ventilation, died on day -8, baby delivered vaginally Case 3: Patient survived and discharged day 15, baby delivered alive by caesarean section due to transverse lie	Authors proposed a synergism in the pathophysiology of COVID-19 and HELLP Syndrome. and combination of both can cause morbidity or mortality risk to fetus and the mother
Takahashi et al[44], 2022	Case report	27, 37	1	Underwent caesarean delivery for infection control measures. Postpartum HELLP syndrome. Both mother and foetus survived	Overlap of clinical features with COVID-19 and HELLP syndrome is plausible explanation
Guida et al[45], 2022	Nested case-control analysis	-	203 women with COVID-19, including 21 with PE and 2 HELLP syndrome	There was no difference in the rate of PE and HELLP syndrome in women with or without COVID-19. However, imminent eclampsia was more frequent complication and overall maternal perinatal outcomes were worse with patients with PE and COVID-19	Prevalence of PE among women with COVID-19 was around 10%. Chronic hypertension and obesity were more likely associated with PE. High caesarean rate and NICU admissions due to prematurity in women with COVID-19
Snelgrove et al[46], 2022	Retrospective cohort study	-	157779 patients during the pandemic compared to 563859 patients delivered between March 2015-september 2019 (historical group)	There was no difference in the rate of PE/HELLP (879, 0.6%) syndrome and severe maternal morbidity (SMM) between the pandemic and historical group (3119, 0.6%). No difference between primiparous and multiparous on severe maternal morbidity and risk of PE/HELLP syndrome. Maternal age, rurality, preexisting comorbidities and use of artificial reproduction therapy were associated with increased risk of PE/HELLP syndrome	Changes in obstetrical care during the pandemic have not increased the risk the PE/HELLP syndrome and adverse maternal outcomes
Arslan[47], 2022	Case report	30, 32	1	Mutigravida pregnancy, emergency Caeserian delivery. Foetus tested positive for SARS-CoV-2 and died 5 d after delivery. Mother had severe COVID-19, required invasive mechanical ventilation and died, 10 d after delivery	Severe COVID-19 as etiological causation of HELLP syndrome is presumptive

COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; HELLP: Hemolysis, elevated liver enzymes, low platelet count; PE: Pre-eclampsia; LDH: Lactate dehydrogenase; HRCT: High-resolution computed tomography; OR: Odds ratio; CI: Confidence intervals; ARDS: Acute respiratory distress syndrome; NICU: Neonatal intensive care unit; IVF: In vitro fertilization.