A PubMed literature search (2000-2015) was performed to identify studies with human data on pregnancy outcomes after exposure to biologic agents during pregnancy. Search strategy was restricted to the articles published in English and Turkish and included the following search terms “tumor necrosis factor (TNF) inhibitors”, “etanercept”, “infliximab”, “adalimumab”, “certolizumab”, “golimumab”, “tocilizumab”, “anakinra”, “rituximab”, “abatacept”, and “pregnancy”. First, titles and abstracts of all 931 references were screened; articles which have insufficient data or do not address the topic of the interest were excluded. Inclusion criteria were data on pregnancy outcomes in patients who were exposed to biologic agents before conception and throughout pregnancy. Additionally a hand-search was made looking for the reference lists of the applicable publications. Adequate documentation was found in 10 reviews, 10 registries, 17 case series and 18 case reports. Published data on reports of biologic therapies are summarized in Table 1.

Efficacy of TNF inhibitors has been demonstrated in reducing disease activity and joint damage and improving health-related quality of life in the patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), and ankylosing spondylitis[14]. Most frequently used TNF inhibitors include etanercept, a soluble p75 TNF-receptor and IgG1 Fc fusion protein; infliximab, a human-murine IgG1 anti-TNF monoclonal antibody; adalimumab, a human IgG1 anti-TNF monoclonal antibody; certolizumab pegol, a pegylated Fab fragment of humanized anti-TNF monoclonal antibody; and golimumab, fully humanized TNF-alpha monoclonal antibody[15].

TNF inhibitors have been rated as Food and Drug Administration (FDA) category B (No evidence of a risk to the fetus was found in animal toxicity studies; however there are no controlled studies which have enrolled pregnant women). TNF inhibitors do not actively cross the placenta during the first trimester and organogenesis, but they are transferred across the placenta during the late second and third trimester[12]. These can be found in newborn’s cord blood in levels that exceed those of the corresponding maternal serum[16,17]. Additionally, they are detectable in blood of the infant for more than six months after the birth, reducing the safety of vaccination[16]. Certolizumab does not contain Fc region, thus it does not actively cross the placenta[18].

Use of TNF inhibitors has been reported in almost 2000 pregnancies of the patients with rheumatic diseases, inflammatory bowel diseases and psoriasis. Based on the published data from case reports[19-29], case series[30-34] and registries on etanercept, infliximab, adalimumab, golimumab and certolizumab[35-37], it has been found that preconception exposure to biologic agents or use of them during pregnancy including first, second and third trimesters is not associated with increased risk of adverse pregnancy outcomes, malformations or birth defects compared with general population.

An FDA database review revealed 61 birth defects in 41 children born to mothers receiving TNF inhibitors[38]. Of these mothers, 22 received etanercept and 19 received infliximab. The most common congenital anomalies were heart defects, spinal deformities, imperforate anus, tracheoesophageal fistula, renal anomalies and limb defects, which were the features of vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities association. These anomalies were found to be linked with use of TNF antagonists and it was suggested that these agents should not be administered during pregnancy.

British society for rheumatology biologics register (BSRBR) is a database which keeps information about RA patients taking TNF antagonists. Between 2005 and 2006, 11473 patients were registered with the BSRBR. Of these patients, 17 received etanercept, 3 received infliximab and 3 received adalimumab. No congenital malformation was observed[37]. After this report, another BSRBR report which assesses the outcomes of 118 pregnancies in patients who were exposed to TNF antagonists was published in 2008[39]. The rate of miscarriage was 27% in the patients who received anti-TNF at the time of conception (group 1), 17% in those with prior exposure to anti-TNF (group 2) and 10% in those who were never exposed to anti-TNF (group 3). The rate of premature delivery was 26% in group 1, 17% in group 2, and 20% in group 3. A perinatal death causing from hypoxia was reported in a patient who was exposed to etanercept at the time of conception. Additionally four cases of congenital anomalies were reported. In group 1, congenital hip dysplasia and pylorostenosis, and in group 2 Marcus Gunn syndrome and infantile hemangioma were observed. The authors suggested that treatment with TNF inhibitors might be linked with an increased risk of spontaneous abortion, however the effects of disease activity and other antirheumatic agents could not be eliminated.

Offiah et al[40] reported a transient collodion membrane in a 2-d-old infant born to mother receiving infliximab for severe psoriasis and PsA throughout pregnancy in United States. The skin turned to normal at age 1 year with mineral oil treatment.

Guiddir et al[41] reported four cases of severe neutropenia in newborn patients exposed to infliximab. High serum infliximab concentrations were detected several months after birth. It was suggested that the mononuclear phagocyte system of a newborn is inadequate to clear the antibody rapidly.

Tetralogy of Fallot, intestinal malrotation, hypothyroidism, intracranial and intrapulmonary hemorrhage, unilateral renal agenesis, serum sickness-like reaction (with infliximab)[35,42-44], infantile kaposiform hemangioendothelioma, Kasabach-Merritt syndrome, renal agenesis, urethral defects, cardiac conduction system abnormalities, pylorostenosis, congenital megacolon (with etanercept)[32,39,45,46], and ventricular septal defect, congenital hip dysplasia, spina bifida with hydrocephalus, aortic valve disease, corpus callosum agenesis, and congenital hypothyroidism (with adalimumab)[47,48] have been reported in the babies born to mothers directly exposed to TNF inhibitors during pregnancy. However rates of these anomalies have been found to be similar to those expected for the general population[35,46,49].

Cheent et al[50] reported use of infliximab during pregnancy in a 28-year-old patient with Crohn’s disease. Newborn had no congenital malformation or intrauterine growth retardation. He was healthy until bacillus calmette-guerin (BCG) vaccine administered at the age of three months. One point five months later he died from disseminated BCG disease which was a rare life-threatening complication of BCG administration.

Certolizumab is different from other TNF inhibitors, it does not contain Fc region, thus it is not actively transported through the placenta[16]. It has only minimal transplacental transmission to newborn via passive diffusion during first, second and third trimesters[17].

The Union Chimique Belge Pharma global safety database revealed 69.5% live birth rate in 190 pregnant women exposed to certolizumab[51]. The rates of spontaneous abortions and elective terminations were 18.9% and 11.6%, respectively. Six birth defects were observed in four infants among all live births: vesicoureteral reflux, congenital morbus, congenital megacolon, congenital talipes equinovarus, aortic arch anomaly, and unilateral hydronephrosis. However these congenital anomalies were not thought to be associated with exposure to certolizumab. These pregnancy outcomes were comparable to those reported for united states general population (65% live births, 17% spontaneous abortions, and 18% elective abortions)[52]. In Pregnancy in Inflammatory Bowel Diseases and Neonatal Outcomes study[53] where women with inflammatory bowel disease exposed to certolizumab in the third trimester of pregnancy were compared with unexposed group, it was suggested that use of certolizumab in the third trimester was not associated with increase in infant infection rates.

Golimumab is a newer TNF inhibitor and there is limited data on its use during pregnancy[54]. In a study by Martin et al[55] performed in cynomolgus monkeys received 25-50 mg/kg golimumab twice weekly during pregnancy, no effect was observed on pregnancy outcomes or fetal immune system. Experience with use of golimumab during pregnancy has been limited to conference abstracts. Lau et al[56] reported pregnancy outcomes of 40 women exposed to golimumab at the American College of Rheumatology (ACR) Annual Meeting in 2013. Outcomes included one unspecific congenital anomaly, 19 live births, 13 spontaneous abortions and 7 induced abortions. Of 13 mothers with spontaneous abortion, 4 had concomitant methotrexate use.

Anakinra is a human IL-1 receptor antagonist certified by FDA for the therapy of RA patients with intermediate/high disease activity[14]. It has been rated as FDA pregnancy category B. It has a half-life of 4-6 h. Because of its short half-life, discontinuance of anakinra before conception is not necessary[18]. Experiences with use of anakinra during pregnancy are limited. Three pregnancies in patients received anakinra for the treatment of adult onset Still’s disease resulted in term live births[57,58]. Chang et al[59] described outcomes of fifteen pregnancies in nine women receiving anakinra for the treatment of cryopyrin-associated periodic syndrome. Outcomes included 14 healthy term infants and one intrauterine fetal demise resulting from renal agenesis.

Tocilizumab is a humanized IL-6 receptor inhibitor used in the therapy of moderate to severe RA and polyarticular and systemic JIA. It is categorized as FDA pregnancy category C. Tocilizumab should be discontinued three months before conception[18]. Experiences with use of tocilizumab during pregnancy were reported by Rubbert-Roth et al[60] at the ACR Annual Meeting in 2010. Of 33 pregnancies, 13 resulted in induced abortion, 7 resulted in spontaneous abortion and 11 resulted in live births. Of 7 mothers with spontaneous abortion, 5 had concomitant methotrexate use.

Rituximab is a chimeric monoclonal antibody against the B cell surface antigen CD20[61]. It is indicated for the treatment of severe refractory RA with inadequate response to TNF inhibitors, certain types of vasculitis, non-Hodgkin’s lymphoma and chronic lymphoid leukemia[42]. It is classified as FDA category C, meaning “it has not been studied on pregnant women, however animal developmental toxicity studies have shown an adverse effects on the fetus”. It has no active transplacental passage during the first trimester and organogenesis, but actively crosses the placenta during the late second and third trimester[62], and may affect fetal and neonatal B cell development, causing increased risk for infections[63]. Chakravarty et al[64] reported pregnancy outcomes in 153 patients exposed to rituximab. Of these pregnancies, 90 resulted in live births, 22 resulted in prematurity and one resulted in perinatal death. 11 infants had hematologic abnormalities at birth (peripheral B-cell depletion, neutropenia, lymphopenia, thrombocytopenia and anemia) and four had perinatal infections. Two infants had congenital defects (congenital talipes equinovarus and cardiac malformation). Sangle et al[65] reported pregnancy outcomes in 5 patients with systemic lupus erythematosus exposed to rituximab before conception. One of the infants was born with esophageal atresia, while the others were healthy. Pendergraft et al[66] reported a miscarriage at 15 wk in a mother exposed to rituximab 7.5 mo prior to conception. Histologic and genetic evaluation of fetus revealed Beckwith-Wiedemann Syndrome. Ojeda-Uribe et al[61] reported two successful outcomes in two women with autoimmune diseases received rituximab in the first trimester of pregnancy.

Preconception and first trimester exposure to rituximab seems not to indicate an excess risk of adverse fetal outcomes. Exposure during second and third trimesters causes decrease in B cells in the fetus[18]. Further studies, especially prospective registries are needed to explore immune response to vaccines and perinatal infections in infants born to mothers received rituximab during second and third trimesters.

Abatacept (CTLA4-Ig) is a recombinant fusion protein that modulates T cell costimulatory signal mediated through the CD28-CD80/86 pathway[67]. It has been approved for the treatment of refractory RA[4]. Abatacept therapy should be stopped three months before conception[18]. Ojeda-Uribe et al[61] reported a healthy infant born to a 33-year-old mother exposed to abatacept in the first trimester.