Biologic Therapy for Immune-Mediated Inflammatory Diseases during Pregnancy and Lactation: Efficacy, Safety, and Challenges

Han Lin¹, Hou Zhenyan²,³, Li Jun⁴, Wang Yan¹, Li Huibo²,³

¹Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
²Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
³Institute for Drug Evaluation, Peking University Health Science Center, Beijing 100191, China
⁴Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China

Corresponding authors: Wang Yan, Chief Physician/Doctoral Supervisor; E-mail: wjgqhn@263.net
Li Huibo, Associate Chief Pharmacist; E-mail: lihuibo@bjmu.edu.cn

Abstract

Immune-mediated inflammatory diseases (IMIDs) frequently affect women of reproductive age, posing challenges in managing drug treatments due to their potential impact on pregnancy outcomes, fetal development, and infant health. This article comprehensively reviews the latest national and international diagnostic and treatment guidelines, along with recent clinical research. It explores the influence of IMIDs disease activity on pregnancy outcomes from the perspective of immune balance and elucidates drug exposure mechanisms of biologics during pregnancy based on placental transport and maternal physiological changes. Additionally, it integrates the latest advancements and safety profiles of biological treatments for IMID patients during pregnancy and lactation. The article presents a comparative analysis of recommended guidelines for using various biological agents in these periods, recommending optimal timing for discontinuation of these agents and neonatal vaccination. Through interdisciplinary collaboration, this work aims to promote the development of effective and safe treatment strategies for IMID patients during the perinatal period, thus safeguarding the health of both mothers and infants.

Keywords: Immune-mediated inflammatory diseases; Pregnancy period; Breastfeeding period; Biological agents; Safety

Immune-mediated inflammatory diseases (IMIDs) represent a group of clinically common conditions, including rheumatoid arthritis (RA), spondyloarthritis (SpA), connective tissue diseases, psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), asthma, and multiple sclerosis [1]. Some IMIDs peak during reproductive age, requiring long-term pharmacological treatment to maintain disease stability. However, the unique physiological stages of pregnancy and lactation complicate therapeutic decision-making. Therefore, family planning should occur when disease is well-controlled, guided by multidisciplinary teams including rheumatology, gastroenterology, dermatology, and obstetrics. During the perinatal period, clinical pharmacists should develop individualized treatment strategies that balance maternal disease control with fetal safety. At delivery, neonatologists should collaborate to establish newborn care protocols. This review examines domestic and international guidelines and clinical research evidence to analyze cutting-edge developments and safety profiles of biologic therapy for IMIDs during pregnancy and lactation, aiming to provide effective and safe treatment protocols for multidisciplinary management of perinatal IMID patients.

1. Impact of IMIDs Disease Activity on Pregnancy Outcomes

During pregnancy, the maternal immune system undergoes complex and finely-tuned adaptive adjustments while maintaining autoimmune defense functions. In early pregnancy, a pro-inflammatory microenvironment induces immune tolerance to ensure normal placental formation and fetal growth. The cytokine environment exists in a balance between pro-inflammatory and anti-inflammatory states, with these changes significantly affecting patients with immune-mediated inflammatory diseases [2]. The changes in the maternal immune system during pregnancy and the balance between pro- and anti-inflammatory factors are illustrated in Figure 1 [FIGURE:1].

Disease control before pregnancy in IMID patients closely correlates with disease activity during gestation. Once disease becomes active, it may adversely affect both mother and infant. Clinical studies have shown that increased RA disease activity during pregnancy is associated with low birth weight in offspring [3], while active IBD before and during pregnancy increases risks of maternal infection, preterm birth, low birth weight, small-for-gestational-age infants, and neurodevelopmental abnormalities [4]. Therefore, IMID patients are recommended to continue effective and safe maintenance therapy during pregnancy.

2. Drug Exposure to Biologics During Pregnancy

Due to placental barrier function, fetal Fc receptor (neonatal Fc receptor, FcRn)-mediated drug transport, and maternal physiological changes, drug exposure levels during pregnancy differ significantly from the general population. FcRn is expressed in human placenta, particularly in syncytiotrophoblast cells [5], facilitating active transport of IgG-type antibodies (Figure 2 [FIGURE:2]). Most biologics are IgG antibodies that can cross the placenta into fetal circulation via FcRn-mediated active transport. However, certolizumab pegol (CZP) lacks the Fc region of IgG1 and crosses the placenta minimally, allowing its use throughout pregnancy [6]. The human embryo during the first 10 weeks of gestation is called an embryo, representing the period of organ differentiation and formation. Other TNFi agents are thought to cross the placenta gradually beginning at 13 weeks of gestation, but their extremely low transfer rate may explain the low rate of congenital malformations associated with TNFi exposure during pregnancy [7].

As the fetus develops, Fc receptors become widely distributed in various tissues, including epithelial cells, endothelial cells, parenchymal cells, and hematopoietic cells. Their recycling function can prolong drug half-life. Meanwhile, the fetal reticuloendothelial system is immature, and FcRn expression is regulated by cytokines or infectious stimuli, thereby affecting drug transport and clearance [5]. Bitter et al. [8] first confirmed that belimumab (BEL) can be transported across the placenta in pregnant patients. In serum, the half-life is prolonged; with the last BEL exposure at the end of the second trimester, the drug can still be detected in neonatal cord blood. After discontinuation, different drugs require an average clearance time of 6-12 months [6], so drug effects should still be considered one year after stopping.

3. Guideline Recommendations and Clinical Evidence for Biologic Use During Pregnancy

In recent years, domestic and international specialty societies—including the Chinese Rheumatology Association [9], the Inflammatory Bowel Disease Group of the Chinese Society of Gastroenterology [10], the European Alliance of Associations for Rheumatology (EULAR) [7], the British Society for Rheumatology (BSR) [6], the British Association of Dermatologists [11], and the American College of Rheumatology (ACR) [12]—have issued guidelines on the safe use of biologics during the perinatal period. However, due to different evidence evaluation systems used in these guidelines, the recommendations and their strengths vary. The recommendations for biologic use during pregnancy and lactation from various guidelines are summarized in Table 1 [TABLE:1].

3.1 TNF Inhibitors (TNFi)

Currently, TNFi agents used internationally for IMIDs include infliximab (IFX), etanercept (ETA), adalimumab (ADA), certolizumab pegol (CZP), and golimumab (GOL). TNFi demonstrates significant efficacy in controlling low disease activity during pregnancy. A prospective study found that patients with axial spondyloarthritis who did not use TNFi before pregnancy showed persistently high disease activity from preconception through postpartum; discontinuing TNFi after a positive pregnancy test increased disease activity (OR=3.08, 95%CI=1.2-7.9), particularly in the second trimester [13].

Whether TNFi application increases the risk of pregnancy complications remains controversial. A retrospective cohort study by Luu et al. [14] found that maintaining TNFi treatment after 24 weeks of gestation did not increase maternal complication risk, but interrupting anti-TNF therapy increased relapse risk. Conversely, a population-based study by Bröms et al. [15] found that compared to non-biologic treatment, pregnant women using TNFi had increased risks of preterm birth (aOR=1.61, 95%CI=1.29-2.02), cesarean section (aOR=1.57, 95%CI=1.35-1.82), and small-for-gestational-age infants (aOR=1.36, 95%CI=0.96-1.92). The study also found that among pregnant women with RA, AS, PsA, or psoriasis, IFX carried greater risks of preterm birth and severe SGA than ETA, though no difference was found between IFX and ADA in IBD. However, due to lack of detailed information on disease activity, it is difficult to determine whether this relates to disease severity alone, and whether biologics are the sole determining factor.

Current research generally considers TNFi use during pregnancy to be essentially safe for the fetus. A systematic review of 143 studies found no difference in birth defect rates or miscarriage rates between pregnant women using TNFi and the general population [16]. Considering that TNFi can cross the placenta, increasing neonatal infection risk and affecting vaccination, expert consensus generally recommends discontinuing TNFi in the second or third trimester, reserving continuation into the third trimester only for patients with active disease.

3.2 Anti-B Cell (CD20): Rituximab (RTX)

RTX is commonly used to treat refractory RA, SLE, and vasculitis, but its safety during pregnancy and lactation remains controversial. Most guidelines [6,9] recommend discontinuing the drug 6 months before conception.

A systematic review of 102 pregnant women treated with RTX within 6 months of pregnancy [17] found that RTX use may not increase the risk of congenital malformations, with a reported spontaneous abortion rate of 12%, similar to the general population. Two additional studies support this view [18-19]. However, Smith et al. [20] found a slightly higher risk of spontaneous abortion after RTX exposure in a population-based study of 74 pregnant women with multiple sclerosis, with 15 (27%) experiencing miscarriage.

Research findings on whether RTX exposure increases pregnancy complications are also mixed. Chakravarty et al. [19] found preterm birth rates in 153 RTX-exposed pregnant patients similar to those reported in women with chronic medical conditions. In contrast, Kümpef et al. [18] found higher preterm birth risk in a prospective cohort study of 68 patients (9.76% vs. 45.45%, P=0.019) compared to those receiving anti-CD20 monoclonal antibodies before pregnancy, though this could not exclude associations with underlying disease or concomitant autoimmune conditions. Thus, limited studies show that RTX use within 6 months of pregnancy does not increase teratogenic risk, but whether it increases miscarriage and preterm birth risk remains controversial.

3.3 IL-6 Receptor Inhibitor: Tocilizumab (TCZ)

TCZ is approved for treating RA and giant cell arteritis and serves as second-line therapy for the inflammatory phase of SARS-CoV-2 infection. Safety of TCZ use during pregnancy remains uncertain, with recommendations to discontinue 3 months before conception [6,9].

Small-sample studies during pregnancy show TCZ does not increase teratogenic risk but may have certain adverse effects. A retrospective study by Jiménez-Lozano et al. [21] including 12 pregnant women with severe COVID-19 found all pregnancies resulted in live births, with 2 cases of hepatotoxicity, 1 case of cytomegalovirus reactivation and congenital infection, possibly related to TCZ use. Nakajima et al. [22] found no increased rates of spontaneous abortion or congenital malformations in a retrospective study of 61 patients. However, Hoeltzenbein et al. [23] found high rates of spontaneous abortion in prospective (21.7%) and retrospective (28.7%) cohorts of 180 and 108 patients, respectively. The study also found slightly higher preterm birth rates after TCZ exposure than in the general population, with 17 neonates exposed during the second and third trimesters, resulting in 6 preterm births and 4 low-birth-weight infants (<2,500 g), though concomitant methotrexate use and high disease activity could not be excluded as contributing factors [23].

3.4 IL-1 Receptor Inhibitor: Anakinra

Anakinra is used to treat RA and certain autoinflammatory diseases. Due to its homology with natural IL-1Ra and short elimination half-life, it is considered a safe alternative for treating pregnant women with periodic fever syndromes [24] and can alleviate cytokine storms induced by viral infection in severe COVID-19 pregnant patients [25]. Mouse model studies of IL-1β elevation found that anakinra protected placental function, increased fetal survival, and reduced neurobehavioral deficits in offspring to improve perinatal outcomes [26]. Chang et al. [27] included 24 pregnant women with cryopyrin-associated periodic syndromes (CAPS) and found that miscarriage rates were lower in women using anakinra than in those not taking it (11% vs. 27%). Youngstein et al. [24] included 10 infants exposed to anakinra through breastfeeding for up to 10 months and 6 infants with paternal exposure, finding no infections or fetal malformations.

However, the safety of anakinra during pregnancy remains uncertain, with recommendations to discontinue upon pregnancy detection, as use in the second and third trimesters may increase risks of neonatal malformations and maternal complications [24,27-29]. Although most neonates are normal, fetal musculoskeletal malformations increase with maternal anakinra exposure (OR=7.18, 95%CI=3.50-14.73) [29]. Additional studies have reported other adverse pregnancy outcomes. Brien et al. [28] included 69 pregnant women exposed to anakinra and found 26.1% experienced pregnancy complications, including preterm labor, vaginal bleeding, hypertension, or oligohydramnios. Thirteen point six percent of neonates had mild complications, including 5 diagnosed with CAPS, 1 with malnutrition, respiratory distress syndrome, and hyperbilirubinemia, and 1 with right hydrocele.

3.5 CTLA4-Ig: Abatacept (ABA)

ABA is approved for treating various rheumatic and immune diseases including RA, psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA). Due to lack of data in pregnant women, its use is not recommended during pregnancy. Women of childbearing potential should use effective contraception throughout treatment and for 14 weeks after the last ABA dose [30]. Current studies have reported adverse outcomes with ABA use during pregnancy. Dernoncourt et al. [29] found a significant relationship between fetal musculoskeletal malformations and maternal ABA exposure (OR=5.09, 95%CI=2.77-9.33). Ghalandari et al. [16] observed a 26.1% miscarriage rate in a systematic review of 153 ABA-exposed cases, higher than the general population (10-20%). Among 88 live births, 7 major congenital malformations were observed: 3 cardiovascular diseases, and 1 each of cleft lip/palate, meningocele, pyloric stenosis, and skull deformity. The congenital malformation rate (7.9%) was slightly higher than the general population (3-5%), though concomitant methotrexate use and high disease activity could not be excluded as contributing factors.

3.6 Anti-BAFF: Belimumab (BEL)

BEL is the only biologic approved for treating SLE, but its use should be avoided during pregnancy due to insufficient data. Ghalandari et al. [31] found that continuous BEL exposure during pregnancy (starting at least 3 months before conception) was associated with a 52.4% fetal mortality rate, higher than the rate in those who discontinued BEL in early pregnancy or earlier (46.4%, OR=1.27, 95%CI=0.48-3.32). Both groups had high fetal mortality rates without statistical significance, possibly influenced by high disease activity and reporting bias. Petri et al. [32] summarized 18 clinical trials and found that the birth defect rate was higher in the BEL exposure group than in the placebo group (5.6% vs. 0%), though no consistent pattern of birth defects was identified in the exposure group. Two case series including 26 SLE patients with BEL exposure during pregnancy reported high preterm birth rates among live births (52.2%, 12/23), including 5 small-for-gestational-age infants and 1 with fetal growth restriction [33-34]. These studies had higher mean maternal ages and recurrent miscarriage rates, and pregnant women with SLE generally have higher risks of congenital malformations and pregnancy complications than the general population or non-SLE populations [35]. Overall, these studies have not identified any pregnancy adverse events directly attributable to BEL, and despite the need for caution and further research, BEL may be a reasonable treatment option for pregnant SLE patients requiring therapy.

4. Biologic Use During Pregnancy and Neonatal Vaccination

Drug half-life determines the duration of immunosuppression in the fetus, which directly affects the timing of neonatal vaccination. Most biologics do not significantly increase infection risk [36-37]. Demortiere et al. [38] analyzed umbilical cord blood from 5 pregnant women with multiple sclerosis who suspended anti-CD20 therapy before pregnancy and found no abnormal B-cell counts. Among 23 RTX-exposed pregnancies with B-cell counts analyzed [17], 9 showed neonatal B-cell depletion, though none experienced infectious complications or adverse vaccination reactions, and all B-cell levels normalized within 6 months.

Some studies have reported contrary findings. Dernoncourt et al. [29] found that after excluding steroid use, BEL exposure had significant effects on neonatal infection (OR=28.49, 95%CI=5.75-141.25). Juliao et al. [35] included a prospective cohort of 55 patients and found that 6 of 46 infants (13%) experienced at least one unexplained infection or fever within the first 4 months after birth. Some researchers have found that fetuses exposed to RTX in utero often have hypogammaglobulinemia, leading to transient lymphopenia and reduced IgG levels on day 1 after birth [29]. Therefore, newborns of mothers treated with RTX and BEL during pregnancy should undergo close monitoring of B-cell levels to enable timely detection and management of potential infections.

EULAR [7] recommends that infants exposed to biologics only before 22 weeks of gestation can be vaccinated according to standard schedules, including live vaccines. For infants exposed during the second and third trimesters, live vaccines should be avoided for the first 6 months after birth. When available, measuring relevant biologic levels in infant serum can help guide live vaccine administration.

BCG, rotavirus, and measles-mumps-rubella vaccines are all live attenuated vaccines. The rotavirus vaccination series must be completed before 24 weeks of age to avoid intussusception risk. In a systematic review by Goulden et al. [39] analyzing vaccination safety in the first year of life for infants exposed to biologics in utero, adverse reactions after BCG vaccination included 1 death, 2 local skin reactions, and 1 axillary lymphadenopathy. Additionally, 4 cases of fatal disseminated BCG infection were observed due to in utero exposure to various TNFi (including IFX, ADA, and other unspecified TNFi). In contrast, infants receiving rotavirus vaccine had milder adverse reactions similar to unexposed infants, while no complications were observed in infants receiving measles-mumps-rubella vaccine. Overall, BCG vaccination before 3 months of age and in utero exposure to IFX were found to be harmful to infants. Rotavirus vaccine is mostly administered within 6 months after birth, and measles-mumps-rubella vaccine is mostly given at 1 year of age, with reassuring post-vaccination outcomes.

5. Biologic Use During Lactation

Most biologics are large protein molecules that are minimally secreted into breast milk, resulting in low relative infant doses and relative safety during lactation [6,40-41]. Anderson et al. [42] showed that the median concentration of RTX in breast milk was only 0.03 μg/mL, with minimal amounts entering the infant's circulation. Additionally, breastfed infants showed no significant differences in growth and development compared to non-breastfed infants. Saito et al. [43] reported that 2 infants exposed to TCZ through breast milk experienced no serious complications. Tada et al. [44] found that TCZ had a transfer rate of 11% in breast milk, which is relatively high, possibly due to high concentrations of proteins and antibodies in colostrum, though TCZ use during lactation is still considered relatively safe. Case reports on ABA also indicate that no adverse effects were found in infants exposed to ABA through breast milk, with ABA secretion in breast milk only 1/200 to 1/300 of serum levels [40].

However, due to limited data, some scholars suggest that lactating women should avoid breastfeeding during RTX treatment and for 6 months after treatment completion [45], and extend this to 14 weeks after ABA treatment [30]. Overall, although biologic use during lactation appears safe, clinical practice still requires careful consideration, with decisions made after fully evaluating individual treatment needs and potential risks.

This review comprehensively examines authoritative domestic and international guidelines and extensive clinical research evidence, systematically analyzing cutting-edge breakthroughs and latest developments in biologic therapy for IMID patients during pregnancy and lactation, with particular emphasis on evaluating safety evidence for these therapeutic strategies during these special periods. However, current research remains limited regarding long-term offspring safety, disease-specific differences, and pregnancy data on novel biologics (such as JAK inhibitors). Future prospective studies are needed to optimize individualized treatment strategies and ensure maternal and infant safety.

Author Contributions: Han Lin contributed to conceptualization, literature review, and manuscript writing. Hou Zhenyan contributed to manuscript revision and figure preparation. Li Jun contributed to feasibility analysis and supervision. Li Huibo contributed to study design, figure preparation, and funding acquisition. Li Huibo and Wang Yan contributed to final version revision and take responsibility for the manuscript.

Conflict of Interest: The authors declare no conflict of interest.

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(Received: 2025-02-02; Revised: 2025-04-10)
(Editor: Jia Mengmeng)