COMMENTARY

Managing Rheumatic Conditions in Pregnancy

Kevin D. Deane, MD

Disclosures

March 02, 2018

Two articles published in February 2018 provide interesting information regarding treatments and outcomes during pregnancy in women with autoimmune diseases.

In the first article, as part of a UCB Pharma-funded postmarketing pharmacokinetic study, investigators studied pregnant women at ≥ 30 weeks of pregnancy in France, Switzerland, the Netherlands, and the United States.[1] These women were receiving the anti-tumor necrosis factor (TNF) alpha agent certolizumab for clinical care for a variety of diseases, including rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, and Crohn disease. Women with pregnancy-related abnormalities on ultrasound or laboratory testing, chronic or acute placental insufficiency, or prior use of other anti-TNF agents that had strong risk for teratogenicity were excluded.

Twenty-one women were using certolizumab for clinical care and were initially screened, but only 16 participated in the analyses of certolizumab levels. Of the 21 women, one was excluded because of placental insufficiency and premature delivery and four were ineligible for other reasons. In the final set of 16 mothers, 15 were taking certolizumab 200 mg every 2 weeks, and one was taking certolizumab 400 mg every 4 weeks.

The authors studied certolizumab levels in the 16 mothers within 24 hours of delivery. Infant cord blood was collected within 1 hour of delivery, and infant blood samples were collected within 24 hours of birth and at postpartum weeks 4 and 8. Certolizumab levels in each sample were evaluated.

The women all had detectable plasma levels of certolizumab. The authors excluded results for two infants: One had missing data at birth, and the other had very high plasma certolizumab levels at birth yet undetectable levels at weeks 4 and 8. The authors deemed this finding for the latter infant implausible, so the results were excluded.

In the 14 remaining infants, 13 had no quantifiable certolizumab levels at birth and one had "minimal" levels. Nine mothers breastfed their infants and also continued certolizumab; none of their infants had quantifiable certolizumab levels. In addition, no anticertolizumab antibodies were detected in the mothers or infants at any time point.

In terms of pregnancy/infant outcomes, among the overall 21 mothers, 15 (∿71%) had at least one adverse event. Most adverse events among the mothers were mild to moderate, although they included arrested and prolonged labor, a premature infant, and a perineal abscess. Among the infants, hypoglycemia, infection and macrosomia were reported.

The authors concluded that there was no to minimal placental transfer of certolizumab to infants in this latter period of pregnancy.

In the second study,[2] two nationwide Norwegian medical registries were used to evaluate pregnancy outcomes in individuals with systemic lupus erythematosus (SLE). From 2006 to 2015, 180 women with SLE who had singleton births were evaluated and compared with singleton births in ∿500,000 controls. SLE activity was assessed during pregnancy using the Lupus Activity Index in Pregnancy (LAI-P).

Overall, the authors found that SLE (active or inactive, per the LAI-P) was associated with lower birthweights and higher rates of preterm births compared with population controls, although the rate of premature births was highest in patients with active SLE. Preeclampsia was more common in patients with active SLE compared with patients with inactive disease or population controls. Among the patients with SLE, use of prednisolone was associated with significantly lower birthweights and risk for preterm birth.

The authors concluded that the risks for low birthweight and preterm birth, especially in patients with active SLE, warrant targeting inactive disease before and throughout pregnancy.

The Take-Home Message

It is becoming clear that for most if not all rheumatic/autoimmune diseases, improved disease control leads to improved long-term disease outcomes. Furthermore, as the therapeutic armamentarium increases, the field is finding it somewhat easier to obtain good disease control for many patients—although given that disease remission rates across a variety of rheumatic/autoimmune diseases are still quite low, the field still has a long way to go.

In addition to knowing that high disease activity is not good for patients and their organs, several studies have already shown that high disease activity leads to adverse outcomes in pregnancy to mothers and infants across a range of rheumatic diseases.[3] The study discussed above by Skorpen and colleagues[2] extends our understanding that disease control matters in SLE, and specifically related to pregnancy-related outcomes. However, it also demonstrated that use of prednisolone may be associated with worse pregnancy-related outcomes.

This latter finding gets to the crux of a major problem with management of rheumatic diseases in and around pregnancy (including lactation): Well-controlled disease may be associated with improved outcomes, but our currently available management strategies may present risks to the mother and baby. Or, at the very least, most agents have not been conclusively demonstrated in well-designed human studies to be safe and effective during pregnancy and lactation. This is especially important issue because although there is a general belief that some diseases, such as RA, may spontaneously improve and not need drug therapy during pregnancy, studies have shown that some drugs are needed to control disease for most women with RA throughout pregnancy, and risk for flare in the postpartum period is high.[3,4] As such, we need to know how optimally to manage these patients.

Unfortunately, because of a lack of controlled trials, clinicians are challenged on how to optimally manage patients with rheumatic/autoimmune diseases in and around pregnancy, as well as in managing male fertility.[4] This is especially true because many of the first-line drugs for a variety of rheumatic/autoimmune diseases are relatively contraindicated in pregnancy/breastfeeding. For example, mycophenolate is considered by many to be first-line therapy for lupus, but it has a US Food and Drug Administration (FDA) category of X (contraindicated in pregnancy).

In addition, information to guide risk/benefit discussions with patients is often very limited. In the United States, a further twist in the realm of understanding the impact of disease-modifying therapy in pregnancy as well as communicating the risks and benefits to patients is that there have been changes in the labeling of drugs regarding pregnancy and lactation, with the FDA changing the classic letter grades (A, B, C, and X) for some drugs in 2015 and replacing these with descriptive terms about the risks.[5]

Of some help in the arena of safety of disease-modifying agents during pregnancy, the small study by Mariette and colleagues[1] shows that the anti-TNF alpha agent certolizumab may not cross to the fetus during the third trimester or to the infant during breastfeeding. This makes some sense, given the structure of the certolizumab molecule that lacks a fragment crystalizable (Fc) portion and thus is not expected to be transported to the fetus across the placenta, at least using mechanisms of antibody transfer that utilize Fc receptor transport.[6] However, some limitations of this study are that it included a small number of women and infants who were highly selected. In addition, this study was performed in the third trimester and postdelivery, and further studies are needed to understand the transfer of drug from mother to fetus across the entire spectrum of pregnancy.

The studies by Mariette and colleagues[1] and Skorpen and colleagues[2] are to be applauded for adding to our understanding of the impact of rheumatic/autoimmune diseases in pregnancy and of the specific agent certolizumab during pregnancy and lactation/breastfeeding.

Although these studies have shed some light on these complex areas, more needs to be done. In particular, transfer of drug to the fetus and infant is only one aspect of the safety of drugs in pregnancy. Maternal effects are also important, including effects of drugs on the "normal" physiology of delivery. As such, additional controls are needed to evaluate the impact of disease-modifying therapies, including anti-TNF alpha agents, on maternal health during pregnancy, and the normal process of delivery.

Because controlled studies are incredibly difficult to perform in pregnancy, observational studies will be of great help. Healthcare providers participate in these by referring their patients to registries so that we can all benefit. In particular, several organizations, including the Centers for Disease Control and Prevention and the Organization of Teratology Information Specialists and its information/research service, MotherToBaby,[7] are working to improve and educate about the risks of medications during pregnancy and lactation/breast feeding. More information about registries can be found through the FDA here.

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