|Year : 2020 | Volume
| Issue : 1 | Page : 10-20
|Pregnancy and lupus nephritis in developing countries: A systematic review
Sukriti Bansal1, Ogochukwu Okoye2, Nilum Rajora3
1 Michael E. DeBakey Department of Surgery, Baylor College of Surgery, Houston; University of Texas Southwestern Medical Center, Dallas, Texas, USA
2 Department of Internal Medicine, Faculty of Heath Sciences, Delta State University, Abraka, Nigeria
3 Nephrology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Click here for correspondence address and email
|Date of Submission||02-Apr-2019|
|Date of Decision||13-May-2019|
|Date of Acceptance||16-May-2019|
|Date of Web Publication||3-Mar-2020|
| Abstract|| |
Systemic lupus erythematosus (SLE) and lupus nephritis (LN) have a significant impact on the course of pregnancy, as well as on maternal and fetal outcomes. LN in pregnancy can increase the maternal risks of SLE flare, acute kidney injury, preeclampsia, and even death. It also affects fetal outcomes by the increased risk of intrauterine growth retardation, premature delivery, and fetal loss. Successful pregnancy outcomes have been well documented in the developed world, but less is known about patients in developing nations. We searched PubMed and Google scholar for all articles published from 1999 to 2016 in developing countries. Twelve of 13 studies were included excluding only one. All studies were independently reviewed. Most of the studies reported a significant association between high flare rates of LN and higher rates of disease flare. Higher rates of active disease at conception were associated with lower live birth rates. Similarly, high flare rates of LN were associated with higher rates of fetal loss. With regard to geographic trends, Indian studies reported lower overall live birth rates and higher rates of active disease at conception. Interestingly, lower rates of preeclampsia were also noted in Indian studies. Higher rates of flare were observed in other Asian studies, but not the Indian studies. Although LN and active SLE at conception are associated with poor fetal outcomes, better outcomes are possible with proper management, even in low-resource settings. More research is necessary to fully understand the relationships between active disease at conception or LN and flare rates, live birth rates, and fetal loss rates in developing countries.
|How to cite this article:|
Bansal S, Okoye O, Rajora N. Pregnancy and lupus nephritis in developing countries: A systematic review. Saudi J Kidney Dis Transpl 2020;31:10-20
|How to cite this URL:|
Bansal S, Okoye O, Rajora N. Pregnancy and lupus nephritis in developing countries: A systematic review. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 May 27];31:10-20. Available from: http://www.sjkdt.org/text.asp?2020/31/1/10/279928
| Introduction|| |
The systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with manifestations including dermatologic rashes, arthritis, nephritis, hemolysis, and thrombosis. Currently, the standard of diagnosis is based on the 2012 Systemic Lupus International Collaborating Clinics guidelines, another diagnostic guideline is the 1997 American College of Rheumatology Guidelines, which requires patients to meet four of 11 criteria.
The prevalence of lupus worldwide varies significantly, in part due to its variable presentation and the changes in diagnostic criteria, but also likely due to differences in access to health-care systems, economics, geographic location, environmental factors, and population genetics. In general, SLE affects women considerably more often than men, particularly women of reproductive age., While SLE has many systemic effects, the fertility of these patients is typically unaltered from the general population. 
| Pregnancy in Systemic Lupus Erythematosus|| |
Historically, pregnancy for patients with SLE has been contraindicated. However, in the past several decades, therapy and disease management for patients with SLE has improved to the point that good outcomes are achievable for many of these patients. Such patients are still considered to have high-risk pregnancies, ideally managed under the coordinated care of a maternal-fetal medicine specialist, a rheumatologist, and other specialists as needed.,
While the exact results of studies vary, the general trend shows that pregnancy in patients with SLE tend to have higher maternal mortality, exacerbations of disease activity, fewer live births, and more complications during pregnancy, including a higher risk of preeclampsia/eclampsia, C-section, prematurity, and post-partum infection.,,, SLE also has unique congenital disorders associated with it, notably neonatal lupus and congenital heart block. , Other fetal conditions associated with SLE pregnancy include prematurity, intrauterine growth restriction (IUGR), neonatal death (NND), and hematologic or hepatic laboratory abnormalities., In addition, the unique immune tolerance that is typically achieved in pregnancy is disordered in patients with SLE., This effect appears to be related to the higher risk of SLE flares during pregnancy and the postpartum period, as the hormonal and cytokine changes of pregnancy, which stimulate the T-helper 2 cell (Th2) response and reduce the T-helper 1 (Th1) cell response.,,,, These same immunological changes may be related to many of the maternal and fetal complications seen in pregnancy with SLE., Further complicating factors in the treatment of SLE with pregnancy are the appropriate use of immunosuppressants many of which are teratogenic’,, This limits the treatment options for patients requiring immunosuppression to maintain quiescence or treat SLE flares for those who are also seeking pregnancy. Available treatment options are steroids, cyclophosphamide (contraindicated in the first trimester), azathioprine, calcineurin inhibitors, and hydroxychloroquine.,,, The use of biologics in treating immunosuppression is largely still unstudied in pregnancy. The management of immunosuppression thus becomes particularly difficult not only for SLE patients seeking pregnancy but also even more so for those SLE patients who have received a transplant.
As such, the current recommendations for pregnancy in patients with SLE are for planned conception after at least six months of disease quiescence, with the appropriate transition to non-teratogenic immunosuppression as needed to maintain quiescence., More recent studies have suggested that the necessary quiescence period may only be four months rather than six months, but this is controversial. Quiescent disease is the only well-established predictive factor for reducing the risk of SLE flare or other pregnancy complications. The risk factors associated with poor outcomes likely also affect the ideal length of remission before pregnancy, but these risk factors remain to be fully elucidated. Several implicated risk factors for poor outcomes (neonatal demise and IUGR), include lupus nephritis (LN), antiphospholipid syndrome (APS), active disease during pregnancy or before conception, arterial hypertension (HTN), and anti-dsDNA antibodies (particularly anti-Ro/La which are associated with congenital heart block in the fetus).,, New onset of disease appears to have the strongest impact on the risk of NND and IUGR.
| Lupus Nephritis and Pregnancy|| |
LN is a common, more severe manifestation of SLE. While SLE can impact the kidney in multiple ways resulting in renal insufficiency, LN refers specifically to glomerulonephritis caused by immunoglobulin complex deposition. Patients with LN compromise a unique population within patients with SLE, particularly when it comes to pregnancy. Unlike most other manifestations of lupus, LN can have an impact on fertility, as chronic kidney disease (CKD) of any cause can reduce fertility, particularly for women with baseline elevated Cr levels., Of the causes of CKD, LN seems to have a greater impact on fertility than others. Immunosuppressants used to treat LN also impact fertility, specifically cyclophosphamide, which has dose-dependent effects on fertility that can be more pronounced in older patients.,,, There have been studies showing that a longer period of quiescence will benefit patients with LN seeking pregnancy, extending it to 12-18 months, rather than the more common guideline of six months, to reduce risks. Complicating factors that impact risks seen with pregnancy in LN include concurrent HTN, proteinuria, APS, anti-Ro/La antibodies, and renal insufficiency. HTN, proteinuria, and renal insufficiency all increase the risk of developing preeclampsia/eclampsia, pre-term delivery, placental abruption, IUGR, and pregnancy loss. Concurrent APS is highly associated with miscarriage [spontaneous abortion (SAB)], intrauterine fetal demise (IUFD), as well as stroke, thrombosis, and preeclampsia/ eclampsia.,,,, APS can also affect renal function, worsening the effects of renal insufficiency on pregnancy. Anti-Ro/La antibodies, besides being associated with congenital heart block and neonatal lupus, can also increase the risk of IUFD and NND.,
Beyond the effects of LN on pregnancy outcomes, pregnancy also appears to have effects on LN and SLE disease activity and progression.,, These effects are less well established than those of SLE on pregnancy outcome. Some studies have noted that pregnancy increases risk of SLE flare, particularly for patients who have LN.,,, The increased risk of SLE flare in pregnancy may be due to the hormonal and cytokine changes that alter the immune system during pregnancy. In particular, the increased Th2 response and decreased Th1 response - Th2 cells primarily modulate SLE.,, Patients with LN have a 2-3-fold higher risk of SLE flare, compared with SLE patients without LN; although the etiology of this is not well understood. The risk of SLE flare during pregnancy also appears to be higher in patients with active disease or quiescence <6 months. For patients with LN, renal flares are of particular concern which presents with worsening renal function, proteinuria, and even progression to end-stage renal disease., As such, proper planning for patients with LN who desire pregnancy is essential to reduce the risk of poor pregnancy outcome, SLE flare, and disease progression.
In addition to patients with a prior diagnosis of SLE, there is also the subgroup of patients who have a new diagnosis of SLE during pregnancy. Patients with a new diagnosis of SLE tend to have more severe disease and worse pregnancy outcomes. Within this group of patients, LN and renal flares appear to be a highly common manifestation, with subsequently poorer outcomes, both in terms of rates of IUGR and NND, as well as on SLE activity and disease state.
Successful pregnancy outcomes have been reported in patients in the developed world, but less is known about patients in developing nations. This prompted us to proceed with a literature search and review as follows.
| Materials and Methods|| |
We searched PubMed and Google Scholar for studies on SLE and/or LN in pregnancy in developing countries, spanning from 1999 to 2016; older studies were excluded given the advances in the management of SLE now compared to over two decades ago. Developing countries were defined using the United Nations list of developing nations created by the Department of Economic and Social Affairs.
Outcomes and complications were defined as follows, miscarriage or SAB as fetal loss <24 weeks gestation, IUFD as fetal loss >24 weeks gestation, pre-term as viable delivery <37 weeks gestation, proteinuria as >0.5 g protein/ 24 h, preeclampsia as blood pressure >140/90 mm Hg and proteinuria developed >20 weeks gestation, eclampsia as preeclampsia with seizure, IUGR as fetal weight <10 percentile, and APS as the presence of antiphospholipid antibodies and history of thrombosis or multiple early pregnancy loss.
Two of the authors reviewed all studies independently. The available data for individual studies included were inconsistent; therefore, studies that lacked the data of interest for a particular analysis were excluded. Data were analyzed to determine if there was any correlation between active lupus disease and SLE flare during pregnancy, presence of LN and renal flare, active disease and pregnancy outcome (live birth and fetal loss), and LN and pregnancy outcome (live birth and fetal loss). In addition, data were divided by geographic region as available, to look for any trends in the variables mentioned above. The geographic regions used were India, Southeast Asia, and Africa. No studies were found for South America.
Percentage of patients with active SLE disease, LN, and flare were calculated to allow a more standardized comparison. Similarly, the percentages of live births and fetal loss from total pregnancies were calculated (fetal loss did not include medical termination, as the legality and ability to obtain termination differs from nation to nation). Data were charted using Microsoft Excel 2013, and analyzed for any correlation.
| Results and Discussion|| |
Thirteen studies were obtained of which one case report was excluded. All included studies utilized the 1997 American College of Rheumatology classification criteria for diagnosis of SLE, and the SLE Disease Activity Index score to diagnose lupus flare. The 12 studies included consisted of 11 single-center retrospective case reviews, and a prospective case series.,,,,,,,,,,, The amount of available information in the studies varied based on geographic location and available laboratory resources.
Relation of active disease to flare, and pregnancy outcomes
Active disease before conception and during pregnancy had no significant relationship to SLE flare. While there are studies illustrating this relationship in the literature from developed countries, it is possible that this effect may have a genetic component. Other factors that might affect the data for the relationship between disease activity at conception and SLE flare rate are immunosuppressive drug regimen, environmental factors, comorbidities, organ systems involved in SLE, age at diagnosis, number of prior flares, and available health care or diagnostic resources. More studies are needed to better understand the effects of active disease on SLE flare rate, as the data remain inconclusive.
The relationship between active disease at conception, and live birth rate and fetal loss, are shown in [Figure 1]. There appears to be a correlation between active disease at conception and live birth rates. In majority of the studies, live birth rates decreased as rates of active disease increased; but an exception to this general trend was the study by Dey et al. They observed a very high rate of active disease at conception (83.3% for n = 7), but a low live birth rate (57.1%); however, the birth rate was still higher than seen in Chandran et al and Gupta et al (46.2% and 45.5%, respectively) despite lower rates of active disease (67.7% and 47.1%, respectively) at conception in both of those studies. This effect could be attributed to the small population studied by Dey et al (n = 7) compared to the larger populations studied by Chandran et al (n = 52) and Gupta et al (n = 33). Other contributing factors could be genetic differences, comorbidities (e.g., APS), immuno- suppressive regimen, age at the diagnosis, and number of prior SLE flares.
|Figure 1: Comparison of live birth rate, rate of fetal loss, and rate of active systemic lupus erythematosus at conception.|
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When the fetal loss rate was compared to the rate of active SLE at conception, there was no correlation between the two. Instead, it appears there may be a baseline rate of fetal loss seen in patients with SLE that is unrelated to rates of active disease at conception. Note that in this study, fetal loss rate included only SAB and IUFD, but excluded medical terminations performed for lupus flare or severe disease. The exclusion of data on terminations may explain the lack of correlation between active disease and fetal loss, especially since there was a correlation between active disease at conception and live birth. In the case of severe lupus flare threatening the mother’s life or poorly controlled disease, medical termination may be indicated. Since medical termination is not legal in every country and the data were unknown in several studies, this factor could not be included in the analysis, and its effects are unknown. More studies are needed, ideally including data on terminations for severe disease and lupus flare, to fully understand the relationship between active disease at conception and fetal loss.
Concerning the relationship between disease activity at conception and risk of lupus flare, live birth rates, or fetal loss; Chandran et al and Phadungkiatwattana et al reported a significant association between active disease and lupus flare. Chandran et al and Ku et al found an association between active disease and live births; again, only these two studies found an association between active disease and fetal loss. In contrast, six studies,,,,, found a significant association between LN and lupus flare; however, only two, reported a significant association between LN and fetal loss. In summary, the majority of the studies reported that there was no significant relationship between active disease state at conception and SLE flare, live birth, or fetal loss. Most studies reported a significant relationship between LN and lupus flare rate, but did not find a significant relationship between LN and fetal loss. Overall, data are inconclusive with regard to the relationships between disease activity or LN and lupus flare or pregnancy outcome. More research is needed to understand these relationships.
Relation of lupus flare rate to pregnancy outcomes
The studies did not show any correlation between SLE flare rate and the live birth rate [Figure 2] ; little was reported on the correlation between SLE flare rate and live birth rate in the literature, presumably because both are typically viewed as outcomes - lupus flare rate as a maternal outcome and live birth rate as a fetal outcome.
|Figure 2: Comparison systemic lupus erythematosus flare rate with live birth rate and rate of fetal loss.|
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Similarly, no correlation was found between lupus flare rates and fetal loss rates [Figure 2]. Again, the absence of data on medical terminations may explain this observation. Overall, lupus flare does not appear to have any effect on the fetal outcome with regard to pregnancy. As with lupus flare rate and live birth, there was not much reported in the literature about a relationship between flare rate and fetal loss, for presumably the same reason.
Relation of lupus nephritis to systemic lupus erythematosus flare rate and pregnancy outcome
When the overall rates of LN and lupus flare rate were compared [Figure 3], there appeared to be a correlation between the two. Namely, higher rates of LN within the population appear to be correlated with higher rates of SLE flare. Of the studies included, five studies did not fit this overall trend: Chandran et al, Gupta et al, Tan et al, Dey et al, and Whitelaw et al. These five studies had a >15% (the standard deviation for overall SLE flare rates across all 12 studies) difference between the rate of LN and the SLE flare rate, which was used as the cutoff for a relationship. However, six studies reported a significant relationship between LN and SLE flare rate. Tan et al did not comment on the relationship between LN and SLE flare rate. The other four studies reported no significant relationship between the two.
|Figure 3: Comparison of lupus nephritis and systemic lupus erythematosus flare rate.|
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Many factors could impact this relationship, most notably genetic or geographic differences, immunosuppressive regimen, the use of aspirin and hydroxychloroquine, age at diagnosis, prior history of SLE flares, disease state at conception, severity of disease, comorbidities, or degree of renal insufficiency. The use of aspirin and hydroxychloroquine during pregnancy is of particular interest as both have been shown to improve maternal and fetal outcomes. Most of the studies did not report on the number of patients using these therapies, and hence, it is possible that the studies with lower SLE flare rates used more of hydroxychloroquine (which reduces risk of flare).
With regard to the impact of genetics on SLE flare rate, Mbuli et al found that their patients of black African ancestry had a significantly higher SLE flare rate compared to patients of mixed ancestry. They did not report on the proportion of black African patients with LN and subsequent SLE flare rates. Other studies have reported on genetic differences among populations in Asia having greater severity of SLE, as well as higher proportions of LN. As such, though there appears to be an overarching relationship between LN and the risk of SLE flare, there are likely genetic factors that impact and alter this relationship. More studies are necessary to fully understand the trend, and hopefully to elucidate the impact of geographic and genetic differences in LN and subsequently the relationship between LN and SLE flare rate during pregnancy.
There appeared to be a correlation between rates of LN and fetal loss rates [Figure 4]. Increased rates of fetal loss were seen within populations with higher rates of LN. The exceptions were Phandungkiatwattana et al, Tan et al, Teh et al, and Aly et al, where high rates of LN in these four studies were not necessarily correlated with high rates of fetal loss. Since LN appears to correlate with SLE flare, the lack of termination data could significantly impact the understanding of any relationship between LN and fetal loss. Interestingly, while many studies noted a correlation between LN and increased rates of fetal loss, only two, reported that this was statistically significant.
|Figure 4: Comparison of lupus nephritis to rate of fetal loss and live birth.|
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Multiple reasons exist for this, including small sample size (ranging from n = 7 to n = 109), genetic differences between populations, the use of aspirin and hydroxychloroquine during pregnancy, other immunosuppressive therapy, disease activity at conception, renal insufficiency, among others. Aspirin reduces the risk of preeclampsia, which has subsequent significant effects on fetal outcomes, including fetal loss. Hydroxychloroquine also affects the risk of preeclampsia, as well as complete heart block; both of which impact the rate of fetal loss. Further studies that consider these other variables are needed to understand the relationship between LN and fetal loss.
A correlation was observed when the rate of LN was compared to the rate of live births [Figure 4]. Higher rates of LN were correlated with lower live birth rates. This effect was less pronounced in Aly et al, Dey et al, and Mbuli et al (all studies from Africa), but still present. Given that the effect was less pronounced in African studies, may suggest a genetic influence. This finding fits with the observation that LN is associated with increased fetal loss. Whether or not these relationships are significant is unknown, as this was not reported in the studies included in this review. Further data are needed to understand the relationship between LN and pregnancy outcomes.
Within the geographic regions, the following general trends were noticed. It appears that the live birth rate was considerably lower in India compared to other regions, and the rate of active disease at conception was relatively higher [Table 1]. Dey et al is an exception to this trend. The other noticeable trend regarding the Indian population compared to the rest of the world is that the rate of preeclampsia was relatively lower [Table 1].
The lower birth rate in India could be attributed to numerous factors, including access to prenatal and obstetric care, access to rheumatologic care, higher rates of active disease at conception, genetic differences, cultural or financial barriers to accessing care, and availability and access of immunosuppressive medication. While Aggarwal et al had a live birth rate more comparable to the other studies; their study included a significantly smaller population (n = 15) when compared to Chandran et al (n = 55) and Gupta et al (n = 33). Thus, numerous factors could explain the overall lower birth rates seen in the Indian population compared to the other studies. Further research controlling for these variables would be needed to determine if there is a genetic component to these outcomes.
The higher percentage of active disease at conception in the Indian studies could be explained by cultural differences between geographic regions, particularly since India is a single country (no other studies were found for the subcontinent), while the other regions encompass multiple countries (with the exception of Ku et al for China). Genetic components may also play a role, as could the health-care systems and access to care. Active disease at conception would (in theory) be related to the availability and accessibility of immunosuppression and rheumatologic care, cultural norms regarding pregnancy and fertility, as well as patients’ access to family planning services and contraception. With women’s healthcare, particularly in regard to family planning, there is a strong intersection with cultural attitudes and norms, all of which would impact the ability of patients to plan for pregnancy during disease remission, assuming that their disease was diagnosed before presentation for prenatal care. As such, numerous factors could affect the higher rates of active disease at conception seen in the Indian population. More research controlling for the many variables is needed to determine which factors affect the higher rates of active disease at conception in the Indian population.
The lower rates of preeclampsia seen within the Indian population are particularly interesting, given the lower overall live birth rate, as well as the higher rates of active disease at conception. Per the literature, higher rates of active disease at conception are associated with a greater risk of developing preeclampsia.,, Preeclampsia also increases risk of fetal loss. Given that the Indian studies have higher rates of active disease at conception, and lower rates of live birth, a higher percentage of patients with preeclampsia would be expected. It is possible that there is a genetic component to explain this trend. The underlying etiology to preeclampsia is poorly understood, thus, more research is needed to elucidate the pathophysiology and mechanisms of preeclampsia, as well as to establish if there is a statistically significant geographic difference in preeclampsia rates for SLE patients.
The other noticeable trend along geographic lines was that the SLE flare rate appeared to be higher in Asia (both Southeast Asia and China) compared to India and Africa [Table 1], although Aly et al is an exception. There is a possible genetic component to this effect, as previous studies have noted more severe disease in Asian patients, as well as higher rates of LN, which could relate to higher flare rates. Other factors that could be related to the higher SLE flare rates seen in the Asian studies are the use of hydroxychloroquine during pregnancy, the disease severity, immunosuppressive regimen, prior history of SLE flares, and access to rheumatologic care, none of which were reported in the studies. More research is needed to determine if there is a statistically significant difference in SLE flare rates across geographic regions. No other trends were noted.
| Conclusion|| |
Overall, data are scarce regarding LN and pregnancy in developing nations. There are numerous reasons for this paucity of research, including fewer resources, reduced access to care, decreased funding for research, and financial barriers to care, provider shortage, underdiagnosis, and cultural differences. These studies do demonstrate that higher rates of live birth and low rates of SLE and LN flare indicating good pregnancy outcomes are possible with appropriate care and coordination of providers, even in low-resource settings. This is of significant benefit to patients. Hopefully, with time, more research can be conducted in developing nations to optimize care and outcomes for these patients.
Conflict of interest: None declared.
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