Biologic therapy for atopic disease appears safe during pregnancy, more research needed
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Key takeaways:
- Women who become pregnant while using biologics for atopic diseases did not appear to experience any increased risks for adverse outcomes if they continue their treatment.
- The lack of published human data on the use of reslizumab, tezepelumab and tralokinumab prohibited the ability to draw any firm conclusions about risks associated with their use.
- According to the authors, future studies should be prospective and include comparable women who have similar disease severity without exposure to biologics to serve as controls.
The use of biologics to treat atopic disease before and during pregnancy does not seem to negatively affect maternal or fetal outcomes, according to a review published in The Journal of Allergy and Clinical Immunology: In Practice.
However, more studies are necessary to confirm these findings, Fnu Shakuntulla, MD, and Sergio E. Chiarella, MD, allergists and immunologists with the division of allergic diseases at Mayo Clinic in Rochester, Minnesota, wrote in the review.
The authors reviewed two cohort studies and 23 case reports or series involving 313 exposures to biologics before or at conception or during pregnancy. Indications for biologics included asthma, chronic urticaria, atopic dermatitis, eosinophilic granulomatosis polyangiitis, hypereosinophilic syndrome and pemphigoid gestationis.
The use of omalizumab
Current recommendations suggest that omalizumab (Xolair; Genentech, Novartis) should not be initiated during pregnancy, but it could be continued if a woman becomes pregnant while receiving it if its benefits are expected to outweigh its harms.
hough there are no published randomized controlled trials (RCTs) involving omalizumab use during pregnancy, bservational tudy during regnancy in 230 women with asthma exposed to before or during pregnancy between 2006 and 2018.
According to its results, there was an increase in low birth weight among women treated with omalizumab for asthma. Rates of congenital anomalies, live births, stillbirths and preterm deliveries, however, were comparable to other populations.
Also, EXPECT included 30 women with chronic idiopathic urticaria treated with omalizumab at least during their first trimester. These women had a 3% spontaneous abortion rate, a 13% premature birth rate and a 7% congenital anomaly rate, which the authors called comparable to patients with asthma in the study.
Another case study of 20 women with asthma exposed to omalizumab before or during pregnancy included three infants with low birth weight and five born prematurely. None of the infants had congenital deformities, but seven developed atopic diseases.
In five other case reports involving six women with severe asthma and omalizumab therapy, all pregnancies led to live births with no congenital deformities. Two births were premature and one had low birth weight, though the authors called these findings unsurprising considering the severity of asthma among these patients.
Six reports and one case series described 12 pregnant women using omalizumab for chronic refractory urticaria during their first trimester. All 14 pregnancies in these studies progressed normally to live, full-term births with normal weights and no congenital abnormalities.
Dupilumab during pregnancy
The authors did not find any published RCTs pertaining to pregnancy and dupilumab (Dupixent, Sanofi Genzyme/Regeneron) exposure, though an enhanced prenatal and postnatal study found no adverse developmental effects in the offspring of pregnant monkeys treated with 10 times the maximum recommended human dose.
Also, seven case reports identified six women with atopic dermatitis and one woman with pemphigoid gestationis who used dupilumab during pregnancy. Each pregnancy resulted in a live birth, with one premature birth and another with low birth weight. Meanwhile, a separate case series found that paternal use did not impact fertility or fetal outcomes.
Other biologics
Similarly, the authors did not find any published RCTs studying the use of mepolizumab (Nucala, GSK), benralizumab (Fasenra, AstraZeneca) or reslizumab (Cinqair, Teva Respiratory), nor did they find any published human data on tezepelumab (Tezspire, Amgen/AstraZeneca) or tralokinumab (Adbry, LEO Pharma), during pregnancy.
However, one case study reported on two women with severe asthma who conceived after two doses of mepolizumab. One of these women terminated her pregnancy due to the unknown effects of the drug on the pregnancy. The other woman paused her therapy and delivered a healthy, full-term child without congenital abnormalities.
In another case report, a woman using benralizumab for hypereosinophilic syndrome and severe eosinophilic gastrointestinal involvement delivered a healthy girl with normal at 38 weeks. The infant then had undetectable eosinophil counts for 7 months and normal growth and development with no sick visits or atopic disorders at year.
An additional case report described a woman with severe eosinophilic asthma who discontinued her benralizumab treatment after conception. But when severe exacerbations occurred, she resumed therapy at 20 weeks’ gestation. She experienced improvements in asthma control, eosinophilia and lower extremity edema. Fetal complications were limited, the researchers said, though no other information was provided.
With no published data on its use during human pregnancies, the review authors called the potential risks on maternal and fetal outcomes with reslizumab unknown. Experiments on pregnant mice and rabbits, however, at exposures exceeding maximum recommended human doses produced no embryo-fetal developmental effects.
A study on cynomolgus monkeys found placental transport of tezepelumab following IV administration during pregnancy but no evidence of fetal harm. Another enhanced developmental study of IV administration of tralokinumab in pregnant monkeys did not find any adverse developmental effects in their offspring either.
Conclusions
These findings support recommendations that women using biologics can continue to do so safely during pregnancy, the researchers wrote, though they cautioned that the data on most of these medications was too insufficient to draw firm conclusions about their risks.
Also, the researchers noted that these women took biologics to address severe disease activity, which may have influenced pregnancy outcomes. Determining whether maternal or fetal abnormalities are caused by the disease or the biologic is difficult.
Unfortunate outcomes such as the woman who terminated her pregnancy and the others who paused their biologic therapy suggest a strong need for future research, the researchers continued.
Prospective studies should include comparable control groups that have not been exposed to biologics, the researchers suggested. Also, they added, specialists should publish cases and enroll qualifying patients they may treat in the appropriate registries.
Perspective
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This paper offers an excellent review of this ever-expanding area of medical care. Of necessity, the authors review many case reports of several different biologics used in this space.
Women who are treated with biologics are women with more severe atopic diseases, and they may be treated with other medications as well. Many of these women have severe asthma and are women whom older practitioners saw treated with high doses of steroids.
The data is basically reassuring, showing no major poor outcomes that could be related to these therapies. The authors point out that they would like to see some cohort types of studies of women with similar disease severity but without medication exposures as a control group. These studies would be difficult to carry out.
Papers like this reinforce the American College of Obstetricians and Gynecologists’ recommendation that women with medical comorbidities receive counseling before conception. As obstetricians, we work with our patients’ medical providers to optimize their prepregnancy medical conditions and medications.
We know that almost half of pregnancies in the U.S. are unplanned, so we also need to provide appropriate contraception to these women until they are in an optimal state for a potentially complex pregnancy.
Finally, the authors appropriately recommend follow-up studies on the infants delivered to assess the effects of biologics on the neonatal and subsequent immune systems.
Perspective
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The findings of this well written report are not surprising, as biologics commonly used in allergy and immunology are felt to be safe in pregnancy. But nevertheless, the report highlights the paucity of information on this topic and the need for rigorous scientific research on it.
Also, this report mirrors my own experience. I have continued biologic therapy in women who have become pregnant while on these medications, and they have experienced no complications and delivered healthy babies. In rare instances, I have also initiated therapy with a biologic during pregnancy because the risk of the underlying disease and concurrent dependence on systemic steroids was felt to be far greater than any potential risk of the biologic. These decisions should be made in conjunction with consultation with high-risk maternal fetal medicine.
Although this report is reassuring, a primary takeaway point is that doctors must enroll their patients on biologics into patient registries, since this is the most practical way to collect this data over time.
The discussion regarding risks and benefits for biologics during pregnancy will be an individual decision, with the clinician detailing these risks and benefits while the patient decides based on this information in the context of their disease and personal preferences.
Continued enrollment of women who are pregnant and on biologics into registries is the most practical way to collect helpful data going forward. Case reports and small case series can also be helpful, although they have notable limitations.Collapse
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