June 3, 2020

Preeclampsia‐like syndrome may be induced by severe COVID‐19

Pregnant women with severe coronavirus disease 2019 (COVID-19) can develop a preeclampsia (PE)‐like syndrome that might be differentiated from actual PE by assessment of angiogenic factors (sFlt-1/PlGF ratio), lactate dehydrogenase (LDH) and uterine artery pulsatility index (UtAPI), according to findings published in BJOG: An International Journal of Obstetrics & Gynaecology. "This knowledge could improve management and reduce misdiagnosis in pregnancies with severe COVID-19," wrote Manel Mendoza, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain, and colleagues.

The authors noted that an increased incidence of PE has been reported among mothers infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared to the general population. However, they say misdiagnoses might have occurred in some cases since COVID-19 and PE have overlapping clinical features, making differential diagnosis challenging in COVID-19 pregnant women presenting with hypertension and proteinuria, thrombocytopenia, or elevated liver enzymes.

The prospective observational study recruited 42 consecutive pregnant women, who had a median gestational age of 32 (IQR 26.0-37.5) weeks. They presented to the emergency department of a tertiary care center for suspected COVID-19 and had laboratory-confirmed SARS-CoV-2 infection, between March 13 and April 10, 2020. Patients were classified as severe and non-severe COVID-19 depending on whether they had severe pneumonia. Recorded data included platelet count, LDH and liver enzyme, among other measures. In women with suspected PE, researchers assessed UtAPI and sFlt‐1/PlGF.

Eight (19.0%) cases developed severe pneumonia and required admission to the intensive care unit. The authors noted that the median maternal age of cases with severe COVID-19 was significantly greater than in the non-severe cases (39.4 [34.2-44.5] vs. 30.9 [25.0-41.8], p=0.006), although no other pregnancy baseline characteristics differed between severity groups.

Six (14.3%) women in the total cohort presented signs and symptoms of PE, with all six being among the severe COVID-19 cases (75.0%). Signs and symptoms included new-onset hypertension and proteinuria and/or thrombocytopenia and/or elevated liver enzymes, with antihypertensive drugs required in all these cases. No instances with diagnostic criteria for PE were found among the 34 non-severe COVID-19 women.

The authors noted that before severe pneumonia, all eight women were normotensive, had normal platelet counts, liver enzymes, LDH and proteinuria, while only one case of UtAPI above the 95th centile was identified. During severe pneumonia, the most frequent findings were elevated liver enzymes to twice normal concentrations (87.5%), proteinuria >300mg/g (75.0%) and hypertension (62.5%).

Cesarean delivery was performed during the ICU stay in four women, with HELLP syndrome, frequently considered a variant of PE, being the indication for delivery in one case, and SARS worsening was attributed in the other three.

After recovery from severe pneumonia, hypertensive therapy was no longer required in all cases and only one woman who had presented with sFlt-1/PlGF >110, LDH >600 and UtAPI above the 95th centile remained with PE diagnostic criteria.

The authors noted among the six cases that had diagnostic criteria for PE/HELLP syndrome, "abnormal angiogenic status, increased LDH and placental underperfusion could only be confirmed in one of them, which indicates that this case was probably an actual PE. These findings suggest that the signs and symptoms compatible with PE/HELLP present in five out of these six cases, could be derived from the complex polypharmacy administrated or from the renal and cardiovascular dysfunction for severe SARS-CoV-2 infection."

They added that "only two of these six cases remained pregnant after severe pneumonia recovery, and then all PE/HELLP features recovered spontaneously. PE and HELLP syndrome do not resolve spontaneously and delivery is the only definitive cure. For these reasons, we believe that the five women with PE/HELLP signs and symptoms, and normal sFlt-1/PlGF, UtAPI and LDH <600, had developed a PE-like syndrome."

The authors explained that "identification of an sFlt-1/PlGF imbalance is detectable in the maternal circulation at least five weeks before the onset of clinical PE. Thus, COVID-19 patients with normal early phase of placental implantation should have normal values of sFlt-1/PlGF and UtAPI in spite of proteinuria, thrombocytopenia, elevated liver enzymes, or hypertension. This hypothesis, however, had not been previously investigated due to the very recent outbreak of the SARS-CoV-2 infection."

The authors pointed to the small size of the study as a reason for considering the results with caution. They also noted that while UtAPI and sFlt-1/PlGF ratio have a high negative predictive value to predict the short-term absence of PE, they are not diagnostic criteria for the condition, and so "we cannot categorically state that the case with PE features and elevated UtAPI and sFlt-1/PlGF was an actual PE and not a PE-like syndrome."

SOURCE: BJOG: An International Journal of Obstetrics & Gynaecology