Biologic therapies have revolutionized the prognosis for the treatment of patients with inflammatory arthropathies. However, their safety during conception, pregnancy, and lactation remains unclear. Data on the safety of these treatments are mostly derived from uncontrolled case reports, and data collected from hundreds of conceptions and early pregnancies in patients with inflammatory arthritis and IBD exposed to anti-TNF therapy have not revealed evidence of adverse pregnancy and fetal regression. Monoclonal antibodies as well as small fragments of recombinant fusion proteins can pass through the placenta in mid- and late-term pregnancies and have effects on the fetus. There is evidence of lymphocytopenia at birth in fetuses exposed to the in utero environment of rituximab. In addition, young children with a history of in utero exposure to biologic agents should not be immunized with live vaccines for at least 6 months after birth. The long-term effects of in utero exposure to biological agents remain unknown. Studies have shown that many of these drugs pass into breast milk in small amounts, but how much is absorbed by the infant is also unknown. Limited reports have not found that paternal exposure to anti-TNF therapy or infliximab at the time of conception resulted in adverse pregnancies. In contrast, data related to other biologic treatments such as anabolic acid and tolimumab are very limited in both sexes. Professor Kimme L. Hyrich from the UK Arthritis Epidemiology Research Centre, Institute of Inflammation and Repair, University of Manchester, UK, reviewed the recent literature on biologics and pregnancy, published in a recent issue of Rheumatology, and concluded that the use of anti-TNF agents and others in pregnancy appears to be safe, while the long-term effects of biologic exposure during pregnancy remain unknown. The introduction of biologic therapies has significantly improved the treatment prognosis of patients with inflammatory arthropathies. between 1999 and 2012, nine biologics were approved for RA treatment, including the anti-TNF inhibitors etanercept, infliximab, adalimum, golimum and certolizumab; the IL-6 inhibitor tolimumab; the anti-CD20 antibody rituximab; the IL-1 receptor antagonist anabasectin, and a T-cell co-stimulatory modulator, abciximab. Many of these drugs, particularly TNF inhibitors, are also approved for the treatment of other inflammatory joint diseases such as PsA (psoriatic arthritis), AS (ankylosing spondylitis), and JIA (juvenile idiopathic arthritis), as well as psoriasis and inflammatory bowel disease. Rituximab has also been used for a long time to treat B-cell non-Hodgkin’s lymphoma (NHL). Information about the safety and efficacy of these drugs is being looked at in clinical trials and in a growing number of long-term observational studies such as drug registration studies. The safety of these therapies during pregnancy is a common concern for both patients and physicians. Inflammatory joint disease often involves men and women during the reproductive years, and there are many traditional DMARDs (disease-modifying antirheumatic drugs) such as MTX (methotrexate) that are contraindicated during pregnancy because of the potential for spontaneous abortion or congenital malformations; discontinuation of a previously effective regimen due to planned pregnancy is likely to result in a recurrence and exacerbation of the disease. The most recent UK biologic drug instructions recommend that patients discontinue the drug prior to pregnancy, with varying intervals required (see Table 1). This is mainly due to the lack of controlled studies on the use of biologic therapies during pregnancy. Studying the safety of new drugs during pregnancy and lactation is challenging. Pregnant women are often excluded from clinical trials and are required to use strict contraception throughout their participation in clinical trials, so information on the safety of these therapies during pregnancy and lactation is scarce, as it is in animal studies. Most post-marketing experience has been gained from studies of uncontrolled incidental exposures. Case reporting has its limitations, such as the unavailability of common characteristics of women treated and the apparent underreporting and selective reporting. For drugs that have been on the market for a long time, pregnancy-related reports have become less novel, and therefore their number is decreasing. Therefore, these relevant cases do not provide the full experience regarding the use of anti-TNF in pregnancy. These limitations aside, the collection of experiences is quite useful in informing potential exposure risks, advising patients preparing for pregnancy or conception to receive treatment, and directly benefiting further research in related fields. This review summarizes recent information on the use of biologic therapies in conception, pregnancy, and lactation, with studies primarily derived from patients with inflammatory bowel disease, but also with data on other applications like IBD, which are included in the discussion. Biologic agent type, composition and latest UK pregnancy drug recommendations Drug structure/function Latest UK pregnancy drug recommendations Enalapril soluble p75 TNF-receptor and IgG1 Fc segment fusion protein Discontinue infliximab anti-TNF human-mouse IgG1 monoclonal antibody chimeras at least 3 weeks prior to conception Discontinue adalimumab anti-TNF fully human IgG1 antibody at least 6 months prior to conception Discontinue golimumab anti-TNF fully human IgG1 antibody at least 5 months prior to conception Discontinue certolizumab polyethyleneglycolated anti-TNF human antibody Fab segment at least 5 months prior to conception Discontinue rituximab anti-CD20 (B-cell) human-mouse IgG1 monoclonal antibody chimeric at least 12 months prior to conception Discontinue anabolic recombinant human IL-1 receptor antagonist no Related Recommendations Abciap extracellular CTLA-4 domain and IgG1 Fc segment fusion protein Discontinue tolimumab anti-IL-6 receptor human-derived IgG1 monoclonal antibody at least 14 weeks prior to pregnancy Discontinue at least 3 months prior to pregnancy Source: http://www.medicines.org.uk孕妇应用生物制剂的潜在风险众所周知 TNF plays an important role in the body’s defense against bacterial and viral infections plays an important role. In contrast, anti-TNF therapy is associated with an increased risk of serious and opportunistic infections. This risk is higher in the early stages of treatment initiation and is manageable as disease activity plateaus. Pregnancy is in a state of relative immunosuppression, so theoretically, the application of anti-TNF therapy during pregnancy increases the risk of infection even more. Among the infection risks associated with the application of anti-TNF therapy, intracellular infections, exemplified by Listeria monocytogenes, are of particular concern. Because such infections are associated with pregnancy loss, neonatal morbidity and mortality, there are proprietary guidelines for safe food intake during pregnancy for women to avoid such infections; this information should be repeatedly communicated to women who have been exposed to anti-TNF drugs before or during pregnancy. Potential risks of biologic therapy to pregnancy/fetus 1. Biologics that can pass through the placenta It is well known that maternal IgG antibodies can pass through the placenta into the fetal circulation, and most of the newborn’s antibodies come from the mother. At the end of pregnancy, immune pregnant women use this mechanism to protect their newborns from bacterial infectious diseases. Antibodies are large proteins (>100 KDa) and, therefore, monoclonal antibodies are unlikely to pass through the placenta by simple diffusion, but rather by active transit through the placenta by Fc segment receptors in the trophectoderm. These receptors begin to form at approximately the beginning of midterm pregnancy (14 weeks), so active transport begins at midterm and grows rapidly during late pregnancy. Eventually, the fetal IgG level exceeds that of the mother. This suggests that maternal antibody exposure during conception and organogenesis is very limited. All biologics currently approved for the treatment of inflammatory arthropathies contain antibody structures, which are mainly monoclonal antibodies. Animal studies suggest that they are processed in a manner consistent with maternally derived antibodies. A small number of human studies have been evaluated using more direct methods, such as measuring drug concentrations in the newborns of women exposed to anti-TNF therapy during pregnancy and in their breast milk. Studies related to infliximab, on the other hand, have been limited primarily by its use in women with IBD. Unlike RA, improvement during pregnancy is not evident in IBD, and therefore many women continue to require treatment during pregnancy. In most cases, levels of infliximab and adalimumab are at least comparable to maternal levels in the newborn and for several weeks thereafter. However, antibody levels in infants continued to decrease in all cases despite continued breastfeeding. Etanercept-related studies found that in neonates, their drug levels were significantly lower than maternal circulating levels, suggesting that fewer of their antibody structures may have passed through the placenta in activated form; and, despite continued breastfeeding, infant antibody levels continued to decline in these cases. However, this is not the case for tolimumab. This drug is a polyethylene glycolized anti-TNF recombinant humanized antibody Fab segment that lacks the segmental receptor for Fc and is therefore not thought to undergo active placental transit, as confirmed by experiments with alternative polyethylene glycolized antibodies in rats. Although trace doses of the drug have still been reported to be detected in neonates, the study data largely confirm this perception. The mechanism of this presumed passive transfer is not known and there are no published reports of rituximab, abciximab, anabolic acid and tolimumab at the neonatal drug level. 2. Effects of anti-TNF drugs on pregnancy and fetus Evidence is growing around the safety of anti-TNF drugs used before or during pregnancy. Most of these reports are case reports or case studies, and recently there have been several systematic reviews that synthesize these cases. Most of the cases were exposures to infliximab, adalimum or etanercept monotherapy dating back as far as when these drugs were approved for use. One review included 472 cases with clear exposure and regression up to 2011. The most recent review included 462 reported cases with preconceptional or maternal exposure to adalimum, infliximab, or certolizumab for the treatment of IBD as of January 2013. The vast majority of women who developed inflammatory joint disease discontinued biologic therapy in early pregnancy, but there were reports of continued treatment during pregnancy. In most cases, it was unclear whether the decision to discontinue treatment was made by the patient herself or by the advice of her physician. Most information on exposure to anti-TNF therapy in the second trimester of pregnancy comes from patients with IBD. These reviews summarize the published literature and found that exposure throughout or before pregnancy and during pregnancy (including mid- and late-term pregnancies) was not associated with an increased risk of adverse pregnancy and congenital malformations compared to the total population. Importantly, the reported incidence of major congenital malformations was lower than the predicted incidence in the background population (3%) and no specific consistent malformations were observed. One child with prenatal exposure to etanercept developed VACTERL syndrome, a congenital malformation in which children can present with three or more malformations including vertebral malformations, anal atresia, cardiac defects, tracheoesophageal fistulas, renal malformations, and limb malformations. The U.S. Food and Drug Administration (FDA) took this seriously, but no other similar cases of VACTERL syndrome have been reported in the FDA database. Information from the manufacturer on 139 pregnant women exposed to certolizumab before or during pregnancy (109 with Crohn’s disease, 17 with RA, 2 healthy, and 1 unknown) was published in abstract form in 2012. 74% of the pregnancies were live births, 15% were miscarriages, 11% were abortions, and 2 infants yielded congenital malformations. This is consistent with other reports related to anti-TNF and the incidence in the general population. Although the current data collected based on case reports consider exposure to anti-TNF therapy at conception and during pregnancy to be safe, these data have their limitations. A large national prospective observational study of anti-TNF therapy actively recommended that women apply these treatments prior to conception, and its data showed a slight trend toward an increased incidence of early spontaneous abortion in women who were inadvertently exposed to anti-TNF therapy at the time of conception. However, because these women were often also exposed to MTX at the time of conception, the data are not easily distinguishable between the two. It is good to note that the incidence of congenital malformations was not elevated, which is consistent with other reports. Developmental risks associated with intrauterine exposure to anti-TNF therapy Due to the placental transport properties of monoclonal antibodies, it is important to recognize the impact of intrauterine and birth exposure to anti-TNF therapy on neonatal and childhood development. Although maternal exposure to anti-TNF has been increasingly reported, little attention has been paid to immune development related to children. A study in macaques during pregnancy and lactation found no difference in immune system development with golimumab injection compared to saline injection. Very limited empirical information suggests that routine childhood immunizations such as DPT appear to be safe and effective. However, the application of live vaccines needs to be done with caution in a case of a 4.5 month old infant who died from Mycobacterium tuberculosis transmission due to BCG vaccination at 3 months of age. Her mother had been treated with infliximab during pregnancy for Crohn’s disease. Some recommendation is to apply live vaccine immunization at least 6 months after birth. If emergency vaccination is required due to travel, it is recommended to seek the help of an immunologist. Rituximab Safety Experience During Pregnancy Information on the use of rituximab in women before and during pregnancy is increasing. The indications for rituximab are broad and the majority of pregnant women treated are not rheumatic, which also includes those with severe hematologic disease or NHL. The details of the combined dosing are not fully known. Chakravarty et al. reported their pregnancy outcomes based on the Rituxan Global Drug Safety Database. Of the 153 pregnancies for which they reported known pregnancy outcomes, there were 90 live births, 33 miscarriages, 28 terminations and one stillbirth and one maternal death. 70 pregnancies occurred on or after the application of rituximab as part of a clinical trial. In these cases, the combined use of drugs and other potentially teratogenic drugs, such as MTX, were documented in detail and applied in more than 50% of cases. There are at least 26 case reports from literature sources, ranging from SLE with preconceptional 22-month exposure to idiopathic thrombocytopenic purpura with late pregnancy exposure. Of course, most of these are also not rheumatic diseases. Preterm delivery was common, but the role of the primary cause and combined medications was not taken into account. There were three cases of congenital malformations, one each of horseshoe foot, esophageal atresia malformation and cardiac malformation. All live births were healthy during the follow-up period, which ranged from a few weeks to several years. For rituximab, the effect of intrauterine exposure to anti-CD20 monoclonal antibody on fetal development, particularly B-cell depletion and immune development, is important. In these cases, B cells were measured at birth in 11 children, of whom 6 had reduced levels. 5 of the 6 children with a history of early pregnancy exposure were born with normal B cell levels and 1 with reduced levels. In the five children with intermediate and late gestational exposures, B-cell levels were reduced or not measured at birth. However, all children’s B-cell levels returned to normal several months after birth and appeared to have a normal immune response to the routine. The effects of prolonged B-cell depletion in utero and early in life due to the long half-life of rituximab (up to 35.9 days) are unknown, and some recommend that women not elect to receive rituximab therapy during pregnancy unless the potential risk of disease necessitates its application. Although current guidelines recommend that women use effective contraception for 12 months following rituximab application, the exact duration of pregnancy that should be avoided is unclear. Reassuringly, a small number of case reports suggest that exposure to rituximab during the first 12 months of pregnancy mostly has no adverse effects on pregnancy or the infant, but these reports are not yet sufficient to change the 12-month requirement in the current guidelines. Anabasectin, abciap and tolimumab Anabasectin, abciap and tolimumab have limited published pregnancy-related reports. 3 patients with adult Still’s disease who were administered anabasectin during pregnancy produced healthy infants. A 36-year-old patient with RA who was exposed to both abciximab and MTX in early pregnancy delivered a healthy infant who remained in good health until 3.5 years of age at follow-up. A total of 31 pregnancy regressions were reported at the 2010 ACR meeting, including 13 elective terminations, 7 spontaneous abortions (5 of which were coadministered with MTX) and 11 full-term deliveries (9 of which were also administered with MTX.) Of the 11 full-term deliveries, 10 were healthy and 1 died 3 days after birth due to complications from placenta previa. The vast majority of information related to biologic therapy and its application while breastfeeding is related to anti-TNF agents. The predominant antibody in breast milk is IgA, with small amounts of IgG and IgM. The levels of anti-TNF therapeutic agents detectable in breast milk are very low compared to the concentrations in the maternal circulation. Despite continued breastfeeding, drug levels in newborns will continue to be reduced or undetectable. At the time of breastfeeding, the amount of breast milk each infant consumes in a day is unknown, and it is not known how much protein is hydrolyzed in the digestive tract and thus affects the absorption of drugs in breast milk. To date, in the few cases where breastfeeding has been continued and anti-TNF therapy has been administered during breastfeeding (mainly etanercept and infliximab), no adverse effects have been observed in the infants. Paternal application of biologic therapy The published literature on the exposure of the male partner to anti-TNF therapy during pregnancy is rather limited. However, this issue is as important as the fact that men should limit the use of DMARDs, including MTX and SSZ, prior to pregnancy. Two older case studies found sperm malformations in men exposed to infliximab. Weak spermatozoa developed in 2 of 4 men who were treated with infliximab for AS. 10 men treated with infliximab for Crohn’s disease showed a trend toward increased semen volume and decreased normal morphology and motility of sperm. In another study including 25 patients with SpA, 15 patients treated with TNF (including infliximab, adalimumab and etanercept) showed no significant change in sperm quality compared to normal controls; patients who did not receive anti-TNF therapy were more likely to have weak spermatozoa. In conclusion, no adverse pregnancy outcome was observed in the male partner exposed to anti-TNF treatment at the time of conception, for both his partner and offspring. The published literature reports 25 pregnancies associated with 20 males, with a total of 23 healthy newborns, 1 miscarriage and 1 early termination due to progressive hydrocephalus (notably, the male partner at the time of conception was on MTX in combination with SpA). Of the 13 pregnancies reported with paternal exposure to certolizumab, 10 were live births, 2 were miscarriages, and 1 was a termination. There was no male infertility associated with anti-TNF therapy in the above reports. Information on paternal exposure associated with other biologics is limited. The Rituximab Global Drug Safety Database has reported eight cases of paternal exposure to Rituxan at the time of pregnancy, with seven full-term deliveries and one spontaneous abortion. To summarize in conclusion, these experiences do not suggest that there are any side effects associated with exposure to anti-TNF therapy at the time of conception. Late pregnancy exposure, especially exposure to monoclonal antibodies, is associated with high drug concentrations in the newborn. Infants with a history of intrauterine biologic exposure should not be immunized with live vaccines for at least 6 months of life. And the long-term effects of biologic agent exposure during pregnancy are still unknown. Although it is tempting to try to draw conclusions from the growing general experience with anti-TNF therapy, selective blockade of cytokines and immune pathways may have different effects on conception, implantation, early embryonic development and neonatal safety. Therefore, the use of other types of biological therapies during this period is not recommended.