Background
Autoimmune rheumatic diseases (ARD) mostly affect women of childbearing age. Although ARD do not represent a cause of infertility in themselves, they may be related to a decrease in parity for multifactorial reasons such as the concern of having a child with ARD, or being unable to care for a child due to the structural damage that may arise. On the other hand, antirheumatic drugs such as cyclophosphamide have the potential to decrease gonadal function. Therefore, it is of fundamental importance to discuss family planning at the time of diagnosis since the desire for a pregnancy in the short or long term will influence the therapeutic choices.
In addition, patients must be aware that pregnancy should not be attempted until the disease is in stable remission because, according to international consensus statements, active disease before conception represents the main predictor of adverse pregnancy outcomes. The treatment of patients with ARD before and during gestation should aim to control maternal disease activity with drugs that are not fetotoxic or teratogenic (see Table 1). Additionally, obstetric risk stratification must take into account general and disease-specific risk factors (see Table 2).
Here, we present a case of a patient with systemic lupus erythematosus (SLE) with previous major-organ involvement, who was on treatment with teratogenic immunosuppressive drugs and desired to have a child. We will describe the patient’s journey regarding family planning, which will showcase the preconception counselling and risk stratification suggested for women with ARD.
Case presentation
The patient was a 37-year-old Caucasian woman who came to our pregnancy clinic for preconception counselling. She was diagnosed with SLE at the age of 33 years, when she presented to our hospital complaining of a 6-month clinical picture of intermittent fever, asthenia, inflammatory peripheral arthralgia, facial and extremities morning edema, and foamy urine. At physical examination, she exhibited polyarthritis of wrists and hands, and hypertension. Blood samples revealed normocytic normochromic anemia (hemoglobin 10.5 g/dL), mild leukopenia (3100x109/L), hypoalbuminemia (2.6 g/dL), hypertriglyceridemia (201 mg/dL), normal creatinine (0.8 mg/dL) and active urinary sediment with a 24 hour proteinuria of 3 g/day.
An immunology panel showed: low complement levels, C3 level of 52 mg/dL (normal range 90–160 mg/dL), C4 of 9 mg/dL (10–40 mg/dL); high titers of antinuclear (1:640, homogeneous pattern) and anti-dsDNA antibodies; positivity for anti-Ro/SSA antibodies; and positivity for the three antiphospholipid antibody (aPL) criteria tests, anti-cardiolipin IgG (61 GPL; cut-off <10 GPL), anti-beta-2 glycoprotein I IgG (0.183 OD; cut-off <0.129 OD), and lupus anticoagulant. Renal biopsy was compatible with class IV lupus glomerulonephritis (GN). A diagnosis of SLE with renal major involvement was made.
Induction treatment was initiated for SLE GN according to the National Institutes of Health protocol, with monthly intravenous cyclophosphamide for 6 months (cumulative dose 8 g) together with 1 mg/kg/day of oral prednisolone, gradually tapered to 5 mg/day over 6 months. Each cyclophosphamide infusion was preceded by a subcutaneous injection of leuprolide (gonadotropin-releasing hormone agonist) for ovarian protection. The patient then began maintenance treatment with mycophenolate mofetil (MMF) 1 g twice a day and reached complete remission after 18 months (no symptoms, no cytopenia, no proteinuria, negative anti-dsDNA, and normal complement levels – SLEDAI 0).
At the first visit to the pregnancy clinic, the patient was taking the following medications: prednisone 5 mg/day for 4 days/week; MMF 2 g/day; low dose acetylsalicylic acid (LDASA) 100 mg/day; ramipril 10 mg/day; omeprazole 20 mg/day; and vitamin D (1500 IU/day). She had been in sustained complete remission for the past two and a half years, and desired to conceive a child. The patient was nulliparous, had a normal body weight (57 kg, body mass index of 22 kg/m2), normal blood pressure (ramipril was given for kidney protection) and did not smoke.
Questions
Question 1. The patient would like to become pregnant within the coming year. How would you counsel her?
Question 2. What therapeutic modifications would you suggest in order for the patient to become pregnant?
Question 3. The patient has anti-Ro/SSA antibodies. What should be your main concern in the presence of this antibody profile?
Question 4. In the event that the patient’s disease was inadequately controlled, she would be advised to postpone pregnancy plans. What contraceptive measures would you recommend in this situation?
Treatment
Preconception counseling and risk stratification should be performed for all women with ARD, ideally at a pregnancy clinic with both rheumatologists and obstetricians. Key features to be considered at this preconception visit are: the evaluation of disease activity, presence of major organ involvement, antibodies profile, associated comorbidities, alcohol and smoking habits, and use of teratogenic drugs.
In women of reproductive age, the ideal time for this evaluation is close to diagnosis, in order to set the timing for a future pregnancy and to avoid, if possible, drugs that can lead to premature gonadal failure such as cyclophosphamide. If this drug is used, ovarian protection should be offered by means of gonadotropin-releasing hormone agonists, as was performed in the case of the this patient. Oocyte cryopreservation can be another option, although not widely available.
In this patient’s case, since SLE disease activity has been in remission for more than a year and she did not have any other comorbidity, she should be advised that she may get pregnant after stopping teratogenic drugs, in this case MMF. Sufficient time should be allowed for proper washout (at least 6 weeks for MMF). She should initiate azathioprine, a well-known antirheumatic drug compatible with pregnancy and breastfeeding, titrated to a maximum of 2 mg/kg/day if needed to keep SLE with previous renal major involvement under control.
In addition, the patient should immediately start hydroxychloroquine 5 mg/kg/day, which is known to be fundamental in prevention of disease flares in SLE patients during pregnancy, and may reduce the occurrence of CHB in mothers with positive anti-Ro/SSA. It may also reduce the incidence of small-for-gestational-age fetus in mothers with SLE GN, and seems able to prevent pregnancy loss and fetal damage in patients with aPL through complement inhibition.
LDASA, which is also compatible with gestation and breastfeeding, should be continued during pregnancy considering the presence of aPL antibodies and its proven role in preventing pregnancy adverse outcomes such as preeclampsia and preterm delivery. ACE inhibitors such as ramipril should be withdrawn after a positive pregnancy test because they may cause fetal malformations. Enoxaparin at a prophylactic dosage can be initiated as soon as the patient becomes pregnant in order to prevent first maternal event and/or obstetric adverse outcome in a patient carrying a high risk aPL profile (triple positivity).
After our preconception visit, the patient began to take hydroxychloroquine, alternating 200 and 400 mg every other day. She stopped MMF and started azathioprine 100 mg/day. She was advised to wait at least 6 months after this change of antirheumatic immunosuppressive drugs to allow proper monitoring of disease, with monthly evaluation of renal parameters and bimonthly evaluation of anti-dsDNA titres and levels of C3 and C4. After this time, considering that her disease remained in remission, she received the “green light” to conceive.
As planned, after a positive pregnancy test, she stopped ramipril and started enoxaparin 4000 IU/day. As recommended for the general obstetric population, she continued to take folic acid (5 mg/day) during the months prior to conception, and started with vitamin D (1000–1500 IU/day) and calcium (500–1000 mg/day) supplements.
Since anti-Ro/SSA antibodies begin to cross the placenta after 16 weeks of gestation and may cause neonatal lupus, for which the most feared manifestation is congenital heart block (CHB), the patient underwent weekly fetal echocardiograms from 16 to 26 weeks of gestation to ensure timely diagnosis of this complication, according to our local practice. However, it is unclear whether such an intensive surveillance during pregnancy is cost-effective. Registries of CHB cases do not provide evidence that the prompt use of fluorinated steroids in cases of isolated CHB significantly alters fetal/neonatal morbidity or mortality. Therefore, the value of early diagnosis of CHB to ensure early treatment is currently under debate.
As SLE is associated with higher risk of adverse pregnancy outcomes, such as preeclampsia and intrauterine growth restriction, compared with the general population, the patient underwent supplementary fetal surveillance with Doppler sonography in the third trimester at monthly intervals.
Outcome and follow up
The patient’s pregnancy was unremarkable. A healthy male baby was born at 39 weeks of gestation by spontaneous vaginal delivery, with adequate weight for gestational age (2680 g). No complications occurred throughout gestation, there were no disease flares, nor obstetric adverse outcomes, nor CHB. The patient decided to breastfeed and maintained the same therapeutic regime as during pregnancy. At 6 weeks after delivery she stopped prophylactic enoxaparin and resumed LDASA which had been stopped at 36 weeks of gestation. She maintained a regular follow up at our lupus clinic and is still in sustained remission. Contraception was discussed with both the rheumatologist and the gynecologist and the patient chose to use a levonorgestrel-releasing intrauterine device.
Discussion
Successful pregnancies are feasible in ARD patients in the presence of the conditions listed below.
- Provision of proper preconception counseling and risk stratification should be timely (since the very first visit, if the patient is of childbearing potential), ideally by a multidisciplinary team composed of rheumatologists and obstetricians. As stated above, key features to be considered at this preconception visit are the evaluation of disease activity, presence of major organ involvement, autoantibody profile, associated comorbidities, alcohol and smoking habits and use of teratogenic drugs.
- Teratogenic drugs must be withdrawn and proper wash-out allowed before conception. Disease activity must be kept under control by other anti-rheumatic drugs that are compatible with pregnancy and breastfeeding.
- Pregnancy should start after a period of at least 6–12 months of stable low disease activity or remission.
- Pregnancy should be managed in a multidisciplinary setting – ideally in a joint clinic composed of rheumatologists, obstetricians and other specialists as needed, with clinical expertise in following pregnant patients with ARD.
This case highlights that having a rheumatic autoimmune disease and being treated with immunosuppressive drugs does not represent a contraindication to pregnancy.