Treat to Target: Rheumatoid Arthritis in Pregnant Patients

“Treat to target” has become one of the most important buzz phrases in rheumatology today, particularly for rheumatoid arthritis (RA). The treat-to-target movement was based, at least in part, on data supporting tight control of other chronic diseases such as diabetes mellitus (DM) and hypertension (HTN) on improved long-term outcomes with reduction in end-organ damage. Indeed, one of the 10 recommendations for treat to target states, “The desired treatment target should be maintained throughout the remaining course of the disease.”¹ Unfortunately, this goal does not always seem to apply to a growing population of RA patients—women who are or desire to become pregnant. It is precisely because of the introduction of successful treatment options for RA and the growing potential for remission that many women of childbearing age now feel healthy enough to consider childbearing and childrearing. However, there remains a reluctance to control disease activity during pregnancy for fear of adverse effects of drug exposure on the fetus. It is likely that, as rheumatologists trained in the prebiologic era, we have had relatively little experience with treating pregnant women in the past, and therefore have some discomfort with this topic.

What the Current Data Show

For many decades, data on RA disease activity during pregnancy supported the notion that the great majority of patients experienced improvement or even remission of active disease during pregnancy, with improvements noted early in gestation and continuing through delivery.² There was little corresponding study of the effects of RA upon pregnancy outcome. However, more recent data have cast some doubt on the magnitude of disease quiescence during pregnancy and the notion that fetal outcomes are unrelated to maternal disease activity. Prospective observational studies performed within the last decade using standardized measures of disease activities have begun to quantify the extent of disease burden during pregnancy. These have shown, in general, that there continues to be a good proportion of RA patients who experience improvements in disease activity during pregnancy.

However, in contrast to earlier reports, these data demonstrate that fewer than half of patients with moderate disease at conception experience a moderate or good response according to European League Against Rheumatism criteria by the third trimester, leaving the remaining women with a Disease Assessment Score–28 of >3.2 (intermediate and severe disease activity) during pregnancy.³ In the nonpregnant patient, this would be considered a failure. One could argue that pregnancy is an exception to the treat-to-target goals for two reasons: 1) this is a short period of time in a woman’s lifetime of RA; and 2) past data suggested no adverse pregnancy outcomes, therefore the risks of active disease to the fetus are too low to consider potential teratogenic risk of medication exposure.

Certainly, a full-term pregnancy is only 40 weeks long, which is a relatively short period in a lifetime of RA. Medications are often withdrawn in anticipation of a pregnancy months before conception and are not restarted until after the completion of breastfeeding. Considering that many women desire more than one child, and newer data suggest that women with RA have increased difficulties conceiving, the total “active reproductive” period of time for a given woman is likely several years at least.⁴ Prospective observational studies and clinical trial data clearly demonstrate that active disease is associated with progression of erosions even within 12 months.⁵ Therefore, over a woman’s reproductive life, periodic undertreated disease during preconception, conception, and pregnancy may result in increased morbidity and damage accrual. Many self-sacrificing mothers may argue that the increased maternal disease burden is worth subsequent protection of the unborn child from medication exposure.

Newer data have shown that active maternal disease, in addition to conferring risks to the mother, is associated with adverse fetal outcomes. Within the past decade, several cohorts of RA patients during pregnancy have confirmed that RA alone is associated with increased rates of adverse fetal outcomes, including small for gestational age infants, intrauterine growth restriction, and premature delivery.⁶ Indeed, prospective studies have associated risks of these pregnancy complications to increased disease activity during pregnancy.⁷ Although the magnitude of small and premature infants is not overtly distressing, even late prematurity (35–37 weeks gestational age) is associated with short- and long-term risks of developmental and physical morbidity.⁸ Therefore, undertreating women with active RA during pregnancy may not only have consequences for the mother, but for her unborn child as well, thus changing the risk–benefit balance for medication use.

In general, physicians are often reluctant to prescribe medications to pregnant patients for fear of directly causing harm (by means of teratogenicity) to the exposed fetus. Complications such as premature delivery due to active disease are harder to implicate directly. Unfortunately, many physicians still carry misconceptions regarding associations between medication exposure and congenital malformations. As much as we all search for something to blame when a tragic congenital anomaly is discovered, the majority have no identifiable cause. When combining both major and minor congenital malformations, the rate in the general obstetric population has been consistently between 3% and 5% of pregnancies, the majority of which are likely genetic in nature. Only a small proportion of birth defects are a direct result of prenatal exposure, and even fewer from medications.⁹ Up to 65% of birth defects have no identifiable cause. Given that most women consume at least one prescribed or over-the-counter medication during pregnancy, it may be easy to attribute the cause of otherwise idiopathic anomalies to medication exposure. Therefore, a single published case report of a birth defect in an exposed infant, irrespective of the strength of the association, may lead physicians to refuse to prescribe that particular medication to women who are or may become pregnant. Although caution in prescribing to pregnant women is always warranted, practices unfortunately do not necessarily change with follow-up data of safety of exposure. There are ample data to suggest that physicians and other healthcare providers commonly overestimate teratogenic risk of medications, often in spite of data suggesting relative safety.¹⁰

Managing Meds Easier Now

The increasing array of available medications approved for the treatment of RA should make the task of treating RA during pregnancy easier. In decades past, when methotrexate was among the strongest disease-modifying antirheumatic drug available, there were few other safe and effective choices for the pregnant patient. With the advent of tumor necrosis factor (TNF) inhibitors and other biologic therapeutics, the arsenal of treatment options has expanded. Of course, whenever a new medication is introduced onto the market, risks of teratogenicity are largely unknown. The TNF story is an excellent example. So far, all TNF antagonists have received U.S. Food and Drug Administration (FDA) category B labels upon licensing: “No evidence of risk in humans. Animal studies have revealed no evidence of harm to the fetus. However, there are no adequate and well-controlled studies in pregnant women.”¹¹ Unfortunately, within the early years of TNF antagonist use, a report was published describing possible associations with a pattern of congenital anomalies (VACTERL syndrome) with in utero TNF antagonist exposure.¹² This report has been widely criticized due to very loose associations of reported anomalies with the VACTERL syndrome, lack of denominator of exposed pregnancies, lack of data regarding timing of exposure, and lack of controlling for concomitant medication exposure; increasing case series and registries in both the rheumatology and inflammatory bowel disease literature have not shown similar findings of increased teratogenic risk.^2,13,14 In addition, very little, if any, immunoglobulin G1 antibodies cross the placenta prior to 16 weeks gestation because placental-derived active transport mechanisms are not yet developed. Because there is a window during the preconception period through the first trimester of pregnancy, TNF inhibitors may be reasonable options to control disease until pregnancy is discovered, followed by discontinuation in the cases where women achieve remission or low disease activity in the first half of pregnancy. These agents can safely be restarted early after delivery, as little active drug is excreted into breast milk.¹⁴

Lessons Learned from Other Chronic Diseases

Just as the treat-to-target concept in RA evolved within the context of promising results following tight control of other chronic diseases, including DM and HTN, lessons learned from the management of DM and HTN during pregnancy may help inform risk/benefit considerations when treating women with active RA during pregnancy. Similar to RA, chronic HTN during pregnancy poses increased risk of adverse pregnancy outcomes, including premature delivery, preeclampsia, and intrauterine growth restriction; pregnancy risks appear to increase with worse disease activity (in this case, higher blood pressure).¹⁵ Similar to RA, there are several antihypertensive agents for which the teratogenic potential generally outweighs any benefit for exposure during pregnancy, including angiotensin blocking agents. However, it is widely recognized that the pregnancy risks posed by untreated HTN during pregnancy outweigh the use of antihypertensive agents with fewer pregnancy risks to achieve adequate blood pressure control throughout gestation.¹⁵ Unlike RA, however, guidelines from numerous agencies strongly recommend actively treating HTN to achieve a level of mild to moderate disease (blood pressure <150/100) during gestation to minimize both maternal and fetal adverse effects. Mild disease can be monitored without intervention.

Pregestational diabetes is another excellent example of extending the treat-to-target principle into pregnancy. Uncontrolled hyperglycemia during pregnancy has dramatic effects on both maternal and fetal health, including not only increased risks of preterm delivery, but also stillbirth, neonatal mortality, macrosomia, and maternal preeclampsia—all are directly related to degree of hyperglycemia rather than the type of diabetes (Type I or II).¹⁶ In fact, rates of congenital malformations are significantly increased in infants born to diabetic mothers (5–12%); again, directly associated with hyperglycemia during the first trimester.¹⁷ Akin to HTN, strict guidelines of glycemic control are strongly recommended, and medical therapy should be initiated to maintain blood sugar within the limits.16 The predominant glycemic agent during pregnancy is insulin, which, incidentally, carries an FDA pregnancy category B.

Both chronic HTN and DM have provided an excellent framework for the treat-to-target principle in nonpregnant individuals who may suffer fewer irreversible complications from undertreated disease as a result of achieving a low-disease state. This paradigm has been nicely translated to RA, with goals of low disease state/remission becoming increasingly possible with a growing arsenal of targeted drug therapy. With the adoption of treat to target, we can expect to see slowing or halting of RA-related damage accrual, including joint destruction, accelerated cardiovascular disease, and malignancy. In HTN and DM, however, treat-to-target goals extend into pregnancy, as it has been widely recognized that tight disease control during pregnancy improves both maternal and fetal outcomes. It is recognized that some therapeutic agents are “safer” than others during pregnancy, so that the medication regimen may need to be adjusted prior to conception, but the benefits of tight disease control far outweigh the risks of antenatal exposure to “safer” medications. Just as the rheumatology community has adopted the treat-to-target paradigm in the nonpregnant state, we should perhaps strongly consider similarly including these concepts during the peripregnancy period in female RA patients. Within the past few years, adverse pregnancy outcomes have been associated with RA, with some suggestion that these are directly related to increased disease activity. At the same time, effective medications that may be considered “safer” have become part of routine RA management. Because RA has been shown to improve during pregnancy, many women can hope to achieve good disease control without medical intervention. However, for the unlucky subset of women with moderate to severe disease during pregnancy, medical intervention may be warranted. The development of specific guidelines for RA control during pregnancy may aid in more widespread acceptance of medication use by both physicians and patients.

Disclosure

Dr. Chakravarty is a consultant for UCB and Genentech

Dr. Chakravarty is an associate member in Arthritis and Clinical Immunology at Oklahoma Medical Research Foundation in Oklahoma City.

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