Abstract
Objective: Childhood IgA vasculitis in remission is not a known risk factor for pregnancy but can lead to complications such as preeclampsia, even in women with a low risk of kidney function decline.
Methods: This retrospective study compared pregnancy outcomes between patients with IgA vasculitis with nephropathy (Henoch–Schönlein purpura nephritis) and those with IgA nephropathy who delivered at Osaka University Hospital between 2010 and 2020.
Results: Seven patients with purpura nephritis and 37 patients with IgA nephropathy had a total of 9 and 53 pregnancies, respectively. Purpura nephritis patients had an earlier gestational age at delivery and higher frequency of preterm birth, fetal growth restriction, and preeclampsia than IgA nephropathy patients, although differences were not significant. Among pregnancies at low risk of kidney function decline, 35 were with IgA nephropathy and 9 were with purpura nephritis. The incidence of preeclampsia was significantly higher with purpura nephritis (44%: 4/9) than with IgA nephropathy (9%: 3/35 including 2 with oocyte donation). Severe and early-onset preeclampsia was noted in 2 pregnancies with purpura nephritis.
Conclusion: Patients with childhood purpura nephritis in remission may develop preeclampsia, with a higher risk of severe and early-onset preeclampsia than patients with IgA nephropathy.
Introduction
Despite advances in the management and treatment of kidney disease, incidence of chronic kidney disease (CKD) has been on the rise year by year, with approximately 0.1–4% of women of childbearing age reportedly developing CKD.1,2) Studies that have evaluated pregnancy outcomes in women with CKD have identified typical adverse effects of CKD on pregnancy such as an increased risk of preterm delivery, fetal growth restriction (FGR), and preeclampsia.3,4) The risk of developing these complications varies by the degree of kidney function impairment as well as the type of underlying disease.4) Management of pregnancy and prevention of adverse outcomes according to risk level are necessary. Prediction of pregnancy outcome based on clinical indicators in early pregnancy is important to improve recommendations provided to patients, especially regarding the onset of preeclampsia given its strong association with kidney disease and potential to cause preterm delivery and FGR.
IgA nephropathy and IgA vasculitis commonly occur during early childhood. IgA vasculitis, a systemic vasculitis, causes systemic complications including nephritis (also called Henoch–Schönlein purpura nephritis) in 25–50% of cases.5) Patients with these conditions are often in remission during sexual maturity; during pregnancy, these patients are managed as being at mild risk of CKD. Indeed, physicians may not even address the conditions if follow-up has been completed, or if patients do not remember to mention their childhood medical history. Moreover, although early childhood IgA nephropathy and purpura nephritis have been reported to progress to chronic renal failure in adulthood,6,7,8) only a few studies have investigated pregnancy outcomes in patients with these diseases, especially purpura nephritis, and no study has compared pregnancy outcomes between women with IgA nephropathy and those with purpura nephritis.
Against this backdrop, the present study aimed to (1) evaluate maternal and neonatal outcomes in pregnant women with a history of purpura nephritis or IgA nephropathy who became pregnant during an 11-year period at our institution, and (2) compare the incidence of preeclampsia in pregnancies classified as low risk of kidney function decline.
Methods
This retrospective cohort study was conducted in patients with purpura nephritis or IgA nephropathy who delivered at Osaka University Hospital between January 2010 and December 2020. If a patient had multiple pregnancies and childbirths, each pregnancy was regarded as a separate case. Exclusion criteria were as follows: unknown exact etiology of CKD, spontaneous abortion, artificial abortion not resulting from pregnancy complications, and fetuses with congenital malformations or chromosomal abnormalities. Extracted data included maternal characteristics, pregnancy and delivery outcomes, and neonatal outcomes. Adverse pregnancy outcomes included preterm delivery, FGR, stillbirth, and preeclampsia.
This study used diagnostic criteria for preeclampsia based on the Japan Society for the Study of Hypertension in Pregnancy definition and classification of “hypertensive disorders of pregnancy (HDP)”.9) Specifically, preeclampsia was diagnosed in patients with normal blood pressure and no proteinuria as new onset of hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg) and proteinuria (≥300 mg/day), or any of the following: thrombocytopenia (platelet count <150,000/dl), impaired liver function (ALT or AST >40 IU/l), impaired renal function (creatinine >1.0 mg/d), new-onset cerebral or visual disturbances, and uteroplacental dysfunction. In patients with preexisting hypertension, superimposed preeclampsia was diagnosed as new-onset or worsening proteinuria, or the above maternal organ involvement or uteroplacental dysfunction was recognized. In patients with preexisting proteinuria or renal impairment, superimposed preeclampsia was diagnosed when new-onset or worsening hypertension occurred. Severe preeclampsia was defined as meeting any one of the following criteria: worsening hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg), maternal organ involvement, or uteroplacental dysfunction. FGR was defined as fetal growth less than 1.5 standard deviations below the mean estimated fetal body weight according to gestational age, and was calculated based on the Japanese standard using ultrasonography data.10) CKD severity was classified according to “The Kidney Disease: Improving Global Outcomes (KDIGO) 2013 Clinical Practice Guideline for the Evaluation and Management of CKD” based on glomerular filtration rate (GFR) and proteinuria, as shown in Figure 1.11)
GraphPad Prism (GraphPad Software, San Diego, CA, USA) was used for all statistical analyses. Data are presented as mean±standard deviation. Between-group comparisons were performed using the chi-squared test or the Mann–Whitney U test, as appropriate. Statistical significance was set at P<0.05.
Ethical approval
The study protocol was approved by the Osaka University Ethics Committee (Approval No. 21306, approved on November 19, 2021) and conducted in accordance with the ethical principles of the Declaration of Helsinki. Due to the retrospective nature of the study, the need to obtain formal informed consent from participants was waived by the approval committee. Data were anonymized to protect participant identity.
Results
During the study period, 7 patients with purpura nephritis had 9 pregnancies, and 37 patients with IgA nephropathy had 53 pregnancies; there was one twin pregnancy in each group. Age at pregnancy was slightly lower in patients with purpura nephritis than in those with IgA nephropathy, although the difference was not significant. Age at disease onset was significantly lower, and the duration from disease onset to pregnancy significantly longer, in patients with purpura nephritis than in those with IgA nephropathy. There was a significant difference in the frequency of follow-up by physicians before pregnancy: most patients with IgA nephropathy were followed, whereas only 30% of patients with purpura nephritis were followed. Baseline kidney function and blood pressure were evaluated as early as possible in cases for which data were available: among the 9 pregnancies with purpura nephritis, 3 were evaluated before pregnancy, 3 were evaluated in the first trimester, and 3 were evaluated in the later stage of pregnancy. Of the 53 pregnancies with IgA nephropathy, 13 were evaluated before pregnancy, 32 were evaluated in the first trimester, and 8 were evaluated in the later stage of pregnancy. Baseline kidney function was significantly better in patients with purpura nephritis than in those with IgA nephropathy. Moreover, patients with IgA nephropathy more frequently experienced other complications compared with those with purpura nephritis. However, there were no differences in the use of antihypertensive drugs and prednisone during pregnancy or the frequency of aspirin administration to prevent preeclampsia (Table 1).
Table 1. Characteristics of pregnant women with purpura nephritis and IgA nephropathy
| Characteristics | Purpura nephritis
n=9 | IgA nephropathy
n=53 | P value |
|---|
| Age (years) | 30.1±5.3 | 34.0±6.1 | 0.074 |
| Age of disease onset (years) | 9.2±4.9 | 21.0±7.3 | <0.0001 |
| Duration from disease onset to pregnancy (years) | 21.0±8.1 | 13.0±8.2 | 0.007 |
| Primipara | 3 (33%) | 29 (55%) | 0.29 |
| BMI (Prepregnancy) (kg/m2) | 21.6±3.3 | 21.7±3.1 | 0.99 |
| ART | 2 (22%) | 13 (25%) | 1.00 |
| Oocyte donation | 0 (0%) | 2 (4%) | |
| Smoker | 0 (0%) | 3 (6%) | |
| Follow-up before pregnancy | 3 (33%) | 45 (85%) | 0.003 |
| Baseline kidney function | | | |
| GFR (ml/min/173m2) | 107.2±14.6 | 92.7±24.4 | 0.043 |
| Urine protein/Cr ratio (g/gCr) | | | |
| <0.15 | 9 (100%) | 36 (68%) | 0.046 |
| 0.15–0.49 | 0 (0%) | 9 (17%) | |
| 0.5< | 0 (0%) | 8 (15%) | |
| Microscopic hematuria | 0 (0%) | 11 (21%) | |
| Blood pressure (mmHg) | | | |
| Systolic | 122.6±17.2 | 119.0±15.3 | 0.33 |
| Diastolic | 71.7±11.7 | 70.8±12.4 | 0.71 |
| Other complicated disease | | | |
| Chronic hypertension | 0 (0%) | 6 (11%) | |
| Diabetes mellitus | 0 (0%) | 2 (4%) | |
| Hyperthyroidism | 0 (0%) | 3 (6%) | |
| Hypothyroidism | 1 (11%) | 2 (4%) | 0.34 |
| Antiphospholipid syndrome | 0 (0%) | 0 (0%) | |
| Medication use | | | |
| Antihypertension | 1 (11%) | 9 (17%) | 1.00 |
| Prednisone | 0 (0%) | 3 (6%) | |
| Aspirin | 1 (11%) | 7 (13%) | 1.00 |
| Twin pregnancy | 1 (11%) | 1 (2%) | 0.27 |
| Consecutive pregnancies of the same patient | 2 (22%) | 15 (28%) | 1.00 |
Values are expressed as mean±standard deviation or number and percentage.
Statistical between-group comparisons were performed using Fisher’s exact test or Mann–Whitney U test, as appropriate.
IgA, immunoglobulin A; BMI, body mass index; ART, artificial reproductive therapy; Cr, creatinine.
With regard to pregnancy and delivery outcomes, patients with purpura nephritis had an earlier gestational age at delivery and higher frequency of preterm birth and preeclampsia than those with IgA nephropathy, although differences were not significant. There was one stillbirth among patients with purpura nephritis (Table 2). Among patients with purpura nephropathy, 1 of 1 (100%) patient with prophylactic aspirin use, and 3 of 6 (50%) with no prophylactic aspirin use, developed preeclampsia. Among patients with IgA nephropathy, 2 of 7 (29%) with prophylactic aspirin use, and 9 of 46 (20%) with no prophylactic aspirin use, developed preeclampsia (data not shown). With regard to neonatal outcomes, birth weight was lower, and the frequency of FGR higher, in patients with purpura nephritis than those with IgA nephropathy, although differences were not significant (Table 3).
Table 2. Pregnancy and delivery outcomes of the purpura nephritis and IgA nephropathy patients
| Purpura nephritis
n=9 | IgA nephropathy
n=53 | Relative risk (95% CI) | P value |
|---|
| GW at delivery | 34.3±7.8 | 38.2±2.0 | | 0.085 |
| Preterm delivery (<37 GW) | 1 (11%) | 6 (11%) | 0.98 (0.13 to 7.22) | 1.00 |
| Spontaneous | 0 (0%) | 2 (4%) | | |
| Preterm delivery (<34 GW) | 1 (11%) | 2 (4%) | 2.9 (0.30 to 29.2) | 0.38 |
| Spontaneous | 0 (0%) | 1 (2%) | | |
| Stillbirth | 1 (11%) | 0 (0%) | | |
| Cesarean delivery | 2 (22%) | 15 (28%) | 0.79 (0.22 to 2.9) | 1.00 |
| Emergency | 1 (11%) | 10 (19%) | 0.59 (0.09 to 4.1) | 1.00 |
| Preeclampsia | 4 (44%) | 11 (21%) | 2.1 (0.87 to 5.3) | 0.20 |
| GW at onset | 28.6±20.7 | 37.5±0.99 | | 0.013 |
| Early-onset <34 GW | 2 (22%) | 0 (0%) | | |
| Severe features | 2 (22%) | 3 (6%) | 3.9 (0.76 to 20.3) | 0.15 |
Values are expressed as mean±standard deviation or number and percentage.
Statistical between-group comparisons were performed using Fisher’s exact test or Mann–Whitney U test, as appropriate.
IgA, Immunoglobulin A; GW, gestational week.
Table 3. Neonatal outcomes of the purpura nephritis and IgA nephropathy patients
| Purpura nephritis
n=10 | IgA nephropathy
n=54 | Relative risk (95% CI) | P value |
|---|
| Birth weight | 2,393±1,027 | 2,948±407 | | 0.33 |
| SD | −0.23±1.2 | 0.11±1.0 | | 0.65 |
| FGR (<−1.5SD) | 2 (20%) | 2 (7%) | 5.40 (0.86 to 34.0) | 0.11 |
| Apgar score <7 (5 min) | 0 (0%) | 1 (2%) | | |
| Cord blood pH | 7.31±0.07 | 7.33±0.08 | | 0.86 |
Values are expressed as mean±standard deviation or number and percentage.
Statistical between-group comparisons were performed using Fisher’s exact test or Mann–Whitney U test, as appropriate.
IgA, Immunoglobulin A; SD, standard deviation; FGR, fetal growth restriction.
According to the KDIGO risk classification, 35 pregnancies with IgA nephropathy, and all 9 pregnancies with purpura nephritis, were classified as low risk for CKD. These assessments were performed at the same time as the results shown in Table 1 (Table 4). In these pregnancies, the risk of developing preeclampsia was significantly higher with purpura nephritis (44%; 4/9) than with IgA nephropathy (9%; 3/35, including 2 cases of oocyte donation). Severe and early-onset preeclampsia occurred in 0 and 2 patients with IgA nephropathy and purpura nephritis, respectively (Table 5). Among patients with IgA nephropathy, 0 of 3 (0%) with prophylactic aspirin use, and 3 of 32 (9%) with no prophylactic aspirin use, developed preeclampsia (data not shown). As for patients with purpura nephritis (Table 6), one patient developed preeclampsia in two consecutive pregnancies (Case 2-1, 2); she was followed by a nephrologist and was considered low risk, as her creatinine levels before pregnancy were low. Two other patients who were not followed by a nephrologist developed early-onset preeclampsia with severe hypertension (Cases 6 and 7). One of these patients (Case 6) had an atypical onset at 13 weeks, with a sFlt1/PlGF ratio of 1183; improvement was noted soon after delivery and was previously reported to be compatible with preeclampsia.13)
Table 4. The risk of CKD classification in purpura nephritis and IgA nephropathy patients
| Type of disease | Total | Low | Moderate | High | Very high |
|---|
| Purpura nephritis | 9 | 9 (100%) | | | |
| IgA nephropathy | 53 | 35 (66%) | 9 (17%) | 6 (11%) | 3 (6%) |
Values are expressed as number and percentage.
CKD, chronic kidney disease; IgA, Immunoglobulin A.
Table 5. Pregnancy and delivery outcomes of the purpura nephritis and IgA nephropathy patients (Low risk of CKD classification)
| Purpura nephritis
n=9 | IgA nephropathy
n=35 | Relative risk (95% CI) | P value |
|---|
| Preterm delivery | 1 (11%) | 3 (9%) | 1.30 (0.15 to 11.0) | 1.00 |
| FGR | 2 (22%) | 2 (6%) | 3.89 (0.63 to 24.0) | 0.18 |
| Preeclampsia | 4 (44%) | 3 (9%) | 5.19 (1.41 to 19.1) | 0.024 |
| GW at onset | 28.6±20.7 | 38.3±2.8 | | 0.086 |
| Early-onset <34 GW | 2 (22%) | 0 (0%) | | |
| Severe features | 2 (22%) | 0 (0%) | | |
Values are expressed as mean±standard deviation or number and percentage.
Statistical between-group comparisons were performed using Fisher’s exact test or Mann–Whitney U test, as appropriate.
CKD, chronic kidney disease; FGR, fetal growth restriction; GW, gestational week.
Table 6. Cases of purpura nephritis
| Case | Age | Primipara | Follow-up before pregnancy | At first visit of pregnancy to our hospital | Aspirin | Preeclampsia | GW at delivery | Birth weight (g) |
|---|
| GW | Blood Pressure (mmHg) | Cr
(mg/dl) | Proteinuria | Microscopic
hematuria | GW at onset | Severe features |
|---|
| 1 | 37 | | | 15 | 129/80 | 0.46 | — | — | | | | 38 | 3,370
2,214 |
| 2-1 | 28 | | + | 13 | 141/77 | 0.58 | — | — | | 37 | | 37 | 2,896 |
| 2-2 | 30 | | + | 4 | 117/75 | 0.59 | — | — | | 36 | | 37 | 3,106 |
| 3 | 31 | + | + | 8 | 91/55 | 0.63 | — | — | | | | 38 | 2,700 |
| 4 | 18 | | | 34 | 100/56 | 0.51 | — | — | | | | 37 | 2,659 |
| 5-1 | 29 | + | | 12 | 122/62 | NA | — | — | | | | 40 | 2,992 |
| 5-2 | 31 | | | 12 | 122/75 | NA | — | — | | | | 39 | 3,070 |
| 6 | 37 | | | 14 | 137/83
(with methyldopa) | 0.51 | 7.6 (g/gCr) | + | + | 13 | Severe HT, Thrombocytopenia | 14 | 30 |
| 7 | 30 | + | | 22 | 122/80 | 0.50 | — | — | | 29 | Severe HT | 29 | 896 |
Case 1 had a twin pregnancy. Cases 2 and 5 were the same patients who had two consecutive pregnancies.
Cr, creatinine; GW, gestational week.
Discussion
We investigated pregnancy outcomes in women with a history of purpura nephritis or IgA nephropathy. Patients with purpura nephritis had a longer duration from onset to pregnancy and better baseline kidney function than those with IgA. In addition, although there were few other complicated diseases, the risk of preterm birth, FGR, and preeclampsia tended to be high among patients with purpura nephritis. Among those with a low risk of kidney function decline, the incidence of preeclampsia was significantly higher for purpura nephritis than for IgA nephropathy. Severe and early-onset preeclampsia was observed only in patients with purpura nephritis. If patients have a history of early childhood purpura nephritis, even those in remission should be considered high risk for developing preeclampsia.
CKD with hypertension, lupus nephritis, antiphospholipid antibody syndrome, diabetic nephropathy, polycystic kidney disease, and pregnancy after kidney transplantation are associated with a high risk of preeclampsia.13,14) However, only a few studies have examined pregnancy outcomes according to histological CKD classifications. IgA nephropathy, a renal disease that typically affects children, is also considered a single-organ manifestation of IgA vasculitis, i.e., a disease common in pregnant women. The rates of spontaneous abortion and preterm birth reportedly increase with the incidence of IgA nephropathy.15,16) In a long-term follow-up study of pediatric IgA nephropathy to adulthood, proteinuria and/or hypertension were observed in 12 (55%) of 22 pregnancies, with a preterm birth rate of 30%. Long-term adult follow-up is necessary even in patients with mild childhood IgA nephropathy, especially during pregnancy and postpartum.6) A systematic review of IgA nephropathy in 2018 reported an incidence of preeclampsia of 15.1%, which is ≥10-fold higher than that reported for low-risk pregnant controls (OR, 11.80; CI 7.53–18.48).17)
Few studies have reported on the long-term prognosis and pregnancy outcome of patients with IgA vasculitis. One study that investigated long-term prognosis in patients with purpura nephritis in 1992 suggested that early childhood purpura nephritis could cause renal failure in adulthood: 78 people were followed for an average of 23.4 years, with 24 women becoming pregnant for a total of 56 times; among 44 who gave live births, 16 (36%) had hypertension, proteinuria, or both.7) Another study in 2002 followed 52 men and 26 women, of whom 30 (64%) had normal renal function, for an average of 24.1 years; 14 became pregnant for a total of 23 times, with 70% developing hypertension or proteinuria during pregnancy.8) Moreover, all women who had developed complications in their first pregnancy developed complications in their subsequent pregnancies (as in our cases 2-1, 2), suggesting that careful management is required during pregnancy, even if renal function at onset is mild.
Previous studies were not solely focused on the prognosis of pregnancy, and few examined in detail the course of the disease before or during pregnancy. One study that investigated 247 pregnancies in patients with a history of IgA vasculitis reported increased miscarriage, preterm birth, and gestational hypertension, with the incidence of gestational hypertension being 10.9% (1.8% in control patients).5) All previous studies, however, were conducted by nephrologists or pediatricians (rather than obstetricians), without clear definitions of gestational hypertension and preeclampsia. In the present study, although a higher proportion of patients with purpura nephritis had interruption of pre-pregnancy physician follow-up than those with IgA nephropathy, similar or more cases of preterm birth, stillbirth, and FGR were noted. The risk of developing preeclampsia also appeared to be higher among patients with purpura nephritis. Even if follow-up was interrupted before pregnancy, a history of purpura nephritis should be considered a risk factor, and kidney function should be evaluated before pregnancy, or at least in early pregnancy, with careful management throughout the course of pregnancy.
In general, the risk of CKD is classified according to serum creatinine levels. Pregnancy is unlikely to affect kidney function if creatinine levels before pregnancy are ≤1.5 mg/dl.3) Piccoli et al. examined the prognosis of CKD during pregnancy for each stage and reported that the risk of developing new hypertension during pregnancy was 7.9% for stage 1, 17.6% for stage 2, 47.1% for stage 3, and 50% for stage 4/5 (5.5% for control).18) Alsuwaida et al. examined pregnancy prognosis in patients with mild CKD and reported that the incidence of preeclampsia was 12.9% at stage 1, 47.4% at stage 2, and 44.4% at stage 3/4. As the risk based solely on serum creatinine levels is easily overlooked, particularly in early CKD, GFR is more useful for estimating pregnancy prognosis.19) Accordingly, the present study used GFR and urinary proteinuria to classify CKD severity, and the prognosis of pregnancy was examined in patients classified as low risk for CKD. Low-risk patients with purpura nephritis had a high incidence of preeclampsia (44%). While 3 low-risk patients with IgA nephropathy also developed preeclampsia, none of these cases was severe, and all were late-onset. In addition, since 2 of these pregnancies were achieved by oocyte donation (which itself is a risk factor for preeclampsia), IgA nephropathy is likely to have had little involvement in the development of preeclampsia. These findings suggest the possibility that purpura nephritis is a risk factor for preeclampsia, even in low-risk patients. Thus, obstetricians should not overlook the potential risk of preeclampsia in patients with purpura nephritis, even if the risk of CKD is low, and provide careful management during pregnancy. With preconception counseling growing in importance in recent years, patients with purpura nephritis may benefit from kidney function management, such as the use of prophylactic aspirin, given the high risk of developing preeclampsia regardless of CKD risk level.
This study has some limitations worth noting. First, the number of patients included in this study was small, and those with unclear disease classification were excluded. When patients themselves did not fully describe their medical history, their true medical history may have been overlooked. Second, follow-up was interrupted before pregnancy in many cases. In addition, since it was difficult to assess baseline kidney function and blood pressure before or in early pregnancy, the timing of evaluation could not be standardized. Finally, there was no unified standard for prophylactic aspirin use. As aspirin is generally administered to high-risk patients, the preventive effect of aspirin was unclear in the present study.
In conclusion, both IgA nephropathy and purpura nephritis, which typically develop in childhood, are associated with a high risk of pregnancy complications. Patients with these diseases are often in remission when they become pregnant, with physician follow-up being completed before pregnancy. In the present study, the number of patients for whom follow-up was interrupted pre-pregnancy was higher among those with purpura nephritis than those with IgA nephropathy, and all patients with purpura nephritis were classified as low risk for CKD. Nonetheless, purpura nephritis was associated with a higher incidence of preeclampsia than IgA nephropathy among low-risk patients, and severe and early onset preeclampsia and recurrence in consecutive pregnancies were only noted in patients with purpura nephritis. Purpura nephritis should be managed with caution given the potential risk of severe and early onset preeclampsia and recurrence of preeclampsia.
Acknowledgments
This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Japan Society for the Promotion of Science (20K09618 and 21K09447). The authors would like to thank Editage (www.editage.jp) for English language editing.
Conflicts of Interest
The authors declare no potential conflicts of interest.
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