Pregnancy in Chronic Kidney Disease: Maternal and Fetal Outcomes

Pregnancy in Chronic Kidney Disease in a Low-Middle Income Country. Guillermo Garcia-Garcia, MD, FASN Hospital Civil de Guadalajara, University of Guadalajara Health Sciences Center, Guadalajara, Jal., Mexico

Pregnancy in Chronic Kidney Disease Chronic kidney disease (CKD) is global public health problem and it s linked to adverse outcomes in pregnant women with CKD. International studies reported that one in every 750 women of reproductive age have CKD stage 3-51. Reported frequency of conception among women of child-bearing age on dialysis ranges from 3 to 15 per 1,000 person-years2 Successful pregnancy in women with CKD has increased from 25% in 1980 to > 70% in 20153 1BMJ. 2008;336:211-2015;2 Nephrology 18 (2013) 276 284; 3CJASN 2015;10:1964-1978; 4Nephrol Dial Transplant 2015; 0: 1 20

Pregnancy in Chronic Kidney Disease Several studies have reported that increasing time and frequency on dialysis prolongs gestation, with a better chance of fetal survival. 4 In addition to intensive dialysis, better anemia management, hypertension control, and frequent obstetric monitoring, contributes to an increased fetal survival. Pregnant women with CKD have an increased risk of maternal and fetal complications, like severe hypertension, preeclampsia, abortion, prematurity and low-birth weight3. 3CJASN 2015;10:1964-1978; 4Nephrol Dial Transplant 2015; 0: 1 20

Maternal and Fetal Outcomes in CKD patients on dialysis Cesarean/Ind uction (%) Hypertension (%) Polyhydramnios (%) Reference Indication for Delivery HD 71 PD 33 43 Iterative Cesarean 57 Chou et al.,2008 Fetal distress, elective, pathological d Doppler None 80 to 20 20 (severe) Bamberg et al.,2007 40 33 to 17 IUGR, failure to progress, comorbid conditions 33 Barua et al., 2008 HELLP, obstetric cholestasis, abruptio placentae, IUGR, PE HD 63 PD 60 NR 55.6 to NR Tan et al., 2006 18 33 to 0 NR 66 (preeclampsia) Malik et al., 2005 42 80 to 0 Fetal Distress 40 (severe) Haase et al., 2005 40 57 to 14 IUGR, PE, PROM, preterm labor 29 (preeclampsia) Eroglu et al., 2004 29 NR NR NR Moranne et al., 2004 One case with preeclampsia 100 80 to NR Abruptio placentae, fetal distress, PROM Luciani et al., 2002 Fetal distress, previous cesarean, placenta previa, preterm labor, PROM 46 46 to 7 53 Chao et al., 2002 Piccoli G Clin J Am Soc Nephrol 2010; 5: 62 71,

Fetal Outcomes. 76% infant survival Gestational Age Preterm Delivery (%) IUGR (%) Stillbirth/Neon atal Death (%) Admission to NICU (%) Reference Birth Weight (g) Chou et al.,2008 30.8 1.6 HD 71 PD 67 1511 284 28.5 HD 28.5/14 PD 33/33 NR Bamberg et al.,2007 32 (30-37) 80 1764 (1274-2465) 80 None 100 Barua et al., 2008 36.2 3.0 NR 2417.5 657 17 None 33 Tan et al., 2006 31 (26-36) 100 1390 705.3 27.3 None 55.6 Malik et al., 2005 31.5 (27- 36) 100 1700 (1115-2300) 70 0/17 NR Haase et al., 2005 32.8 3.3 80 1765 554 NR None NR Eroglu et al., 2004 32 (26-36) 100 1400 (420-2640) 14 0/14 NR Moranne et al., 2004 31 (24-34) NR 1495 NR 0/20 NR Luciani et al., 2002 28.6 4.0 100 1431 738 NR 0/20 NR Chao et al., 2002 32 (23-36) 100 1542 (512-2660) 80 8/23 NR Piccoli G Clin J Am Soc Nephrol 2010;5:62 71

Conception in CKD Women Conception before or on dialysis 33% (182) Conception before dialysis Conception on dialysis 67% (370) Piccoli G Nephrol Dial Transplant 2015; 0: 1 20

Dialysis during Pregnancy 10% Peritoneal Dialysis Hemodialysis 90% Nephrol Dial Transplant 2015;0:1 20

Dialysis Schedule Reference Dialysis Dialysis schedule EPO, iron and vitamins, heparin 6days/w; 17.7 4h/w Panaye et al., 2014 HD NR EPO; heparin; Iron; vit B12; vit D; folic acid; Zn Stahl et al., 2014 HD Individualized; 6days/w 2.5-4h Hladunewich et al., 2014 HD 6-8h 6-7days/w NR HD PD >6hrs 7 days/w 4h 6 days/w Piccoli et al., 2014 NR Espinoza et al. 2013 HD 19.5 2.7h/w EPO, Transfusions Zanlorenci et al., 2013 HD NR EPO Bernasconi et al., 2012 HD 3 days/w 5-6days/w EPO, vit B, heparin Abou-Jaoude et al., 2012 HD Median 18hr/w (12-30) NR Macias et al., 2012 PD 63.3L/w NR Hadj Sadek et al., 2011 HD 4h 3 days/w or 4h 4 days/w EPO, heparin, oral iron, transfusions Mean 23.2 1.8h/w Sulaiman et al., 2011 HD EPO Bahadi et al., 2010 HD 4-6 days; duration to 6h EPO, oral iron, transfusions Luders et al., 2010 HD Mean 15 (9-21)h/w EPO, aspirin, CaCO3, transfusions Sato et al., 2010 HD 12-20h/week NR, transfusions V zquez-Rodr guez et al., 2010 HD 4hx 3days/w Oral iron, vit B, folic acid, transfusions Jefferys et al., 2008 PD 5.4-7.5L. Cycler: 10Lin 9hr + 1 daytime exchange EPO, oral iron, vit D Nephrol Dial Transplant (2015) 0: 1 20

Dialysis duration (h/week) Piccoli G. Nephrol Dial Transplant 2015 0:1 20

Correlation between dialysis duration and prematurity Piccoli G. Nephrol Dial Transplant 2015: 0: 1 20

Maternal and fetal outcomes in women with and without CKD CKD N=778 No-CKD N=778 p Preterm Delivery (%) 19.4 13.6 0.002 Cesarean delivery (%) 32.3 26.6 0.01 LBW (%) 13.1 6.0 <0.001 BW (g) 3106 675 3,314 560 <0.001 Admission to NICU (%) 9.6 5.8 <0.001 Kendrick J. AJKD 2015;66:55-59

Association of kidney disease with adverse maternal and fetal outcome OUTCOME OR (CI) Preterm delivery 1.52 (1.16-1.99) Delivery by C-section 1.33 (1.06-1.66) LBW (<2,500 g) 2.38 (1.64-3.44) Admission to NICU/infant death 1.71 (1.17-2.51) Admission to NICU 1.80 (1.22-2.65) Kendrick J. AJKD 2015;66:55-59

Pregnancy in Chronic Kidney Disease In Mexico there are few studies on CKD in Pregnancy. The high prevalence of CKD in the Mexican population, socioeconomic disparities and a fragmented health-care system, increase the risk of adverse maternal and fetal outcomes in pregnant women without medical insurance. Furthermore, to ensure provision of adequate renal care by offering more hours on dialysis to pregnant women with CKD, results in a higher burden to the public health system. *Ginecol Obstet Mex 2010;78(9):486-492

Objective To evaluate maternal and fetal outcomes in poor pregnant women with CKD, we conducted a prospective observational study at the Hospital Civil de Guadalajara (HCG) between July 2013 to September 2015.

Methods CKD was defined according to KDIGO guidelines. Pregnant patients with with persistent ( 3 months previous to conception) GFR <60ml/min/1.73m2 and/or with markers of kidney damage: abnormalities in histology, structural abnormalities detected by imaging or proteinuria for >3months were included. A group of pregnant women without kidney disease that delivered at our hospital in the same period of study, was selected as a historic control group.

Methods GFR was estimated by the MDRD equation. Blood urea nitrogen (BUN) 45 mg/dL, fluid overload, and hyperkalemia and acidosis, were indications to initiate dialysis. In addition to intensive hemodialysis, all patients received anemia management, hypertension and diabetes control, and frequent obstetric monitoring during pregnancy.

Maternal and Fetal Outcomes Maternal outcomes: Preeclampsia was defined according to the American College of Obstetrics and Gynecologist guidelines 2013. Anemia as per WHO definition preterm delivery (delivery <37 weeks gestation) delivery by cesarean section maternal death

Maternal and Fetal Outcomes Fetal outcomes: Low birth-weight (<2,500 g) Gestational age by Capurro s Method5 IUGR Respiratory distress syndrome Admission to NICU Abortion (spontaneous) Stillbirth/Neonatal death 5J Pediatr 1978;93:120-122

Results Pregnant women with CKD (June 2013 September 2015) n=27 HD (n=10) Non-dialysis (n=17) Control Group (n=48) Maternal and Fetal Outcomes

Baseline clinical and laboratorial characteristics of women with CKD n=27 (%) First Visit to Nephrologist: weeks of pregnancy (m) Trimester: First (%) Second (%) Third (%) Serum Creatinine (mg/dL) eGFR (ml/min/1.73m2) Urea (mg/dL) Proteinuria (g/day) CKD Stage Stage 1-2 Stage 3 Stage 4 Stage 5 Overweight-Obesity (%) 20.2 8.7 6 (22) 11 (41) 10 (37) 3.3 2.94 39.7 36.2 78.63 65.7 2.54 1.77 4 (14.8) 9 (33.3) 10 (37) 4 (14.8) 3 (11)

Etiology of CKD 11% Unknown Etiology Glomerulonephritis Diabetes-associated 18% 71%

Clinical characteristics of pregnant women with and without CKD Controls CKD Characteristics p-value n= 48 n= 27 Mean Age (y) 27.5 7.04 22.5 6.86 0.004 19 years old(%) 3 (6.3) 6 (22.3) 0.002 Diabetes Mellitus (%) 1 (2.1) 3 (11.1) 0.09 Hypertension (%) 1 (2.1) 14 (51.9) < 0.001 Serum Creatinine (mg/dL) 0.52 0.103 3.3 2.94 < 0.001 GFR (ml/min/1.73m2) 145.9 45.2 39.7 36.2 < 0.001 Proteinuria* (mg/dL) 6.62 19.4 169 121 < 0.001 Haemoglobin (g/dL) 12.5 1.28 10.3 2.03 < 0.001 * By dipstick Hernandez-Ibarra M J Nephrol. 2017 Dec;30(6):773-780

Maternal Complications Controls CKD group Outcomes p-value n= 48 n= 27 Preeclampsia/eclampsia (%) 2 (4.16) 10 (44.7) < 0.001 Polyhydramnios (%) 0 ( 0) 1 (3.7) 0.13 Oligohydramnios (%) 1 (2.08 ) 1 (3.7 ) 0.67 Cesarean section (%) 33 (69) 19 (70.4) 0.88 Hernandez-Ibarra M J Nephrol. 2017 Dec;30(6):773-780

Fetal Outcomes Fetal Outcomes Non CKD n = 48 (98) 38.2 1.57 7 (14.28) 3022 455 6 (12.24) 49.01 2.07 6 (12.8) CKD group n = 24 (89) 35.9 3.11 13 (48.14) 2253 739 13 (54.16) 44.26 5.29 7 (36.8) 4 (17) Outcomes p-value Gestational Age (Wk) Capurro Preterm Delivery (%) Birth Weight (g) Low birth weight (<2500g) (%) Height (cm) SGA (%) Low Apgar (5 minutes <7) 0.002 0.001 <0.001 < 0.001 <0.001 0.04 n/a 0 (0) Respiratory Distress Syndrome- Silverman (%) 9 (18.75) 11 (45.9) 0.009 Admission to NICU (%) 2 (4.081) 7 (29.2) 0.006

Fetal Outcomes. Non CKD CKD group Outcomes p-value n = 49 n = 27 Spontaneous Abortions (%) 0 (0) 2 (7.4) Stillbirths (%) 1 (2.08 ) 1 (3.7) 0.59 Live Birth (%) 48 (98) 24 (89) 0.13

Association of kidney disease with adverse maternal outcomes Maternal Complications Controls CKD Odds Ratio 95% p-value n=48 n=27 (OR) Confidence Interval Preeclampsia 2 (4.2) 10 (37) (2.686 - 68.153) 13.529 <0.001 Hypertension 1(2.1) 14(51.9) (6.077 - 421.552) 50.615 <0.001 Anemia 8(16.7) 20(74.1) (4.534 - 45.011) 14.286 <0.001

Association of kidney disease with adverse fetal outcomes Risk of Maternal and Fetal Complications in CKD Women Fetal Complications Controls CKD Odds Ratio 95% p-value n=48 n=24 (OR) Confidence Interval Preterm Delivery 6(12.5) 13(54.2) (2.559 - 26.740) 8.273 <0.001 Admission to NICU 2(4.2) 7(29.2) (1.788 - 50.160) 9.471 0.005 Low Birth Weight 6(12.5) 13(54.2) (2.559 - 26.740) 8.273 <0.001 Respiratory Distress Syndrome 9(18.8) 11(52.4) (1.552 - 14.637) 4.767 0.008

Baseline characteristics of women with CKD with and without dialysis Characteristics CKD without HD n=17 15 (88) p-value CKD with HD n=10 2 (20) CKD diagnosis prior to conception First visit to nephrologist: pregnancy weeks CKD Stage: 1-2 3 4 5 eGFR (ml/min/1.73m2) Urea (mg/dL) Hemoglobin 0.001 19.7 9.30 21.0 8.37 0.732 4 (23.5) 7(41.2) 6 (35.3) 0 (0) 50.4 40.09 48.22 5.91 11.52 1.07 0 (0) 2 (20) 4 (40) 4 (40) 21.7 19.30 123.46 29.71 8.31 1.68 0.03 <0.001 0.03 <0.001

HD Treatment during Pregnancy Indications for HD: 10 (100) * BUN 45mg/dL * Hiperkalemia and Metabolic Acidosis 2 (20) * Fluid overload 1 (10)

Characteristics of HD Treatment Blood/Dialysate Flow (ml) Hours of Dialysis/week Kt/V URR (%) 300-350 (350 500) 15.4 3.76 1.26 (0.54-2.60) 61.62 (53.09-70.80)

Adverse maternal outcomes in women with CKD with and without dialysis Maternal Outcomes Without HD n=17 11 (64.70) 7 (41.17) CKD with HD n=10 9 (90) 3 (30) p-value Anemia (%) Preeclampsia (%) 0.14 0.56

Adverse fetal outcomes in women with CKD with and without dialysis Outcomes Without HD n=17 16 (94) 7 (47) 37 2.15 2460 693.65 3 (17) CKD with HD n=10 8 (80) 5 (63) 31.22 3.76 1837 684.17 4 (40) p-value Live Birth Preterm Delivery Gestational age (Capurro) Birth Weight Admission to NICU 0.26 0.51 0.005 0.05 0.11

Conclusions Pregnancy is becoming a frequent event in women with CKD. Our data indicate that CKD is a significant risk factor for adverse maternal and fetal outcomes. However our study confirms the feasibility of pregnancy in CKD, demanding dialysis schedule and closer follow-up. through a more

Conclusions An obstetricians and nephrologists is required to improve outcomes in pregnant women with CKD. interdisciplinary approach involving Nephrologists should discuss fertility and contraception with this group of patients. Women with CKD that want to become pregnant should have counseling. preconception

Acknowledgment Nephrology Department Margarita Ibarra-Hernandez (Leading investigator) Luz Alcantar Fernando Tamez Angela Soto Paulina Albarran Sara Reyes Obstetrics Department Patricia Jimenez Francisco Villa Martin Gonzalez Jose J Diaz Arnoldo Guzman

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