The European League Against Rheumatism (EULAR) recommends family planning for all patients of childbearing age and stresses the importance of regularly emphasising the benefits of family planning for individuals with inflammatory diseases.4 Preconception counselling should range from contraceptive measures for individuals who do not wish to become pregnant to treatment options for those who are willing to conceive. In the latter group of patients, the main issues to be addressed will be: potential influence of the disease on fertility, impact of the disease on pregnancy and vice versa, adaptation of treatment, maternal-foetal risk factors, etc.

It is especially advisable that all this information be communicated clearly and consensually, which requires close collaboration between the various care teams, including rheumatologists, primary care physicians, midwives, obstetricians, and hospital pharmacists (especially in patients receiving drugs dispensed in the hospital). Good communication between professionals and patients can significantly reduce the risks and increase chances of success, leading to better compliance and disease control. Table 1 illustrates a list of frequently asked questions surrounding management during the preconception phase.

Various studies have yielded contradictory results as far as the impact of the disease on fertility is concerned; while some show no correlation between the two whatsoever,8,9 others reveal lower fertility in patients with these diseases.10–12 Likewise, certain drugs have been seen to affect fertility both in women (prednisone [depending on the dose], non-steroidal anti-inflammatory drugs, or prior use of cyclophosphamide) and men (sulphasalazine).10–13 The multidisciplinary team of this study advocated the need to explain that, although these patients may have greater difficulties in conceiving, pregnancy is possible in this population and that there is the possibility of using assisted reproduction techniques in those patients who experience difficulties in conceiving.7

From the point of view of heritability, it is important to explain to the patient that, although the probability of transmitting the disease may be higher than in the general population,14 that does not necessarily mean that they will transmit the disease to their child.

During the preconception phase, a gynaeco-obstetric assessment and rheumatological history-taking is recommended, in addition to the usual prenatal care routinely provided to women (diet, physical activity, risk factors, etc.).15 Likewise, an individual evaluation of the activity of the disease, the treatments used, and the presence of comorbidities or contraindications to pregnancy is recommended, to make it possible to elaborate an effective action and follow-up plan.16Table 2 displays the most relevant considerations, at the discretion of the multidisciplinary team, to be followed during the preconception stage by both patients and healthcare professionals.

One of the key aspects to be addressed during family planning is whether to continue or adjust treatment. The treatment algorithm should be modified to accommodate the needs of the different stages (preconception, pregnancy, postpartum, and breastfeeding) and generally pursue 2 objectives: (1) efficacy, keeping disease activity under control, and (2) maternal and foetal safety, circumventing the risks to the mother or foetus/ infant posed by the use of drugs that cross the placenta and/ or breast milk.17 The authors highly recommend that low disease activity or remission be achieved for at least 3−6 months prior to pregnancy, which may entail considering postponing pregnancy until the disease is controlled or in remission.17 At this stage, therapeutic options should be appraised on an individual basis and, if necessary, the treatment prescribed by the different healthcare teams should be adjusted and agreed upon with the patient, always taking her preferences into account.5 During pregnancy planning, discontinuation of less safe treatments, such as methotrexate, leflunomide, mycophenolate mofetil, or some biologics is advisable.5,7,18 Treatment with hydroxychloroquine, azathioprine, or sulfasalazine is considered to be compatible with pregnancy.7 Treatment with tumour necrosis factor (TNF) antagonists is deemed safe during a planned pregnancy, inasmuch as it has been demonstrated that immunoglobulin G does not cross the placenta during the first trimester19,20 (Table 3). If considering anti-TNF treatment, it is important to consider the potential placental transfer throughout the pregnancy and the possibility of being able to use the drug throughout the pregnancy, in order to avoid a change of treatment during gestation. Within the group of biologics, certolizumab pegol (CZP) is the only one with prospective studies of placental transfer and levels in breast milk that support the update of its label to include its potential use during pregnancy and breastfeeding in women with immune-mediated inflammatory diseases.2,21,22 There are limited data regarding the compatibility of other biologics during pregnancy.7

Table 3.

Compatibility of major drugs in conception, pregnancy, breastfeeding, and paternal exposure.

DMARDs: disease-modifying antirheumatic drugs; TNF: tumour necrosis factor.

The colour of the cells indicates, from darkest (black) to lightest grey, the following categories: not recommended for use based on scientific evidence; conditionally not recommended for use based on limited scientific evidence; conditionally recommended for use based on limited scientific evidence, or recommended for use based on scientific evidence. White cells indicate that there are no data available. Adapted by Götestam et al.,5 Sammaritano et al.,7 Flint et al.18

In the case of unplanned pregnancies, it is important to assess whether there has been exposure to non-recommended drugs. In this case, the exact date of exposure should be confirmed and an ultrasound examination of the foetus should be performed.5

It is important to explain the most common symptoms associated with pregnancy, noting that these can vary from one patient to another, and that attention must be paid to any changes in symptomatology that can be attributed to the disease.

Several studies have shown that disease symptoms may improve during pregnancy, especially in patients with RA.17,23,24 However, symptoms may remain unchanged or even worsen in some cases and approximately 50% of patients have been seen to require treatment to control disease activity during pregnancy.3 This will depend to a large extent on the disease activity prior to conception and during pregnancy, so it is recommended that the disease be as controlled as possible throughout pregnancy. Likewise, treatment discontinuation due to pregnancy is associated with an increased risk of pre-term delivery25 and it is vital that patients not make any changes to their medication without first consulting with their treating physician. Table 1 displays the response to pregnancy-related questions at the discretion of the multidisciplinary team.

Regardless of whether the pregnancy is planned or unplanned, the appropriateness of treatment in the different trimesters of pregnancy must be assessed on a case-by-case basis.26 Some medications, such as methotrexate and leflunomide, should be withdrawn due to their contraindication during pregnancy.5,27 Other drugs can be continued, such as sulphasalazine supplemented with folic acid5 or hydroxychloroquine.28 A recent study has demonstrated that the use of antimalarials during pregnancy is associated with a lower risk of pre-eclampsia.29 As for TNF antagonists, CZP is the only one compatible with all 3 trimesters of gestation with minimal placental transfer as the absence of Fc in its structure prevents its transfer mediated by neonatal FcRn receptors.18,30 In the prospective CRIB study, minimal levels of CZP were detected in the plasma of newborns.22 An earlier study revealed that placental transfer was lower with CZP than with adalimumab and infliximab.31,32 Etanercept exhibits less placental exchange than adalimumab and infliximab and will therefore be an alternative in cases in which CZP cannot be used. Treatment with other anti-TNF agents (infliximab, etanercept, adalimumab, or golimumab) should be interrupted in the third trimester if the disease is controlled, to avoid the risk of placental transfer.7 There are not sufficient safety data with respect to other biologics do and, thus, should be discontinued during pregnancy.4,33Table 3 describes the compatibility of the leading drugs for the treatment of RA, PsA, and AxSpA during conception, pregnancy, breastfeeding, and paternal exposure.

During this stage, it is fundamental that the different care teams that will follow the pregnancy (gynaecologists, obstetricians, midwives, primary care physicians and nurses), treat the immune-mediated inflammatory disease (rheumatologists), and validate and dispense the treatments in most cases (hospital pharmacists) be coordinated and brought together.

In the opinion of the multidisciplinary team, it is important that during this period, the pregnant woman be informed of the different methods of delivery and the implications they have for her health. RA, in particular, has been associated with increased Caesarean births and pre-eclampsia, as well as with an increased risk of low birth weight.34 This again underlines the importance of maintaining adequate disease control throughout pregnancy. Despite this, it is important to note that vaginal delivery is possible in most of these patients. Table 1 illustrates the answers to some of these questions in order to help professionals provide as clear and complete information as possible.

It has been reported that disease activity sometimes worsens after delivery, which can complicate the care of the newborn.17,24 Studies have proven a 50%–90% incidence of reactivation of inflammation in patients during the first 4 weeks following delivery.10 Consequently, monitoring the status of the disease throughout this stage is essential.10 The specialist must assess and adjust treatment based on the patient’s condition, always in line with the therapeutic objectives, i.e., to control disease activity without compromising the health of the newborn.2,4 The multidisciplinary team also considered it relevant that patients be informed that they can ask for help from different professionals (paediatrician, nurses, physiotherapists, occupational therapists) to adapt the various parenting tasks to their functional possibilities.

Scientific evidence supports the benefits of breastfeeding for the health of newborns.35 It is important to note that breastfeeding is possible for patients with immune-mediated inflammatory diseases. It is advisable that the decision to breastfeed be make jointly by the patient and the specialists, bearing in mind the mother’s wishes, the medication she is using, the level of control of the disease, and the needs of the newborn.26 During this stage, the disease must also be controlled as much as possible to reduce the intrinsic difficulties that this period entails and that could be aggravated by the disease itself. The option of not breastfeeding or resorting to mixed breastfeeding can also be considered if the mother so wishes or the circumstances so require.

When breastfeeding is chosen, guarantees must be made to ensure that the treatment administered is compatible with breastfeeding, avoiding drugs that pass into breast milk. Certain drugs, like sulfasalazine or hydroxychloroquine, are not contraindicated during breastfeeding, while methotrexate or leflunomide are. With respect to anti-TNF agents, continuing with these medications is not contraindicated, given that very little of them actually transfers to breast mild.5 Based on the publication of the prospective CRADLE study, CZP is compatible with breastfeeding, as it has minimal transfer into breast milk (<0.2%).36 Other biologics, such as anakinra, ustekinumab, abatacept, or tocilizumab, among others, have not presented data about their use in nursing mothers.5