Rheumatologists warn that the EMA’s proposed leaflet edits on hydroxychloroquine in pregnancy may scare patients into stopping the medication.
The European Medicines Agency’s proposed update on hydroxychloroquine in pregnancy might cause harm to patients and their babies, rheumatologists have warned.
The EMA has recommended that the product summary and package leaflet advice around using hydroxychloroquine during periconception and pregnancy be updated, removing references to observational studies and meta-analyses and adding data from a study that found a small increased risk of congenital malformations with high-dose hydroxychloroquine during pregnancy.
The patient leaflet would say that “[hydroxychloroquine] may be associated with a small increased risk of major malformations and should not be used during pregnancy unless your doctor considers the benefits outweigh the risks”.
It would also add that hydroxychloroquine should not be used during breastfeeding unless the patient’s doctor believes the benefits outweigh the risks.
But an international group of rheumatologists said the EMA’s recommended changes should include “a more scientifically accurate statement”.
“Our unease relates to the update of the background section and the amendment of the patient leaflet, which now states there is a small increased risk of major malformations as outlined,” they wrote in The Lancet Rheumatology.
“We are concerned that this update might cause direct and indirect harm to patients and their babies.”
They said the study showed an overall significant risk of malformations in children exposed to hydroxychloroquine (RR 1·26), but said that significance was lost (RR 0·95) for patients treated with doses lower than 400mg per day.
“Importantly, no comparison was made between hydroxychloroquine exposure at usual rheumatology dosing of up to 400mg per day and atypical dosing of more than 400mg per day.”
They said the update might cause direct harm to patients who would benefit from the drug’s immunomodulation effects during pregnancy “if the absence of complete published evidence in the summary” led doctors to be more hesitant in prescribing the drug and patients less willing to take it.
Pharmacists might also advise women to stop hydroxychloroquine treatment, they said.
“Stopping hydroxychloroquine might lead to worsening of symptoms or disease flares, and active inflammatory disease has been widely associated with pregnancy complications such as miscarriage, intrauterine death, placental insufficiency, fetal growth restriction, pre-eclampsia, and preterm birth.”
They added that patients might also face indirect harm through emotional distress or anxiety about potential negative effects to their unborn child, while being unaware of the risk of poorly controlled disease if they stopped taking hydroxychloroquine.
The authors said they had three main concerns: that previous evidence, including observational data and a meta-analysis, had been replaced with a single study; that the data from this study showing a small increase in risk of malformations at doses of 400mg per day or higher did not show a consistent pattern of malformations and were based on very small numbers; and that the removal of all previous data from the background section without including more recent data gave a biased presentation of existing information.
They said for women who needed hydroxychloroquine doses higher than 400mg per day, “physician–patient shared decision making would probably conclude that the need for keeping maternal disease under control likely outweighs a possible slight increase in the risk of malformations”.
“However, each case should be individually managed as maternal disease can be different and risk perception might widely vary across people,” they said.
They suggested that the summary could say that the offspring of mothers exposed to hydroxychloroquine during pregnancy could have a slightly higher risk of birth defects, but that risk was not associated with the duration of exposure, not found for doses of hydroxychloroquine lower than 400mg per day, and no specific pattern of malformations had been identified.
In a Q and A section, the authors also suggested ways of communicating the risks of hydroxychloroquine to patients.
The rheumatologists were inspired to make the global statement when they gathered at the inaugural meeting of the EULAR study group for Reproductive Health and Family Planning in Milan earlier this year.
“In times of unmonitored and unverified sources of information, such as social media and artificial intelligence tools, we believe that regulators and other public domains have an increasingly important role and responsibility to show complete, accurate, and balanced information about the safety, risk, and benefit of medication use in pregnancy,” they wrote.
The British Society of Rheumatology guideline working group also raised concerns about the EMA’s recommendation, writing in a letter in Rheumatology in July that the safety alert did not change the society’s 2022 pregnancy recommendations and called for “more supportive wording”.
“Safety alerts on medication use in pregnancy have far-reaching consequences on prescribing of drugs used by rheumatologists,” they said.
The working group said they were concerned that the EMA’s statement emphasising a possible small risk of harm over established benefit “may encourage healthcare professionals and patients to stop HCQ in pregnancy and risk disease relapse to the detriment of mother and fetus”.
“A more supportive wording would acknowledge the potential for a small increased risk of major congenital malformations at doses higher than those normally used in rheumatological conditions and state ‘the benefits and risks of HCQ during pregnancy should be considered with your specialist before conception’.
“It would therefore encourage consultations with specialists to balance the benefits of HCQ to prevent maternal disease flare and harm to the baby that may occur if this drug is stopped in pregnancy against potential small risks of congenital malformations at high dose.”
The authors cited the Medicines and Healthcare products Regulatory Agency’s warnings about using ondansetron in the first trimester as an example of the consequences of safety alerts.
They said those warnings were based on findings that showed a small but statistically significant increase in risk, with the absolute increased risk of oral clefts from ondansetron being three extra cases per 10,000 women treated.
“Consequently, healthcare professionals and patients were deterred from use of this drug in pregnancy.
“As the substantial suffering from hyperemesis gravidarum not infrequently results in termination of pregnancy, expert opinion remains that ondansetron is an effective low-risk treatment of this condition that should be an option to the informed pregnant woman.”