|Ahead of print publication
Pregnancy counseling in rheumatic diseases: Where science meets the steps
Anu Balakrishnan, Pankti Mehta, Latika Gupta
Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Submission||06-Apr-2020|
|Date of Acceptance||24-Jun-2020|
Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Most rheumatic diseases (RDs) have a predilection for women in the reproductive age group. Common drugs used in rheumatology practice have identified risks to the fetus; thus, adequate pregnancy counseling is of utmost importance. Contraception and adequate preparation for the same can enhance the experience of motherhood and decrease intra as well as peripartum complications. The knowledge, as well as practices of contraception in autoimmune diseases, are low and varied in various populations. The challenges faced in different RDs are unique and keen understanding can be fruitful toward better patient care. A multi-disciplinary team effort between the patient, obstetricians, and the rheumatologist is the key to better maternal and fetal outcomes.
Keywords: Congenital heart block, lupus, myositis, pregnancy, rheumatology, scleroderma, vasculitis
| Introduction|| |
Most rheumatic diseases (RDs) have a predilection for women with reproductive potential. The advent of better therapeutics and better disease control with treat-to-target strategies have led substantial proportions of women with RDs to consider conception.
The challenges in various RDs differand a keen understanding can be lead to improved care. Apart from the effects of disease on the pregnancy and vice versa, teratogenicity intra-partum and safety during lactation merit consideration. A multi-disciplinary team effort between the patient, obstetricians and the rheumatologist is vital to meticulous obstetric care and better maternal as well as fetal outcomes.
Thus, we reviewed recent literature on pregnancy counseling in RDs by following the search strategy proposed by Gasparyan et al. Articles available on MEDLINE, published anytime, were reviewed using search words ((”pregnancy” [MeSH Terms] OR “pregnancy” [All Fields]) AND (”rheumatology” [MeSH Terms] OR “rheumatology” [All Fields]). Of the 2041 articles obtained, 1690 were human studies, and 1055 were published in the past 10 years. Seven hundred and twenty-two articles were obtained using the (NOT “review”) filter, which were further screened for relevant data. Additional information pertaining to specific diseases was obtained through an individualized search strategy.
| General Aspects|| |
Contraception in rheumatic diseases
An open discussion about family planning with the patient is vital to good obstetric care. It is ideal to make an informed choice relevant to the drugs being prescribed. In young women planning to marry, it is vital to inform them that such discussions could be deferred until then. Such discussions can go a long way in gaining patient trust and ensuring compliance. In those married and planning conceptions at a later point in time, contraception ought to be discussed. Unfortunately, only one-third (32.1%) of women with RD use contraception despite being on at least one fetotoxic medication. A vast majority of Indian women with RD are not advised contraception in the clinic. The various means of contraception are delineated in [Table 1].
Drugs and their effects on fertility merit special mention here as most patients express concerns regarding their safety [Table 2].
|Table 2: Effect of drugs on fertility, pregnancy and recommended drug free period before conception|
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While some drugs (such as methotrexate) are teratogenic and rated as category X, recent evidence suggests certain drugs (such as leflunomide) might be safer than previously believed to be. The advent of pegylated forms of biologics has lent another class of drugs which can be deemed safe due to their original molecular size and crossover properties across the placental membrane.,
Another concern is the misbelief of reduced fertility in RDs. It is essential to explain to the patients that not all RDs affect fertility adversely, making contraceptive usage of utmost importance. Several factors can affect fertility in both males and females, as detailed in [Figure 1]a. A Norwegian cohort from the birth registry with RDs showed a lower incidence of live births with longer interpregnancy intervals and reduced fertility rate. However, diseases such as lupus do not have an effect on fertilityde novo unless cytotoxic regimens such as cyclophosphamide have been used. The low conception rates could be arising out of the interplay of various social, cultural, and pathophysiologic factors. Wang et al., in a single-center retrospective review, found that age is the most critical determinant for gonadal toxicity, and CYC usage did not result in amenorrhea in patients aged 14–20. However, for patients with >36 g of total exposure, the relative risk of sustained amenorrhea was 2.1 (1.46–4.02), regardless of age. Thus, the timing of conception might be a more relevant issue to discuss with the patients instead.
|Figure 1: (a) Factors affecting fertility. (b) Physiological changes in pregnancy in the light of rheumatic diseases|
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Heritability of rheumatic diseases
Most of the RDs have genetic as well as environmental risk factors. Genetic risk factors can be either MHC related or nonrelated genes. The risk of familial transmission of each disease includes heritability of the disease along with shared environmental risk factors. Autoimmune diseases have a chance of familial transmission, and inherited disease can be the same or some other. Studies on the heritability of RDs are few and are limited by the distribution of diseases in different regions as well as confounding environmental factors. Studies which are available are consolidated in [Table 3].
Relative risks to the offspring
The patients often express a concern of transmission to the child at the time of pregnancy counseling, and this should be addressed with due diligence.
| Preparing Patients for Pregnancy (Preconception Checklist)|| |
Duration of remission
The EULAR recommends 6 months of disease quiescence before planning conception in patients with lupus. The risk of flare is higher with active disease in the 6 months before conception. Tedeschi et al. found that in 147 pregnancies among 113 patients of lupus, the odds for organ-specific flare were much higher in women with the same type of organ involvement in the preceding 6 months. Thus, it seems imperative to pay more attention to the organs previously involved in a particular patient while screening, as the nature of flares over time could be similar in each patient.
Organ damage and high risk
It is of utmost importance to assess patients for organ-specific damage and avoid pregnancy when deemed appropriate. The highest risk for adverse obstetric outcomes is seen in patients with pulmonary hypertension (spa >50 mm Hg), renal insufficiency (creatinine level >2.8 mg/dL), severe restrictive lung disease (forced vital capacity [FVC] <1 L), and active heart failure. Blood pressure control should be optimal as the odds for maternal and fetal adverse pregnancy outcomes (APOs) increase with uncontrolled hypertension. Patients with previous lupus nephritis are also deemed to be at higher risk than those without a history of it. In all such cases, alternative solutions to complete a family, such as surrogacy and adoption, should be offered.
Screening anti-phospholipid and anti-Ro/La antibodies
Antibodies against phospholipids and SSA and SSB antigens confer additional and specific risks for recurrent abortions and fetal congenital heart block as well as neonatal lupus syndromes. Thus, the antibody screen for APLA and secondary Sjogren's should be done in patients with known rheumatological diseases as well as those with bad obstetric history. It is important to note that anti-Ro antibodies can be present in up to 1% of the general population and even higher in RDs, thus making it crucial to check these in women with any known rheumatic illnesses.
Optimization of drugs
Once the drug list is checked [Table 2] and safety ensured, it is prudent to assure them of the safety and benefits of continuing HCQ, use of the same reduces disease flares in the intra and peripartum period and is highly advisable in cases with systemic lupus erythematosus (SLE). However, the he dose of glucocorticoids is best kept to the minimum required (preferably <10 mg).
e) Finally, all women should be screened for thyroid disorders and the routine antenatal screen as recommended by the obstetrician. A detailed flow-chart for prepregnancy screening is provided in [Figure 2].
| Special Situations in Pregnancy|| |
Interpretation of clinical signs and laboratory tests
Interpretation of specific findings during pregnancy merits caution due to confounding by the physiologic changes during pregnancy. The intravascular volume increases by 30%–50%, thus proteinuria up to 300 mg/24 h is considered to be normal. Further, chloasma gravidarum can be confused with the malar rash of lupus. Complement levels show a physiologic rise during pregnancy, hence in patients of lupus, failure to rise or fall from the baseline (although within normal limits) should be viewed with caution.
Symptoms of GERD increase during pregnancy due to a decrease in the tone of the lower esophageal sphincter and needs careful interpretation in patients with scleroderma (SSc). Pregnancy itself is a hypercoagulable state and may lead to thromboembolic complications akin to anti-phospholipid antibody syndrome. Finally, there is an increase in ligament laxity, and hence, joint pain in patients with RA may worsen. Furthermore, ESR rises physiologically and needs to be interpreted carefully in patients with inflammatory arthritis. Several SpA symptoms such as lumbar night pain, morning stiffness, and fatigue may also be overestimated in pregnancy [Figure 1]b.
Obstetric antiphospholipid syndrome
Antiphospholipid Syndrome (APS) is one of the most important acquired causes of pregnancy loss. Although APS has a theoretical risk of decreased fertility, there is limited data on it, and as of today, testing and treating is not required for those undergoingin vitro fertilization.[51,52] In the EUROAPS registry data, the rate of fetal loss, and obstetric complications were 22.2 and 52.2% respectively. Thrombosis was seen in 6.5% of patients mainly in the postpartum period and 7% of patients evolved to lupus later. The live birth rate increased from 49.6% in untreated patients to 85 % in the patients who were treated as per the recommended regimen patients with no treatment showed a poor birth rate. The risk is worse in those with previous APO, thrombosis in the previous 6–12 months, co-existent SLE, and triple antibody positivity. The classification, risk score as well as management of obstetric APS is mentioned in [Table 4].
Congenital heart block
The most prominent concern with the presence of anti-SSA/SSB antibodies is the risk of autoimmune congenital heart block [Figure 3]. Mothers can be asymptomatic carriers as well. The presence of these antibodies has a 2% risk of congenital heart block, which increases to 17% in women with a previous history of a similarly affected fetus. Hydroxychloroquine (HCQ) significantly decreases the risk to 7.5% in these women. The Preventive Approach to Congenital Heart Block with HCQ study (NCT01379573) is currently recruiting patients to prospectively assess the effects of HCQ on the other cardiac outcomes.
Other rare complications of anti-Ro antibodies can be heart failure, endomyocardial fibroelastosis, and valvular disease. For women with a history of fetal congenital heart block, screening with fetal 2D echocardiography is generally recommended weekly from 16 weeks onward through 26 weeks. Anti-SSA or anti-SSB/La-positive mothers with no previous history of congenital heart block, most cardiologists recommend an initial cardiac ultrasound scan at 16–20 weeks with a repeat at 28 weeks when normal. The frequency of cardiac screening in the foetus has been studied in the PR Interval, and Dexamethasone Evaluation study, where out of the 98 pregnancies analysed, 1st degree heart block was uncommon and did not always precede a complete heart block. Further, advanced heart block and cardiomyopathy can, at times, occur within a week of a normal fetal cardiac scan. Thus, frequent cardiac screening may not always detect a CHB in a timely fashion. On the other hand, frequent cardiac screening can pose a significant financial burden, cause maternal anxiety and increase the load on health services. However, detecting a heart block when it is afirst degree in nature may be more amenable to treatment with fluorinated glucocorticoids, although this is not firmly established.
Other features of neonatal lupus syndrome include a transient subacute cutaneous lupus rash exacerbated by exposure to ultraviolet radiation after birth, hematological manifestations (such as cytopenia) and hepatobiliary disease. This is a lesser concern usually, as most of these manifestations resolve in thefirst 6–9 months of life as maternal anti-SSA/Ro antibodies are cleared from the infant's circulation.
Preeclampsia versus lupus nephritis
Preeclampsia is ten times more common in patients with lupus; with an incidence varying from 2% to 35% as compared to 2%–8% in the general population,, although the prospective PROMISSE cohort estimated a higher risk (15%). The difficulty in differentiating a lupus flare from preeclampsia in the presence of hypertension, proteinuria, oedema and thrombocytopenia could account for varied reports of incidence. [Supplementary Table 1] delineates the approach to differentiating between the two conditions.
The various factors predictive of preeclampsia include preexisting hypertension, diabetes, nulliparity, history of preeclampsia, and lupus-specific factors such as active disease, previous proliferative lupus nephritis, the presence of anti-phospholipid antibodies, thrombocytopenia, and low complements. At times, a renal biopsy may be required to differentiate the two. Although biopsy is contraindicated in thefirst and third trimesters, it could be done in the 2nd trimester of pregnancy, when deemed indispensable.
Patients with preeclampsia require intensive monitoring of blood pressure and frequent investigations such as uric acid and urine protein levels for early detection of APOs. Newer biomarkers such as the placental growth factor, serum endoglin, FMS like tyrosine kinase, alternative complement products have been studied to predict APOs. Simple calculators have been devised by Wu et al. to predict APOs with a Area Under the Curve of 0.88. The authors identified three variables that independently predicted fetal loss: unplanned pregnancies (odds ratio [OR] 2.8, 1.1–7.2), low C3 (5.5, 2.3–13.0), and 24-h urinary protein (2.1, 2.3–15.1).
| Salient Features of Rheumatic Diseases|| |
Systemic lupus erythematosus
A recent metanalysis substantiated 25% higher risk of mild flares and 5% for severe flares in lupus during pregnancy. Active disease in the preceding 6 months is the single most important determinant of an intra-partum flare. HCQ has consistently shown a remarkable effect in lowering the risk for flares both intra-partum and peri-partum (RR − 1.83–1.26).
Patients with pSS report dyspareunia from dryness, and an increased risk of neonatal deaths (OR 1.8, 1.3–1.5) compared to other RDs, apart from fetal heart block, as previously described.
Unexplained subfertility in RA is well-described, and speculations are rife about the role of NSAID and/or prednisolone usage and high disease activity. The PARA study further affirmed a longer time to pregnancy in RA (in 42%), especially in the older and nulliparous, apart from the afore-mentioned groups. Thus, maximum control of disease and reduced drug usage should be ensured preconception.
Uncontrolled disease incurs a higher risk of hypertension, prematurity, IUGR, and lower segment cesarean section in patients, although most (48%–60%) decreased disease activity postpartum.
The limited data on APO in spondyloarthritis, suggests flare rates ranging from 25% to 80%,, being the highest in active disease, high C reactive protein and TNFi discontinuation in early pregnancy. Further, a higher rate of preterm deliveries, IUGR, and cesarean section is observed in patients with Ankylosing spondylitis.
On the other hand, pregnancy outcomes are reportedly excellent in psoriatic arthritis, with a visible decline in cutaneous and musculoskeletal disease, although flares are described postpartum.
As in all other diseases, hormonal changes in pregnancy, lead to Th1 suppression and Th2 polarization. Thus, many types of vasculitis (Takayasu's arteritis [TA] and Bechet's disease [BD]) have reportedly lower flare rates in pregnancy, whereas ANCA associated vasculitis (AAV) flares often, while data on other forms of vasculitis is limited.
Most studies have focused on the pregnancy outcomes in TA and BD, as these affect women under 40 years of age. TA has a significant negative impact on maternal (hypertension) as well as fetal complications (IUGR and prematurity). Studies from India also showed that fertility in TA is not different from the general population. The scoring system by Wong et al. predicted low fetal weight with accuracy by a weighted score (0–2) of four parameters: involvement of the abdominal aorta, highest MAP in the third trimester, treatment started from which trimester of the pregnancy and co-existing preeclampsia in Indian women with TA, whereas the standard outcome measures could not.
On the other hand, pregnancy does not seem to have a significant impact on disease activity, with flare rates described as 5%. With reasonable control of hypertension, the outcome can be improved in patients with stable disease, although cesarean section rates were higher than the general population.
Patients with BD have good obstetric outcomes, with flares in 30%–36% patients, mostly manifest as oral or genital ulcers, arthritis, uveitis, erythema nodosum, and less frequently, thrombosis, although lower with colchicine. Notably, a history of thrombosis poses a high risk of APOs.,
AAV affects older individuals, reducing potential co-occurrences with conception, although a systemic review recently described successful pregnancy in 86.5%.
Scleroderma and mixed connective tissue disease
Erectile dysfunction and decreased sexual activity account for lower fertility rates in both men and women with SSc. The various physiological changes associated with pregnancy, such as an increase in the blood volume, cardiac output, decrease in the vascular resistance, and decreased tone of the lower esophageal sphincter, are more marked during the pregnancy in SSc. Raynaud's phenomenon improves during pregnancy, whereas GERD symptoms are aggravated.
Among those who conceive, a lower FVC (<50%), moderate-to-severe pulmonary artery hypertension, renal failure, or cardiomyopathy (Ejection fraction < 30%) leads to a higher risk of intrapartum complications such as preterm delivery, IUGR, and SGA than those without end-organ complications.
Patients with rapidly progressive skin disease, anti-topoisomerase or anti RNAPIII antibodies and those receiving high dose glucocorticoids have a heightened risk of developing the SSc renal crisis; necessitating stringent control of blood pressures at earliest possible. Despite the risk of oligohydramnios in pregnancy, ACEIs are the drug of choice. Notably, previous SRC does not increase the risk for a recurrence when controlled for several years before conception. In patients with sine SSc SRC, it is difficult to distinguish from other thrombotic microangiopathies that can occur during antepartum or postpartum. However, the presence of antibodies may help in some situations.
| Idiopathic Inflammatory Myositis|| |
Most IIM tolerate pregnancy well in quiescent disease, with good maternal outcomes though preterm delivery and SGA are reported. A high spontaneous abortion rate was recently observed in the absence of clinical or serologic APS in a cohort of women with IIM from India, suggesting a possible impact of health-care policy in the developing world in chronic diseases.
The heterogeneity of IIM calls for collaborative efforts to identify the risk factors in stratified population sets, and gather more evidence on the impact of models of healthcare delivery in the different countries, and sociocultural factors on outcomes.
| Postnatal Period and Lactation|| |
The higher risk of flares of RDs in the postnatal period requires adequate vigilance in the postpartum period. Drug safety in lactation is another important consideration. The unique benefits of breastfeeding to the child and the mother; calls for a close consideration of the disease status and safety review of ongoing medicines while making an informed choice with the patient [Table 5]. Lipid soluble, non-ionized, non-protein bound small molecules are more likely to get transferred in breast milk, an important guiding factor while prescribing drugs in that period.
| Social and Ethical Issues in India|| |
Apart from medical and obstetric issues, it is important to be mindful of the sociocultural concerns which come to the fore in such times. Chronic RDs run the risk of social stigmatization, worse when compounded by illiteracy and poverty. Contraception usage can be dismal in some societies, influenced by sociocultural and religious choices.
Patient confidentiality is a right that ought to be respected at all times. Oftent, imes the patients are unable to return for follow-up for long periods due to social or personal constraints, this being the prime deciding factor for drug choices. It is important to discuss all treatment options and their benefits and risks with the patient (and their kin) for an informed choice. Spouse's rights when a woman chooses confidentiality are a grey area and oft-encountered but potentially challenging to manage. A counselor on the team could be an important resource to delve into the psychosocial intricacies. The engagement of voluntary women's support groups could be another potential solution.
Further, contraception failures are not unknown, and being diagnosed with an unplanned pregnancy could signify the risk of teratogenicity from ongoing drugs, alongside the huge decision to continue with the pregnancy versus not, keeping in mind the risk to both the fetus and the mother. Recently, a landmark amendment of the MTP act in India suggested abortion irrespective of gestational age for medical reasons when substantial fetal anomalies were detected after the certification from a medical board appointed by the state. This is not legalized as an act till now. In times when the patient's decision is to continue the pregnancy (which could be for various reasons) despite all risks, the patient's right has to be respected after appropriate documentation.
Finally, understanding sociocultural issues at interplay is an active area of research that merits consideration to prepare physicians toward better management of this oft encountered situation.
| Conclusion|| |
Pregnancy in patients with RDs should be regarded as a high-risk situation that mandates vigilant monitoring by a multidisciplinary team comprising a rheumatologist, obstetrician, and social worker, where feasible. The limited treatment options and various challenging situations make it important to weigh maternal benefits against the perceived fetal risk. With appropriate preconceptional counseling and a coordinated multidisciplinary approach, optimum outcomes can be achieved.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]