The following is a collection of my top 10 takeaways from the ACR Reproductive Health Summit.
1. Introduction. Speakers reviewed the scope of the issue. Of the 6 million pregnancies that will occur in the USA each year, nearly half are unintended and unplanned. It is estimated that nearly 15% of pregnant women will have significant comorbid conditoins (arthritis, depression, asthma, diabetes, etc), hence its not surprising that 90% of pregnant women will take at least one medication and an estimated 50% will take 3 or 4 medications during pregnancy. Better information on drug and disease management during is sorely needed.
2. The FDA has made considerable efforts in the last decade to issue guidance documents for the study of drug exposures, pharmacokinetics during pregnancy, lactation studies and pregnancy registries. Since 2007 the FDA has asked companies to study the consequences of drug exposure in their post-marketing efforts. Currently there are postmarketing committments by the manufacturers of leflunomide, tocilizumab, TNF inhibitors, abatacept, rituximab, tofacitinib,and others. OTIS is highly regarded for its ability to gather comprehenxive data on drug exposed pregnancies, But there are considerable challenges for Pharma, OTIS and the FDA in recruiting enough patients to study the effects of drug exposures during pregnancy.
3. New Pregnancy and Lactation rule. The FDA is concerned that the old A-X Pregnancy categories are too simplistic and do not adequately portray risks. The FDA has proposed a new Pregnancy and Lactation Labeling Rule (PLLR) that went into effect on 12/14/14. The new rule replaces the A, B, C, D, X categories with narrative descriptions on drug risk summary with detailed data from studies, postmarketing reports and detailed info on breast feeding, breast milk drug levels, infant effects, pregnancy testing, contraceptoin and infertility. Many of the clinicians at the meeting voiced concern about replacing the simplicity of the category system with the complexity of these narratives.
4. Disease activity and untreated disease may be more hazardous to the mother and fetus than the unclear risks tied to the use of a class B or C drug during conception or pregnancy. However a flare of disease activity is; and compromises both maternal health and possibly infant outcomes.
5. Pregnancy is not an adverse event. Although this was not discussed in detail, some discussion centered around the difficulty of acquiring outcome data on women exposed to certain drugs. Hence, a woman who becomes pregnant during a clinical trial is automatically removed from that trial as an "adverse event". Moreover, many studies do not require complete follow up of that patient and pregnancy once they are dropped from the trial. What better way to get outcome data from women exposed in a clinical trial. Pregnancy is priviledged state and population, not an adverse event.
6. Mycophenolate is a No-No. Dr. Gideon Koran reviewed his career and experience in forming and managing motherrisk.org. A Canadian organization devoted to informing mothers and physicians about the effects of drug exposure. He reviewed the data on current teratogens - stating there are only 30 known teratogens. He highlighted the labeling change for mycophenolate mofetil as a clear teratogen. Although listed as Categor X drugs - the evidence that methotrexate and leflunomide will increase the odds of fetal malformations is really lacking if one looks at the clinical evidence available. Nevertheless, these should be avoided in women planning to become pregnant.
7. Women in Clinical Trials. Martha Nolan from the Society for Womens Health Research reviewed the history behind regulations affecting women in research. In 1977 the FDA prohibited women from participation in drug development randomized clinical trials - largely over concerns about the risk of fetal exposure to new medicines. This staye in effect until 1993 when the SWHR lobbied for the NIH Health Revitalization Act and FDA Guidelines change calling for the inclusion of women in RCTs. This wasn't fully accepted until 2001 when the Institute of Medicine issued a report entitled, "Does Sex Matter". Given the fact that 1/12 women and 1/20 men will develop an autoimmune disorder, the inclusion of women in research was clearly needed. More effort are needed to change regulatory, IRB and liability issues regarding women receiving experimental or conventional medicines.
8. Lactation. Dr. Lisa Sammaritano reviewed the benefits of breast-feeding and the concerns regarding drug use while breast-feeding. The American Academy of Pediatrics issues an annual report on drug use in breast feeding that dispells the concerns as being unfounded for most medicines - including biologics. Most agree that if breast feeding it would wise to AVOID methotrexate, mycophenolate, leflunomide, cytotoxics as these can be found in breast milk. These high risk drugs have NO data, just theoretical risks. There appears to be low risk when breast-feeding with Plaquenil, Prednisone, Azulfidine, heparin, warfarin, NSAIDs (avoid long acting NSAIDs).
9. GI knows better. Dr. Uma Mahadevan reviewed the impressive experience from IBD patients who are young and frequently become pregnant. But unlike RA, these patients do not improve or remit and often have active disease during the pregnancy. She reviewed the 1289 patient prospective PIANO study wherein the offspring outcomes of mothers exposed to a) no drug; b) thiopurines (6MP, AZA); c) TNF inhibitors; or d) TNF inhibitors + thiopurines. Basically there were no significant differences in most outcomes between exposed and unexposed mothers. Interestingly, ulcerative colitis is more difficult to manage during pregnancy as they have more flares and adverse outcomes.Ulcerative colitis patients also have more adverse pregnancy outcomes than Crohns patients. It is unknown if this is related to biologic or drug use differences.
10. Communication Problems. The most disappointing fact is that physicians who care for pregnant women with arthritis and autoimmune don't communicate or communicate well or at all. The ACR summit did have several OB's from Maternal Fetal health, but our messages are not likely to reach or affect their current practices. As a result of this summit, the ACR seems committed to developing multidisciplinary guidelines in the future. Such guidelines will be critical to who physicians will counsel and communicate with their patients before, during and after pregnancy.