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 Medications are often withdrawn in anticipation of a pregnancy months before conception and are not restarted until after the completion of breastfeeding.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.
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.
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.
Newer data have shown that active maternal disease is associated with adverse fetal outcomes.
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.
