Original Investigation Risk Factors for Pregnancy Outcomes in Patients With IgA Nephropathy: A Matched Cohort Study Youxia Liu, PhD,* Xinxin Ma, MD,* Jicheng Lv, MD, Sufang Shi, MD, Lijun Liu, MD, Yuqing Chen, MD, and Hong Zhang, MD, PhD Background: The outcomes of pregnancy in immunoglobulin A nephropathy (IgAN) are uncertain. This study assessed the effects of pregnancy on kidney disease progression and risk factors for adverse pregnancy outcomes in IgAN. Study Design: A matched-cohort study. Setting & Participants: Women with IgAN with at least one pregnancy, 1 year of follow-up, and kidney function and proteinuria measurement at baseline (time of biopsy) matched with nonpregnant women with IgAN from Peking University First Hospital. Predictors: Pregnancy, treated as a time-dependent variable; proteinuria; hypertension; and estimated glomerular filtration rate (eGFR). Outcomes: Kidney disease progression, defined as eGFR halving or end-stage kidney disease; rate of eGFR decline; and adverse pregnancy outcomes, including severe pre-eclampsia, intrauterine death, embryo damage, fetal malformation, and induced and spontaneous abortions. Results: Of 239 female patients, 62 women had 69 pregnancies and 62 matched nonpregnant patients were selected as controls. Pregnant patients had median proteinuria at baseline with protein excretion of 1.27 (range, 0.06-7.25) g/d and mean eGFR of 102.3 (range, 40.0-139.0) mL/min/1.73 m2. During a mean followup of 45.7 months, 4 patients in the pregnancy group and 6 in the nonpregnancy group had kidney disease progression events. Time-dependent Cox analysis showed that pregnancy was not an independent risk factor for kidney disease progression events (HR, 1.2; 95% CI, 0.3-5.7). There was no significant difference in the median rate of eGFR decline in the 2 groups (22.5 vs 22.4 mL/min/1.73 m2 per year; P 5 0.7). Adverse pregnancy outcomes were observed in 15 patients. Proteinuria during pregnancy (OR, 1.39; 95% CI, 0.96-2.01) was a borderline predictor of adverse pregnancy outcomes. Limitations: Retrospective study, most patients had preserved kidney function, study underpowered to detect a difference in kidney failure events. Conclusions: The study does not permit a definitive conclusion about the effect of pregnancy on kidney disease progression in IgAN. Am J Kidney Dis. 64(5):730-736. ª 2014 by the National Kidney Foundation, Inc. INDEX WORDS: Immunoglobulin A nephropathy (IgAN); pregnancy; chronic kidney disease (CKD); kidney disease progression; renal function; pregnancy outcomes.
I
mmunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease globally, with a peak incidence in young adults aged 20-30 years.1,2 For these patients who are women, pregnancy is a major concern. Conception in patients with IgAN may be associated with damaging effects on both kidney disease progression and pregnancy outcomes even if kidney function is preserved.3,4 However, it also has been reported that pregnancy does not influence the course of IgAN5-9 and that pregnancy in women with chronic kidney disease (CKD) stage 2 or 3 is not a risk factor for kidney failure and adverse pregnancy outcomes.10 Thus, outcomes of pregnancy
in patients with IgAN remain uncertain. We therefore evaluated the safety of pregnancy in women with IgAN, as well as their risk factors for adverse pregnancy outcomes.
From the Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China. * Y.L. and X.M. contributed equally to this work. Received December 13, 2013. Accepted in revised form June 9, 2014. Originally published online August 15, 2014.
Address correspondence to Jicheng Lv or Hong Zhang, Renal Division, Peking University First Hospital, Institute of Nephrology, Peking University, No. 8, Xishiku Street, Xicheng District, Beijing, China. E-mail: [email protected] or [email protected] 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.06.021
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METHODS Study Cohort We reviewed records of a large Chinese IgAN database based at Peking University First Hospital, a kidney center in North China. This cohort was established in 2003 and continued through June 2012; a total of 1,245 patients were registered. Patients with acute kidney failure (n 5 61), male sex (n 5 354), and age younger than 18 or older than 40 years at the time of diagnosis (n 5 174) were excluded. To observe kidney disease progression events, those
Am J Kidney Dis. 2014;64(5):730-736
Pregnancy in Patients With IgA Nephropathy who were followed up for less than 12 months (n 5 417) also were excluded. Of the 239 included patients, 62 had at least one pregnancy outcome during follow-up. Pregnancies prior to the onset of kidney disease were excluded. We used stratified sampling to identify 62 matched nonpregnant patients in the same database. Patients were stratified by CKD stage (1, 2, or 3) and proteinuria (protein excretion , 1, 1-2, or .2 g/d) and selected from each of the 9 groups using computergenerated random numbers. The study was approved by the Ethics Committee of Peking University First Hospital (approval number 2013548), and all participants provided written informed consent.
Measurements Data were collected at the time of biopsy, during pregnancy, and after delivery, with patients followed up every 1-6 months as routine clinical practice. Participants who become pregnant were followed up at least every month. Survival status was confirmed by telephone annually. Baseline clinical and demographic data collected from all patients at the time of kidney biopsy included systolic blood pressure (SBP), diastolic blood pressure, proteinuria, serum creatinine level, and estimated glomerular filtration rate (eGFR). eGFR was estimated according to the CKD-EPI (CKD Epidemiology Collaboration) 2-level race equation.11 Rate of kidney function decline was expressed as the slope of eGFR, which was obtained by fitting a straight line through the calculated eGFR using linear regression and the principle of least squares. Mean arterial pressure (MAP) was defined as two-thirds diastolic blood pressure plus one-third SBP. Average MAP was determined for each 3-month block during pregnancy or follow-up, and the average of every 3-month period’s MAP was defined as timeaveraged MAP.12 In a manner similar to time-averaged MAP, time-averaged proteinuria during pregnancy represented an average of the mean of every 3-month period’s proteinuria measurements during pregnancy or follow-up. Renal lesions were graded according to the Haas classification at the time the database was established.13 Pregnancies of at least 20 weeks’ duration and that occurred after kidney disease onset were the main exposure of interest for kidney disease outcomes. Pregnancy was treated as a time-dependent variable whereby women were considered nonpregnant between disease onset and conception and pregnant thereafter, including additional pregnancies.
Outcomes Kidney disease progression events were defined as a 50% decrease in eGFR or end-stage kidney disease without remission after observation for at least 4 weeks or until the end of the followup. End-stage kidney disease was defined as eGFR , 15 mL/min/ 1.73 m2 or initiation of renal replacement therapy (including long-term dialysis or kidney transplantation). The rate of kidney function decline was measured by the slope of eGFR. Severe preeclampsia, cesarean delivery, vaginal delivery, preterm delivery (live birth before week 37 of gestation), intrauterine death (after week 20 of gestation), embryo damage, fetal malformation, induced and spontaneous abortions, and birth weight were recorded through medical review and confirmed with the patients. Adverse pregnancy outcomes included severe pre-eclampsia, intrauterine death, embryo damage, fetal malformation, and induced and spontaneous abortions. Severe pre-eclampsia was defined as severe hypertension (blood pressure . 160/110 mm Hg), severe proteinuria (protein excretion . 5 g/d), and additional symptoms including headache and abdominal pain. Low birth weight was defined as a live-born infant weighing , 2,500 g.
variables were expressed as mean 6 standard deviation or median and range. Kaplan-Meier analysis was used to compare renal survival in the pregnant and matching nonpregnant groups. In our analysis, we used an extended Cox model with pregnancy status as a time-dependent exposure and time of biopsy as the start of follow-up, in both the matched cohort and all those included in the study (prematching; N 5 239). On the basis of results in patients with IgAN, we assumed that pregnancy accelerated the annual GFR decline rate by at least 1.2 6 4.1 mL/min/1.73 m2 per year.8 On the basis of this assumption, we estimated that this cohort study required 123 patients for a to equal 0.05 (2-tailed test) and power of 0.80 (t test). Linear regression analyses were used to evaluate pregnancy on the rate of eGFR decline. In the 62 women with pregnancy during follow-up, a multivariate logistic regression model was used to evaluate risk factors for adverse pregnancy outcomes. Relevant variables significantly associated with adverse pregnancy outcomes by univariate analysis were included in multivariate models. A 2-sided P , 0.05 was regarded as statistically significant. All statistical analyses were performed using SPSS, version 16.0 (IBM).
RESULTS Study Cohort From the database based at Peking University, 239 women who had been entered into the IgAN cohort between 2003 and 2012 and were followed up for at least 1 year were identified (Fig 1). Overall, 62 patients had at least one pregnancy. Eleven cases of induced abortion during the first trimester were excluded from this study. Sixty-two patients had 69 pregnancies, 65 of which continued beyond week 20. Sixty-two comparable nonpregnant women were selected as controls in the main analysis for kidney survival. Baseline characteristics of the 2 groups were similar, including age, baseline serum creatinine concentration, proteinuria, and blood pressure (Table 1). Mean follow up times were 45.7 6 26.2 and 43.9 6 22.5 months in the pregnancy and nonpregnancy groups, respectively, with 20 and 15 mean visits (Table 2).
Statistical Analysis Depending on distribution, baseline and follow-up data were compared using t tests or nonparametric tests. Continuous Am J Kidney Dis. 2014;64(5):730-736
Figure 1. Flow chart for patient selection. 731
Liu et al Table 1. Baseline Clinical Characteristics at the Time of Kidney Biopsy Characteristic
Pregnant Group (n 5 62)
Nonpregnant Groupa (n 5 62)
P
0.5
Age (y)
27.3 6 3.6
27.8 6 4.4
Serum creatinine (mg/dL)
0.82 6 0.23
0.80 6 0.20
0.6
102.3 6 21.9
103.4 6 20.8
0.5
49 (79) 11 (18) 2 (3)
50 (81) 10 (16) 2 (3)
1.27 (0.06-7.25)
1.09 (0.06-8.37)
27 (44) 16 (26) 19 (31)
29 (47) 14 (23) 19 (31)
114.9 6 13.5 73.1 6 9.9
116.3 6 11.6 73.8 6 8.9
MAP (mm Hg)
87.0 6 10.5
88.0 6 9.2
0.6
Hypertension
7 (11)
4 (6)
0.5
Haas classificationc I/II III IV V
8 (13) 32 (52) 22 (36) 0 (0)
6 (10) 22 (36) 32 (52) 2 (3)
Treatment before pregnancy Untreated RAS blocker treatment alone Glucocorticoids and/or other immunosuppressive agents
32 (52) 22 (36) 8 (13)
4 (67) 31 (50) 27 (44)
eGFR (mL/min/1.73 m2) CKD stageb 1 2 3 Proteinuria level (g/d) Proteinuria category ,1 g/d 1-2 g/d .2 g/d Systolic BP (mm Hg) Diastolic BP (mm Hg)
0.9
0.9
0.3 0.7
0.1
,0.001
Note: Values for categorical variables are given as number (percentage); values for continuous variables are given as mean 6 standard deviation or median (range). Conversion factor for serum creatinine in mg/dL to mmol/L, 388.4. Abbreviations: BP, blood pressure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; MAP, mean arterial pressure; RAS, renin-angiotensin system. a Matched by stratified sampling. b CKD stages 1, 2, and 3 were divided by eGFR $90, 60-89, and 30-59 mL/min/1.73 m2. c Histologic grading was classified according to the pathologic scheme proposed by Haas.13
Kidney Disease Progression Sixty-two patients with 65 pregnancies that lasted more than 20 weeks were included in the kidney disease progression analysis (Table 2). During a mean 46-month follow-up, 4 (7%) patients in the pregnancy group developed kidney disease progression events, including 3 reaching end-stage kidney disease and one experiencing a 50% reduction in eGFR, whereas 8 (13%) patients developed persistent hypertension after delivery. Worsening of proteinuria was observed in 19 pregnancies, with 12 having nephrotic-range proteinuria (protein excretion . 3.5 g/d). In 4 of the latter group, proteinuria did not revert to its previous level after delivery. The change in proteinuria profile between the time of detection of pregnancy and 2 years after delivery can be seen in Fig 2. In the nonpregnancy group, 6 patients (10%) developed kidney disease progression events. Kidney survival rates were similar in the pregnant and nonpregnant groups (log-rank test, P 5 0.5; Fig 3). Time-dependent Cox stepwise proportional hazards 732
analysis showed that pregnancy was not a risk factor for kidney disease progression events even after adjustment for baseline eGFR, SBP, and proteinuria (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.3-5.7; P 5 0.8). After excluding the first year of follow-up, the result was consistent (HR, 1.3; 95% CI, 0.2-7.6; P 5 0.8). We did a sensitivity analysis in all those included in the study (prematching; N 5 239), with 29 kidney disease progression events. Baseline characteristics of pregnant (n 5 62) and nonpregnant women (n 5 177) are shown in Table S1 (provided as online supplementary material). In adjusted analysis including age, eGFR, SBP, proteinuria, and Haas classification, pregnancy was not an independent risk factor for kidney disease progression (HR, 1.7; 95% CI, 0.7-10.0; P 5 0.1). Median rates of eGFR decline in the pregnancy and nonpregnancy groups, measured by the slope of eGFR, were 22.5 and 22.4 mL/min/1.73 m2 per year, respectively. There was no significant difference Am J Kidney Dis. 2014;64(5):730-736
Pregnancy in Patients With IgA Nephropathy Table 2. Follow-up Clinical Characteristics Characteristic
Pregnant Group (n 5 62)
Nonpregnant Group (n 5 62)
P
0.7
45.7 6 26.2
43.9 6 22.5
Follow-up after delivery (mo)
19.7 (3 to 77)
NA
Time-averaged MAP During pregnancy (mm Hg) During follow-up (mm Hg)
85.9 6 9.9 86.4 6 8.6
NA 85.4 6 7.3
0.6
0.50 (0.05 to 8.28) 0.67 (0.10 to 6.72)
NA 0.68 (0.07 to 4.30)
0.9
4 (6) 3 (5) 1 (2)
6 (10) 4 (7) 2 (3)
0.8
1.2 (0.3 to 5.7)
1.00 (reference)
0.8
22.5 [26.7 to 0.06]
22.4 [27.1 to 2.4]
0.7
29 (47) 27 (44) 6 (10)
NA NA NA
Follow-up (mo)
Time-averaged proteinuria During pregnancy (g/d) During follow-up (g/d) Kidney disease progression events eGFR decreased . 50% ESKD Adjusted HR (95% CI) for kidney disease progression eventsa 2
Change in eGFR (mL/min/1.73 m ) Treatment after pregnancy Untreated RAS blocker treatment alone Glucocorticoids and/or other immunosuppressive agents
Note: Unless otherwise indicated, values for categorical variables are given as number (percentage); values for continuous variables are given as mean 6 standard deviation, median (range), or median [interquartile range]. Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; HR, hazard ratio; MAP, mean arterial pressure; NA, not applicable; RAS, renin angiotensin system. a Time-dependent Cox proportional hazards model adjusted for baseline eGFR, systolic blood pressure, and proteinuria.
between these 2 groups (n 5 124) after adjustment for baseline eGFR, SBP, and proteinuria (regression coefficient, 0.06; 95% CI, 20.2 to 0.3; P 5 0.7). Pregnancy Outcomes The 69 pregnancies resulted in cesarean delivery in 42 (61%), vaginal delivery in 17 (25%), and infant loss in 10 (15%; Table 3). Six pregnancies (9%) were accompanied by severe pre-eclampsia. There were 2 (3%) intrauterine deaths, 3 (4%) embryo damage, 3
(4%) fetal malformation, 1 (2%) spontaneous abortion, and 1 (2%) induced abortion for uncontrolled proteinuria and hypertension. Mean birth weight was 2,972 6 654 (range, 1,050-3,900) g, with 8 infants (14%) having low birth weight. Of 59 infants (86%) who survived beyond the perinatal period, 52 deliveries were at full term, with a mean birth weight of 3,166 6 417 g. There were 7 (10%) preterm deliveries (mean birth weight, 1,835 6 652 g). Overall, 69 pregnancies resulted in 15 patients having adverse pregnancy outcomes. Univariate logistic analysis showed that proteinuria (odds ratio [OR], 1.53; 95% CI, 1.09-2.1; P 5 0.01) and blood pressure during pregnancy (OR, 1.07; 95% CI, 1.011.14, P 5 0.03) were risk factors for adverse pregnancy outcomes, while multivariate logistic regression analysis found that only time-averaged proteinuria during pregnancy (OR, 1.39; 95% CI, 0.96-2.01; P 5 0.08) was a borderline statistically significant risk factor for adverse pregnancy outcomes (Table 4). Time-averaged proteinuria during pregnancy showed a linear correlation with the body weight of live infants after adjustment for gestational age (r 5 20.61; P , 0.001; Fig 4). A sensitivity analysis among the patients with full-term delivery did not change the trend (r 5 20.45; P 5 0.005).
DISCUSSION Figure 2. Change in proteinuria between the time of detection of pregnancy and 2 years after delivery. Black circles represent mean values, and vertical lines represent standard errors. Am J Kidney Dis. 2014;64(5):730-736
In the current study, of a cohort of nearly 130 women with IgAN from a prospective database, we 733
Liu et al
Figure 3. Renal survival in groups of pregnant and nonpregnant women with immunoglobulin A nephropathy.
showed that pregnancy in patients with preserved kidney function was not associated with increased risk of kidney disease progression. Kidney survival was similar in pregnant and nonpregnant patients with IgAN. However, pregnancy in these women, even those with preserved kidney function, resulted in a relatively high risk of adverse pregnancy outcomes (22%). Proteinuria during pregnancy was correlated closely with adverse pregnancy outcomes in univariate analysis and was borderline significant in multivariate analysis. In addition, the amount of protein excreted in urine was associated linearly with the body weight of live infants. These results suggest the importance of controlling proteinuria during pregnancy in women with IgAN.
Table 3. Pregnancy Outcomes of Pregnant Patients With IgA Nephropathy Variable
Live birth Preterm delivery
Value
59 (86) 7 (10)
Delivery by cesarean section
42 (61)
Vaginal delivery Fetal death Intrauterine death Embryo damage Fetal malformation Spontaneous abortion Induced abortion
17 10 2 3 3 1 1
Maternal severe pre-eclampsia Low birth weighta,b Mean birth weight (g)b
(25) (15) (3) (4) (4) (2) (2)
6 (9) 8 (14) 2,972 6 654
Note: Values for categorical variables are given as number (percentage); values for continuous variables, as mean 6 standard deviation. Abbreviation: IgA, immunoglobulin A. a Low birth weight was defined as a live-born infant weighing ,2,500 g. b Data for birth weight were available for only 59 of the 69 pregnancies. 734
Through systematic review, we identified 3 previous studies including 211 patients with 307 pregnancies that reported renal or pregnancy outcomes in patients with IgAN.7,8,10 Abe7 studied patients with baseline eGFRs . 60 mL/min/1.73 m2 and reported no adverse influence of gestation on the natural history of IgAN during 5 years’ follow-up. A prospective comparison of eGFRs at the time of pregnancy and 3 years after delivery in 29 patients with IgAN with CKD stages 1-3 found that pregnancy did not accelerate loss of kidney function.10 Similarly, a 10year follow-up study including 136 women with serum creatinine levels , 1.2 mg/dL also found that pregnancy had no effect on the progression of kidney disease.8 These data suggest that conception can be considered in patients with IgAN with preserved kidney function. However, pregnancy in patients with IgAN introduces a high risk for adverse pregnancy outcomes, with only 86% live births in our study, which is much lower than the rate of 99% in the general Chinese population.14 Similarly, frequencies of caesarean delivery (61% vs 42%),15 preterm delivery (10% vs 7%),16 and low birth weight (14% vs 6%)17 in patients with IgAN in this study were all higher than those in the general Chinese population. Although previous studies have focused on the effects of pregnancy on kidney disease progression, fewer have evaluated risk factors for fetal outcomes in patients with IgAN. We found that proteinuria during pregnancy was a borderline statistically significant risk factor for adverse pregnancy outcomes. GFR was not found to be associated with adverse pregnancy outcomes, partially because only a few patients with decreased kidney function were involved in this cohort. In a cohort of 49 patients with CKD stages 3-5, both protein excretion . 1 g/d and eGFR , 40 mL/min/1.73 m2 were associated with low birth weight, small for gestational age, or fetal death.18 Additional studies are needed to evaluate risk factors that could predict adverse outcomes in newborns. In our study, urinary protein excretion during pregnancy was associated closely with the body weight of live infants even after adjustment for premature delivery. This result was consistent with that from a previous study.9 However, we cannot prove a causal relationship. Also, the proteinuria may have been related to the occurrence of pre-eclampsia. Future studies should evaluate the effect on pregnancy outcomes of interventions to reduce proteinuria, such as optimal blood pressure control or corticosteroid therapy in individuals with heavy proteinuria. The major limitation of this study was that most patients included had preserved kidney function, with only 2 pregnant patients having eGFRs , 60 mL/ min/1.73 m2. Therefore, we cannot evaluate the effect of reduced kidney function on pregnancy outcomes in Am J Kidney Dis. 2014;64(5):730-736
Pregnancy in Patients With IgA Nephropathy Table 4. Univariate and Multivariate Logistic Regression Analysis of Factors at Baseline and During Pregnancy Influencing Adverse Pregnancy Outcomes Univariate Characteristic
OR (95% CI)
Multivariate P
OR (95% CI)
P
Age, per 1-y older
1.04 (0.88-1.12)
0.7
Haas classification I/II III IV
1.00 (reference) 1.33 (0.14-13.09) 4.27 (0.45-40.44)
0.8 0.2
Proteinuria Baseline, per 1-g/d greater Time-averaged during pregnancy, per 1-g/d greater
1.35 (0.94-1.93) 1.53 (1.09-2.13)
0.1 0.01
1.39 (0.96-2.01)
0.08
Mean arterial pressure Baseline, per 102mm Hg greater Time-averaged during pregnancy, per 102mm Hg greater
0.99 (0.94-1.05) 1.07 (1.01-1.14)
0.8 0.03
1.39 (0.69-2.82)
0.4
Baseline eGFR, per 102mL/min/1.73 m2 greater
0.98 (0.95-1.00)
0.06
Therapy before pregnancy (yes or no)
3.33 (0.95-11.71)
0.06
Note: Adverse pregnancy outcomes defined as severe pre-eclampsia, intrauterine death, embryo damage, fetal malformation, and voluntary and spontaneous abortions. Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate; OR, odds ratio.
patients with IgAN. Owing to the limited evidence, maternal and fetal outcomes in patients with IgAN and decreased kidney function remain undetermined. In addition, the sample size was small, with few kidney disease progression events, so our study is underpowered to detect HR effect estimates of the magnitudes observed here. The annual kidney disease progression rate in our general IgAN population is estimated at 3.45 per 100 person-years.19 This means we would need more than 400 patients with a 5-year follow-up to have 80% power (a 5 0.05) to detect the estimated HR effect (1.7) on kidney disease progression events. Finally, although we found a trend of
Figure 4. Correlation between birth weight of infants and time-averaged (TA) proteinuria during pregnancy. Am J Kidney Dis. 2014;64(5):730-736
heavy proteinuria during follow-up being associated with low birth weight and adverse pregnancy outcome, the causal relationship was not confirmed. In conclusion, this study does not permit a definitive conclusion about the effect of pregnancy on kidney disease progression in IgAN. Proteinuria during pregnancy may predict a higher rate of adverse pregnancy outcomes. Further studies are needed to evaluate the mutual effects of pregnancy and IgAN in patients with decreased kidney function.
ACKNOWLEDGEMENTS Support: This work was supported by grants from the National Natural Science Foundation of China (81270795, 81322009), Program for New Century Excellent Talents in University from the Ministry of Education of China grant NCET-12-0011, Capital Clinical Research grant Z12110700100000, 2011-4021-06, Beijing Science and Technology Plan (Z121107001012137), the Beijing Natural Science Foundation (grant 7131016), and the Natural Science Fund of China to the Innovation Research Group (81021004). Study sponsors had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. Financial Disclosure: The authors declare that they have no other relevant financial interests. Contributions: Research idea and study design: JL, HZ; data acquisition: SS, LL, YC; data analysis/interpretation: YL, XM; statistical analysis: YL; supervision or mentorship: JL, HZ. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. JL and HZ take responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. 735
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SUPPLEMENTARY MATERIAL Table S1: Baseline characteristics of the 239 included IgAN patients. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2014.06.021) is available at www.ajkd.org
REFERENCES 1. Pan X, Xu J, Ren H, et al. Changing spectrum of biopsyproven primary glomerular diseases over the past 15 years: a single-center study in China. Contrib Nephrol. 2013;181:22-30. 2. D’Amico G. The commonest glomerulonephritis in the world: IgA nephropathy. Q J Med. 1987;64(245):709-727. 3. Packham DK, North RA, Fairley KF, Whitworth JA, Kincaid-Smith P. IgA glomerulonephritis and pregnancy. Clin Nephrol. 1988;30(1):15-21. 4. Kincaid-Smith P, Fairley KF. Renal disease in pregnancy. Three controversial areas: mesangial IgA nephropathy, focal glomerular sclerosis (focal and segmental hyalinosis and sclerosis), and reflux nephropathy. Am J Kidney Dis. 1987;9(4):328-333. 5. Surian M, Imbasciati E, Cosci P, et al. Glomerular disease and pregnancy. A study of 123 pregnancies in patients with primary and secondary glomerular diseases. Nephron. 1984;36(2): 101-105. 6. Jungers P, Houillier P, Forget D, et al. Influence of pregnancy on the course of primary chronic glomerulonephritis. Lancet. 1995;346(8983):1122-1124. 7. Abe S. The influence of pregnancy on the long-term renal prognosis of IgA nephropathy. Clin Nephrol. 1994;41(2):61-64. 8. Limardo M, Imbasciati E, Ravani P, et al. Pregnancy and progression of IgA nephropathy: results of an Italian multicenter study. Am J Kidney Dis. 2010;56(3):506-512. 9. Barcelo P, Lopez-Lillo J, Cabero L, Del Rio G. Successful pregnancy in primary glomerular disease. Kidney Int. 1986;30(6): 914-919.
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10. Shimizu A, Takei T, Moriyama T, Itabashi M, Uchida K, Nitta K. Effect of kidney disease stage on pregnancy and delivery outcomes among patients with immunoglobulin A nephropathy. Am J Nephrol. 2010;32(5):456-461. 11. Kong X, Ma Y, Chen J, et al. Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating glomerular filtration rate in the Chinese population. Nephrol Dial Transplant. 2013;28(3):641-651. 12. Reich HN, Troyanov S, Scholey JW, Cattran DC. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol. 2007;18(12):3177-3183. 13. Haas M. Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases. Am J Kidney Dis. 1997;29(6):829-842. 14. Feng XL, Guo S, Hipgrave D, et al. China’s facilitybased birth strategy and neonatal mortality: a populationbased epidemiological study. Lancet. 2011;378(9801):14931500. 15. Mi J, Liu F. Rate of caesarean section is alarming in China. Lancet. 2014;383(9927):1463-1464. 16. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379(9832):21622172. 17. Chen Y, Li G, Ruan Y, Zou L, Wang X, Zhang W. An epidemiological survey on low birth weight infants in China and analysis of outcomes of full-term low birth weight infants. BMC Pregnancy Childbirth. 2013;13:242. 18. Imbasciati E, Gregorini G, Cabiddu G, et al. Pregnancy in CKD stages 3 to 5: fetal and maternal outcomes. Am J Kidney Dis. 2007;49(6):753-762. 19. Li X, Liu Y, Lv J, et al. Progression of IgA nephropathy under current therapy regimen in a Chinese population. Clin J Am Soc Nephrol. 2014;9(3):484-489.
Am J Kidney Dis. 2014;64(5):730-736
I
mmunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease globally, with a peak incidence in young adults aged 20-30 years.1,2 For these patients who are women, pregnancy is a major concern. Conception in patients with IgAN may be associated with damaging effects on both kidney disease progression and pregnancy outcomes even if kidney function is preserved.3,4 However, it also has been reported that pregnancy does not influence the course of IgAN5-9 and that pregnancy in women with chronic kidney disease (CKD) stage 2 or 3 is not a risk factor for kidney failure and adverse pregnancy outcomes.10 Thus, outcomes of pregnancy
in patients with IgAN remain uncertain. We therefore evaluated the safety of pregnancy in women with IgAN, as well as their risk factors for adverse pregnancy outcomes.
From the Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China. * Y.L. and X.M. contributed equally to this work. Received December 13, 2013. Accepted in revised form June 9, 2014. Originally published online August 15, 2014.
Address correspondence to Jicheng Lv or Hong Zhang, Renal Division, Peking University First Hospital, Institute of Nephrology, Peking University, No. 8, Xishiku Street, Xicheng District, Beijing, China. E-mail: [email protected] or [email protected] 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.06.021
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METHODS Study Cohort We reviewed records of a large Chinese IgAN database based at Peking University First Hospital, a kidney center in North China. This cohort was established in 2003 and continued through June 2012; a total of 1,245 patients were registered. Patients with acute kidney failure (n 5 61), male sex (n 5 354), and age younger than 18 or older than 40 years at the time of diagnosis (n 5 174) were excluded. To observe kidney disease progression events, those
Am J Kidney Dis. 2014;64(5):730-736
Pregnancy in Patients With IgA Nephropathy who were followed up for less than 12 months (n 5 417) also were excluded. Of the 239 included patients, 62 had at least one pregnancy outcome during follow-up. Pregnancies prior to the onset of kidney disease were excluded. We used stratified sampling to identify 62 matched nonpregnant patients in the same database. Patients were stratified by CKD stage (1, 2, or 3) and proteinuria (protein excretion , 1, 1-2, or .2 g/d) and selected from each of the 9 groups using computergenerated random numbers. The study was approved by the Ethics Committee of Peking University First Hospital (approval number 2013548), and all participants provided written informed consent.
Measurements Data were collected at the time of biopsy, during pregnancy, and after delivery, with patients followed up every 1-6 months as routine clinical practice. Participants who become pregnant were followed up at least every month. Survival status was confirmed by telephone annually. Baseline clinical and demographic data collected from all patients at the time of kidney biopsy included systolic blood pressure (SBP), diastolic blood pressure, proteinuria, serum creatinine level, and estimated glomerular filtration rate (eGFR). eGFR was estimated according to the CKD-EPI (CKD Epidemiology Collaboration) 2-level race equation.11 Rate of kidney function decline was expressed as the slope of eGFR, which was obtained by fitting a straight line through the calculated eGFR using linear regression and the principle of least squares. Mean arterial pressure (MAP) was defined as two-thirds diastolic blood pressure plus one-third SBP. Average MAP was determined for each 3-month block during pregnancy or follow-up, and the average of every 3-month period’s MAP was defined as timeaveraged MAP.12 In a manner similar to time-averaged MAP, time-averaged proteinuria during pregnancy represented an average of the mean of every 3-month period’s proteinuria measurements during pregnancy or follow-up. Renal lesions were graded according to the Haas classification at the time the database was established.13 Pregnancies of at least 20 weeks’ duration and that occurred after kidney disease onset were the main exposure of interest for kidney disease outcomes. Pregnancy was treated as a time-dependent variable whereby women were considered nonpregnant between disease onset and conception and pregnant thereafter, including additional pregnancies.
Outcomes Kidney disease progression events were defined as a 50% decrease in eGFR or end-stage kidney disease without remission after observation for at least 4 weeks or until the end of the followup. End-stage kidney disease was defined as eGFR , 15 mL/min/ 1.73 m2 or initiation of renal replacement therapy (including long-term dialysis or kidney transplantation). The rate of kidney function decline was measured by the slope of eGFR. Severe preeclampsia, cesarean delivery, vaginal delivery, preterm delivery (live birth before week 37 of gestation), intrauterine death (after week 20 of gestation), embryo damage, fetal malformation, induced and spontaneous abortions, and birth weight were recorded through medical review and confirmed with the patients. Adverse pregnancy outcomes included severe pre-eclampsia, intrauterine death, embryo damage, fetal malformation, and induced and spontaneous abortions. Severe pre-eclampsia was defined as severe hypertension (blood pressure . 160/110 mm Hg), severe proteinuria (protein excretion . 5 g/d), and additional symptoms including headache and abdominal pain. Low birth weight was defined as a live-born infant weighing , 2,500 g.
variables were expressed as mean 6 standard deviation or median and range. Kaplan-Meier analysis was used to compare renal survival in the pregnant and matching nonpregnant groups. In our analysis, we used an extended Cox model with pregnancy status as a time-dependent exposure and time of biopsy as the start of follow-up, in both the matched cohort and all those included in the study (prematching; N 5 239). On the basis of results in patients with IgAN, we assumed that pregnancy accelerated the annual GFR decline rate by at least 1.2 6 4.1 mL/min/1.73 m2 per year.8 On the basis of this assumption, we estimated that this cohort study required 123 patients for a to equal 0.05 (2-tailed test) and power of 0.80 (t test). Linear regression analyses were used to evaluate pregnancy on the rate of eGFR decline. In the 62 women with pregnancy during follow-up, a multivariate logistic regression model was used to evaluate risk factors for adverse pregnancy outcomes. Relevant variables significantly associated with adverse pregnancy outcomes by univariate analysis were included in multivariate models. A 2-sided P , 0.05 was regarded as statistically significant. All statistical analyses were performed using SPSS, version 16.0 (IBM).
RESULTS Study Cohort From the database based at Peking University, 239 women who had been entered into the IgAN cohort between 2003 and 2012 and were followed up for at least 1 year were identified (Fig 1). Overall, 62 patients had at least one pregnancy. Eleven cases of induced abortion during the first trimester were excluded from this study. Sixty-two patients had 69 pregnancies, 65 of which continued beyond week 20. Sixty-two comparable nonpregnant women were selected as controls in the main analysis for kidney survival. Baseline characteristics of the 2 groups were similar, including age, baseline serum creatinine concentration, proteinuria, and blood pressure (Table 1). Mean follow up times were 45.7 6 26.2 and 43.9 6 22.5 months in the pregnancy and nonpregnancy groups, respectively, with 20 and 15 mean visits (Table 2).
Statistical Analysis Depending on distribution, baseline and follow-up data were compared using t tests or nonparametric tests. Continuous Am J Kidney Dis. 2014;64(5):730-736
Figure 1. Flow chart for patient selection. 731
Liu et al Table 1. Baseline Clinical Characteristics at the Time of Kidney Biopsy Characteristic
Pregnant Group (n 5 62)
Nonpregnant Groupa (n 5 62)
P
0.5
Age (y)
27.3 6 3.6
27.8 6 4.4
Serum creatinine (mg/dL)
0.82 6 0.23
0.80 6 0.20
0.6
102.3 6 21.9
103.4 6 20.8
0.5
49 (79) 11 (18) 2 (3)
50 (81) 10 (16) 2 (3)
1.27 (0.06-7.25)
1.09 (0.06-8.37)
27 (44) 16 (26) 19 (31)
29 (47) 14 (23) 19 (31)
114.9 6 13.5 73.1 6 9.9
116.3 6 11.6 73.8 6 8.9
MAP (mm Hg)
87.0 6 10.5
88.0 6 9.2
0.6
Hypertension
7 (11)
4 (6)
0.5
Haas classificationc I/II III IV V
8 (13) 32 (52) 22 (36) 0 (0)
6 (10) 22 (36) 32 (52) 2 (3)
Treatment before pregnancy Untreated RAS blocker treatment alone Glucocorticoids and/or other immunosuppressive agents
32 (52) 22 (36) 8 (13)
4 (67) 31 (50) 27 (44)
eGFR (mL/min/1.73 m2) CKD stageb 1 2 3 Proteinuria level (g/d) Proteinuria category ,1 g/d 1-2 g/d .2 g/d Systolic BP (mm Hg) Diastolic BP (mm Hg)
0.9
0.9
0.3 0.7
0.1
,0.001
Note: Values for categorical variables are given as number (percentage); values for continuous variables are given as mean 6 standard deviation or median (range). Conversion factor for serum creatinine in mg/dL to mmol/L, 388.4. Abbreviations: BP, blood pressure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; MAP, mean arterial pressure; RAS, renin-angiotensin system. a Matched by stratified sampling. b CKD stages 1, 2, and 3 were divided by eGFR $90, 60-89, and 30-59 mL/min/1.73 m2. c Histologic grading was classified according to the pathologic scheme proposed by Haas.13
Kidney Disease Progression Sixty-two patients with 65 pregnancies that lasted more than 20 weeks were included in the kidney disease progression analysis (Table 2). During a mean 46-month follow-up, 4 (7%) patients in the pregnancy group developed kidney disease progression events, including 3 reaching end-stage kidney disease and one experiencing a 50% reduction in eGFR, whereas 8 (13%) patients developed persistent hypertension after delivery. Worsening of proteinuria was observed in 19 pregnancies, with 12 having nephrotic-range proteinuria (protein excretion . 3.5 g/d). In 4 of the latter group, proteinuria did not revert to its previous level after delivery. The change in proteinuria profile between the time of detection of pregnancy and 2 years after delivery can be seen in Fig 2. In the nonpregnancy group, 6 patients (10%) developed kidney disease progression events. Kidney survival rates were similar in the pregnant and nonpregnant groups (log-rank test, P 5 0.5; Fig 3). Time-dependent Cox stepwise proportional hazards 732
analysis showed that pregnancy was not a risk factor for kidney disease progression events even after adjustment for baseline eGFR, SBP, and proteinuria (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.3-5.7; P 5 0.8). After excluding the first year of follow-up, the result was consistent (HR, 1.3; 95% CI, 0.2-7.6; P 5 0.8). We did a sensitivity analysis in all those included in the study (prematching; N 5 239), with 29 kidney disease progression events. Baseline characteristics of pregnant (n 5 62) and nonpregnant women (n 5 177) are shown in Table S1 (provided as online supplementary material). In adjusted analysis including age, eGFR, SBP, proteinuria, and Haas classification, pregnancy was not an independent risk factor for kidney disease progression (HR, 1.7; 95% CI, 0.7-10.0; P 5 0.1). Median rates of eGFR decline in the pregnancy and nonpregnancy groups, measured by the slope of eGFR, were 22.5 and 22.4 mL/min/1.73 m2 per year, respectively. There was no significant difference Am J Kidney Dis. 2014;64(5):730-736
Pregnancy in Patients With IgA Nephropathy Table 2. Follow-up Clinical Characteristics Characteristic
Pregnant Group (n 5 62)
Nonpregnant Group (n 5 62)
P
0.7
45.7 6 26.2
43.9 6 22.5
Follow-up after delivery (mo)
19.7 (3 to 77)
NA
Time-averaged MAP During pregnancy (mm Hg) During follow-up (mm Hg)
85.9 6 9.9 86.4 6 8.6
NA 85.4 6 7.3
0.6
0.50 (0.05 to 8.28) 0.67 (0.10 to 6.72)
NA 0.68 (0.07 to 4.30)
0.9
4 (6) 3 (5) 1 (2)
6 (10) 4 (7) 2 (3)
0.8
1.2 (0.3 to 5.7)
1.00 (reference)
0.8
22.5 [26.7 to 0.06]
22.4 [27.1 to 2.4]
0.7
29 (47) 27 (44) 6 (10)
NA NA NA
Follow-up (mo)
Time-averaged proteinuria During pregnancy (g/d) During follow-up (g/d) Kidney disease progression events eGFR decreased . 50% ESKD Adjusted HR (95% CI) for kidney disease progression eventsa 2
Change in eGFR (mL/min/1.73 m ) Treatment after pregnancy Untreated RAS blocker treatment alone Glucocorticoids and/or other immunosuppressive agents
Note: Unless otherwise indicated, values for categorical variables are given as number (percentage); values for continuous variables are given as mean 6 standard deviation, median (range), or median [interquartile range]. Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; HR, hazard ratio; MAP, mean arterial pressure; NA, not applicable; RAS, renin angiotensin system. a Time-dependent Cox proportional hazards model adjusted for baseline eGFR, systolic blood pressure, and proteinuria.
between these 2 groups (n 5 124) after adjustment for baseline eGFR, SBP, and proteinuria (regression coefficient, 0.06; 95% CI, 20.2 to 0.3; P 5 0.7). Pregnancy Outcomes The 69 pregnancies resulted in cesarean delivery in 42 (61%), vaginal delivery in 17 (25%), and infant loss in 10 (15%; Table 3). Six pregnancies (9%) were accompanied by severe pre-eclampsia. There were 2 (3%) intrauterine deaths, 3 (4%) embryo damage, 3
(4%) fetal malformation, 1 (2%) spontaneous abortion, and 1 (2%) induced abortion for uncontrolled proteinuria and hypertension. Mean birth weight was 2,972 6 654 (range, 1,050-3,900) g, with 8 infants (14%) having low birth weight. Of 59 infants (86%) who survived beyond the perinatal period, 52 deliveries were at full term, with a mean birth weight of 3,166 6 417 g. There were 7 (10%) preterm deliveries (mean birth weight, 1,835 6 652 g). Overall, 69 pregnancies resulted in 15 patients having adverse pregnancy outcomes. Univariate logistic analysis showed that proteinuria (odds ratio [OR], 1.53; 95% CI, 1.09-2.1; P 5 0.01) and blood pressure during pregnancy (OR, 1.07; 95% CI, 1.011.14, P 5 0.03) were risk factors for adverse pregnancy outcomes, while multivariate logistic regression analysis found that only time-averaged proteinuria during pregnancy (OR, 1.39; 95% CI, 0.96-2.01; P 5 0.08) was a borderline statistically significant risk factor for adverse pregnancy outcomes (Table 4). Time-averaged proteinuria during pregnancy showed a linear correlation with the body weight of live infants after adjustment for gestational age (r 5 20.61; P , 0.001; Fig 4). A sensitivity analysis among the patients with full-term delivery did not change the trend (r 5 20.45; P 5 0.005).
DISCUSSION Figure 2. Change in proteinuria between the time of detection of pregnancy and 2 years after delivery. Black circles represent mean values, and vertical lines represent standard errors. Am J Kidney Dis. 2014;64(5):730-736
In the current study, of a cohort of nearly 130 women with IgAN from a prospective database, we 733
Liu et al
Figure 3. Renal survival in groups of pregnant and nonpregnant women with immunoglobulin A nephropathy.
showed that pregnancy in patients with preserved kidney function was not associated with increased risk of kidney disease progression. Kidney survival was similar in pregnant and nonpregnant patients with IgAN. However, pregnancy in these women, even those with preserved kidney function, resulted in a relatively high risk of adverse pregnancy outcomes (22%). Proteinuria during pregnancy was correlated closely with adverse pregnancy outcomes in univariate analysis and was borderline significant in multivariate analysis. In addition, the amount of protein excreted in urine was associated linearly with the body weight of live infants. These results suggest the importance of controlling proteinuria during pregnancy in women with IgAN.
Table 3. Pregnancy Outcomes of Pregnant Patients With IgA Nephropathy Variable
Live birth Preterm delivery
Value
59 (86) 7 (10)
Delivery by cesarean section
42 (61)
Vaginal delivery Fetal death Intrauterine death Embryo damage Fetal malformation Spontaneous abortion Induced abortion
17 10 2 3 3 1 1
Maternal severe pre-eclampsia Low birth weighta,b Mean birth weight (g)b
(25) (15) (3) (4) (4) (2) (2)
6 (9) 8 (14) 2,972 6 654
Note: Values for categorical variables are given as number (percentage); values for continuous variables, as mean 6 standard deviation. Abbreviation: IgA, immunoglobulin A. a Low birth weight was defined as a live-born infant weighing ,2,500 g. b Data for birth weight were available for only 59 of the 69 pregnancies. 734
Through systematic review, we identified 3 previous studies including 211 patients with 307 pregnancies that reported renal or pregnancy outcomes in patients with IgAN.7,8,10 Abe7 studied patients with baseline eGFRs . 60 mL/min/1.73 m2 and reported no adverse influence of gestation on the natural history of IgAN during 5 years’ follow-up. A prospective comparison of eGFRs at the time of pregnancy and 3 years after delivery in 29 patients with IgAN with CKD stages 1-3 found that pregnancy did not accelerate loss of kidney function.10 Similarly, a 10year follow-up study including 136 women with serum creatinine levels , 1.2 mg/dL also found that pregnancy had no effect on the progression of kidney disease.8 These data suggest that conception can be considered in patients with IgAN with preserved kidney function. However, pregnancy in patients with IgAN introduces a high risk for adverse pregnancy outcomes, with only 86% live births in our study, which is much lower than the rate of 99% in the general Chinese population.14 Similarly, frequencies of caesarean delivery (61% vs 42%),15 preterm delivery (10% vs 7%),16 and low birth weight (14% vs 6%)17 in patients with IgAN in this study were all higher than those in the general Chinese population. Although previous studies have focused on the effects of pregnancy on kidney disease progression, fewer have evaluated risk factors for fetal outcomes in patients with IgAN. We found that proteinuria during pregnancy was a borderline statistically significant risk factor for adverse pregnancy outcomes. GFR was not found to be associated with adverse pregnancy outcomes, partially because only a few patients with decreased kidney function were involved in this cohort. In a cohort of 49 patients with CKD stages 3-5, both protein excretion . 1 g/d and eGFR , 40 mL/min/1.73 m2 were associated with low birth weight, small for gestational age, or fetal death.18 Additional studies are needed to evaluate risk factors that could predict adverse outcomes in newborns. In our study, urinary protein excretion during pregnancy was associated closely with the body weight of live infants even after adjustment for premature delivery. This result was consistent with that from a previous study.9 However, we cannot prove a causal relationship. Also, the proteinuria may have been related to the occurrence of pre-eclampsia. Future studies should evaluate the effect on pregnancy outcomes of interventions to reduce proteinuria, such as optimal blood pressure control or corticosteroid therapy in individuals with heavy proteinuria. The major limitation of this study was that most patients included had preserved kidney function, with only 2 pregnant patients having eGFRs , 60 mL/ min/1.73 m2. Therefore, we cannot evaluate the effect of reduced kidney function on pregnancy outcomes in Am J Kidney Dis. 2014;64(5):730-736
Pregnancy in Patients With IgA Nephropathy Table 4. Univariate and Multivariate Logistic Regression Analysis of Factors at Baseline and During Pregnancy Influencing Adverse Pregnancy Outcomes Univariate Characteristic
OR (95% CI)
Multivariate P
OR (95% CI)
P
Age, per 1-y older
1.04 (0.88-1.12)
0.7
Haas classification I/II III IV
1.00 (reference) 1.33 (0.14-13.09) 4.27 (0.45-40.44)
0.8 0.2
Proteinuria Baseline, per 1-g/d greater Time-averaged during pregnancy, per 1-g/d greater
1.35 (0.94-1.93) 1.53 (1.09-2.13)
0.1 0.01
1.39 (0.96-2.01)
0.08
Mean arterial pressure Baseline, per 102mm Hg greater Time-averaged during pregnancy, per 102mm Hg greater
0.99 (0.94-1.05) 1.07 (1.01-1.14)
0.8 0.03
1.39 (0.69-2.82)
0.4
Baseline eGFR, per 102mL/min/1.73 m2 greater
0.98 (0.95-1.00)
0.06
Therapy before pregnancy (yes or no)
3.33 (0.95-11.71)
0.06
Note: Adverse pregnancy outcomes defined as severe pre-eclampsia, intrauterine death, embryo damage, fetal malformation, and voluntary and spontaneous abortions. Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate; OR, odds ratio.
patients with IgAN. Owing to the limited evidence, maternal and fetal outcomes in patients with IgAN and decreased kidney function remain undetermined. In addition, the sample size was small, with few kidney disease progression events, so our study is underpowered to detect HR effect estimates of the magnitudes observed here. The annual kidney disease progression rate in our general IgAN population is estimated at 3.45 per 100 person-years.19 This means we would need more than 400 patients with a 5-year follow-up to have 80% power (a 5 0.05) to detect the estimated HR effect (1.7) on kidney disease progression events. Finally, although we found a trend of
Figure 4. Correlation between birth weight of infants and time-averaged (TA) proteinuria during pregnancy. Am J Kidney Dis. 2014;64(5):730-736
heavy proteinuria during follow-up being associated with low birth weight and adverse pregnancy outcome, the causal relationship was not confirmed. In conclusion, this study does not permit a definitive conclusion about the effect of pregnancy on kidney disease progression in IgAN. Proteinuria during pregnancy may predict a higher rate of adverse pregnancy outcomes. Further studies are needed to evaluate the mutual effects of pregnancy and IgAN in patients with decreased kidney function.
ACKNOWLEDGEMENTS Support: This work was supported by grants from the National Natural Science Foundation of China (81270795, 81322009), Program for New Century Excellent Talents in University from the Ministry of Education of China grant NCET-12-0011, Capital Clinical Research grant Z12110700100000, 2011-4021-06, Beijing Science and Technology Plan (Z121107001012137), the Beijing Natural Science Foundation (grant 7131016), and the Natural Science Fund of China to the Innovation Research Group (81021004). Study sponsors had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. Financial Disclosure: The authors declare that they have no other relevant financial interests. Contributions: Research idea and study design: JL, HZ; data acquisition: SS, LL, YC; data analysis/interpretation: YL, XM; statistical analysis: YL; supervision or mentorship: JL, HZ. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. JL and HZ take responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. 735
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SUPPLEMENTARY MATERIAL Table S1: Baseline characteristics of the 239 included IgAN patients. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2014.06.021) is available at www.ajkd.org
REFERENCES 1. Pan X, Xu J, Ren H, et al. Changing spectrum of biopsyproven primary glomerular diseases over the past 15 years: a single-center study in China. Contrib Nephrol. 2013;181:22-30. 2. D’Amico G. The commonest glomerulonephritis in the world: IgA nephropathy. Q J Med. 1987;64(245):709-727. 3. Packham DK, North RA, Fairley KF, Whitworth JA, Kincaid-Smith P. IgA glomerulonephritis and pregnancy. Clin Nephrol. 1988;30(1):15-21. 4. Kincaid-Smith P, Fairley KF. Renal disease in pregnancy. Three controversial areas: mesangial IgA nephropathy, focal glomerular sclerosis (focal and segmental hyalinosis and sclerosis), and reflux nephropathy. Am J Kidney Dis. 1987;9(4):328-333. 5. Surian M, Imbasciati E, Cosci P, et al. Glomerular disease and pregnancy. A study of 123 pregnancies in patients with primary and secondary glomerular diseases. Nephron. 1984;36(2): 101-105. 6. Jungers P, Houillier P, Forget D, et al. Influence of pregnancy on the course of primary chronic glomerulonephritis. Lancet. 1995;346(8983):1122-1124. 7. Abe S. The influence of pregnancy on the long-term renal prognosis of IgA nephropathy. Clin Nephrol. 1994;41(2):61-64. 8. Limardo M, Imbasciati E, Ravani P, et al. Pregnancy and progression of IgA nephropathy: results of an Italian multicenter study. Am J Kidney Dis. 2010;56(3):506-512. 9. Barcelo P, Lopez-Lillo J, Cabero L, Del Rio G. Successful pregnancy in primary glomerular disease. Kidney Int. 1986;30(6): 914-919.
736
10. Shimizu A, Takei T, Moriyama T, Itabashi M, Uchida K, Nitta K. Effect of kidney disease stage on pregnancy and delivery outcomes among patients with immunoglobulin A nephropathy. Am J Nephrol. 2010;32(5):456-461. 11. Kong X, Ma Y, Chen J, et al. Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating glomerular filtration rate in the Chinese population. Nephrol Dial Transplant. 2013;28(3):641-651. 12. Reich HN, Troyanov S, Scholey JW, Cattran DC. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol. 2007;18(12):3177-3183. 13. Haas M. Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases. Am J Kidney Dis. 1997;29(6):829-842. 14. Feng XL, Guo S, Hipgrave D, et al. China’s facilitybased birth strategy and neonatal mortality: a populationbased epidemiological study. Lancet. 2011;378(9801):14931500. 15. Mi J, Liu F. Rate of caesarean section is alarming in China. Lancet. 2014;383(9927):1463-1464. 16. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379(9832):21622172. 17. Chen Y, Li G, Ruan Y, Zou L, Wang X, Zhang W. An epidemiological survey on low birth weight infants in China and analysis of outcomes of full-term low birth weight infants. BMC Pregnancy Childbirth. 2013;13:242. 18. Imbasciati E, Gregorini G, Cabiddu G, et al. Pregnancy in CKD stages 3 to 5: fetal and maternal outcomes. Am J Kidney Dis. 2007;49(6):753-762. 19. Li X, Liu Y, Lv J, et al. Progression of IgA nephropathy under current therapy regimen in a Chinese population. Clin J Am Soc Nephrol. 2014;9(3):484-489.
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