Preeclampsia Prevention Krishna Khanal, MD RIII Cedar Rapids Medical Education Foundation

Objectives To highlight the role of anti platelet agents. To highlight the role of anti platelet agents. To describe the role of Calcium/Vitamin D supplementation and antioxidants. To describe the role of Calcium/Vitamin D supplementation and antioxidants. To explore the effectiveness of life style modification. To explore the effectiveness of life style modification. To improve standard of patient care in residency. To improve standard of patient care in residency.

Pathogenesis: Preeclampsia

Risk Factors Nulliparity Nulliparity Preeclampsia in a previous pregnancy Preeclampsia in a previous pregnancy Age >40 years or 40 years or <18 years Family history of preeclampsia Family history of preeclampsia Chronic hypertension/Chronic renal disease Chronic hypertension/Chronic renal disease Antiphospholipid antibody syndrome or inherited thrombophilia/Vascular or connective tissue disease Antiphospholipid antibody syndrome or inherited thrombophilia/Vascular or connective tissue disease Diabetes mellitus (pregestational and gestational) Diabetes mellitus (pregestational and gestational) Multifetal gestation/High body mass index Multifetal gestation/High body mass index Male partner whose mother or previous partner had preeclampsia Male partner whose mother or previous partner had preeclampsia Hydrops fetalis Hydrops fetalis Unexplained fetal growth restriction/Woman herself was small for gestational age/Fetal growth restriction Unexplained fetal growth restriction/Woman herself was small for gestational age/Fetal growth restriction Abruptio placentae, or fetal demise in a previous pregnancy Abruptio placentae, or fetal demise in a previous pregnancy Prolonged inter pregnancy interval Prolonged inter pregnancy interval American College of Obstetricians and Gynecologists practice bulletin Jan., 2002

Overview: SOGC Recommendations Preconception counseling for pre-existing HTN. SOGC Grade III-I Preconception counseling for pre-existing HTN. SOGC Grade III-I Obstetric consult during first prenatal visit for high risk. SOGC Grade II-2B Obstetric consult during first prenatal visit for high risk. SOGC Grade II-2B Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations

Overview Cont’d…. Women at increased risk: Women at increased risk: - Low dose aspirin before 16 wks. SOGC Grade I-A - Calcium supplementation > 1 gm/day with low calcium intake. SOGC Grade I-A - Abstain from alcohol. SOGC Grade II-2E - Periconceptual use of folate containing Vitamin. SOGC Grade I-A - Smoking Cessation. SOGC Grade I-E Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations

Overview: Strategies may be helpful Avoiding interpregnancy weight gain. SOGC Grade II-2E Avoiding interpregnancy weight gain. SOGC Grade II-2E Increased rest at home during third trimester. SOGC Grade I-C Increased rest at home during third trimester. SOGC Grade I-C Reducing work load or stress. SOGC Grade III-C Reducing work load or stress. SOGC Grade III-C Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations

ACOG Recommendations Does not recommend low dose aspirin to prevent preeclampsia in women at low risk. (ACOG level A) Does not recommend low dose aspirin to prevent preeclampsia in women at low risk. (ACOG level A) Does not recommend daily calcium supplementation to prevent preeclampsia. (ACOG level A) Does not recommend daily calcium supplementation to prevent preeclampsia. (ACOG level A) Obstet Gynecol Jan; 99(1):

JNC 7 Recommendations Identify high risk women. Identify high risk women. Perform close clinical and laboratory monitoring for early recognition. Perform close clinical and laboratory monitoring for early recognition. Institute intensive monitoring or delivery when indicated. Institute intensive monitoring or delivery when indicated. Hypertension 2003 Dec; 42(6): Full-text

WHO Recommended Interventions Recommendation Quality of evidence Recommendations strength Calcium with low dietary intake ModerateStrong Baby aspirin in high risk ModerateStrong WHO Summary of recommendations 2011 on prevention and treatment of Preeclampsia/Eclampsia

WHO: No Recommendations Recommendations Evidence Quality Recommendations Strength Rest at home for high risk LowWeak Strict bed rest for HTN LowWeak Salt restriction ModerateWeak Vitamin D Very low Strong Vitamin C and E HighStrong WHO Summary of recommendations 2011 on prevention and treatment of Preeclampsia/Eclampsia

AAFP Recommendations Calcium supplementation decreases the incidence of HTN and preeclampsia, respectively among all women (NNT-11 and NNT-20), women at high risk of HTN disorders (NNT-2 and NNT-6) and women with low calcium intake (NNT-6 and NNT- 13). Level 1 evidence Calcium supplementation decreases the incidence of HTN and preeclampsia, respectively among all women (NNT-11 and NNT-20), women at high risk of HTN disorders (NNT-2 and NNT-6) and women with low calcium intake (NNT-6 and NNT- 13). Level 1 evidence Am Fam Physician Jul 1; 78(1):

AAFP Recommendations Low dose aspirin daily has small to moderate benefits for the prevention of preeclampsia (NNT-72), preterm delivery (NNT-74) and fetal death (NNT-243). The benefit of aspirin is greatest (NNT-19) for prevention of preeclampsia in women at highest risk (previous severe preeclampsia, diabetes, chronic HTN, renal disease or autoimmune disease) Level B Evidence Low dose aspirin daily has small to moderate benefits for the prevention of preeclampsia (NNT-72), preterm delivery (NNT-74) and fetal death (NNT-243). The benefit of aspirin is greatest (NNT-19) for prevention of preeclampsia in women at highest risk (previous severe preeclampsia, diabetes, chronic HTN, renal disease or autoimmune disease) Level B Evidence Am Fam Physician Jul 1; 78(1):

Anti-platelet agent Systematic review of 59 randomized trials with 37,560 women at risk of developing preeclampsia. Systematic review of 59 randomized trials with 37,560 women at risk of developing preeclampsia. Comparing anti-platelet agent vs. placebo. Comparing anti-platelet agent vs. placebo. 6.6% vs. 8% preeclampsia rate (NNT 72). 6.6% vs. 8% preeclampsia rate (NNT 72). 16.7% vs. 18% preterm birth (NNT 77). 16.7% vs. 18% preterm birth (NNT 77). No significant difference between low dose aspirin after 16 wks gestation and placebo. No significant difference between low dose aspirin after 16 wks gestation and placebo. Cochrane Library 2007 Issue 2: CD

Anti-platelet agent Cont’d…. 34 trials evaluating incidence of preeclampsia and IUGR with use of anti-platelet agent vs. placebo in 11,348 subjects. 34 trials evaluating incidence of preeclampsia and IUGR with use of anti-platelet agent vs. placebo in 11,348 subjects. Preeclampsia in analysis of 9 trials with 764 women: NNT- 9 Preeclampsia in analysis of 9 trials with 764 women: NNT- 9 IUGR in analysis of 9 trials with 853 women: NNT- 11 IUGR in analysis of 9 trials with 853 women: NNT- 11 Obstet Gynecl 2010 Aug; 116 (2 part 1): 402

Heparin 4 trials compared heparin with no treatment in women at risk of placental dysfunction in 324 women. 4 trials compared heparin with no treatment in women at risk of placental dysfunction in 324 women. Lower risk of preeclampsia in analysis of two trials with 100 women. NNT 4-10 Lower risk of preeclampsia in analysis of two trials with 100 women. NNT 4-10 Eclampsia in one trial with 110 women, NNT- 8. Eclampsia in one trial with 110 women, NNT- 8. IUGR NNT 5-12 IUGR NNT 5-12 Cochrane Database Syst Rev 2010 Jun 16; (6): CD

Prophylactic Enoxaparin 160 women with previous placental abruption without fetal loss during first pregnancy randomized to enoxaparin vs. no enoxaparin. 160 women with previous placental abruption without fetal loss during first pregnancy randomized to enoxaparin vs. no enoxaparin. Composite placental complications 12.5% vs. 31.3% NNT 6 Composite placental complications 12.5% vs. 31.3% NNT 6 Abruptio placenta 1.3% vs. 3.8% Abruptio placenta 1.3% vs. 3.8% Preeclampsia in 7.5% vs. 22.5% NNT 2 Preeclampsia in 7.5% vs. 22.5% NNT 2 NOH-AP trial (Thromb Hemostat 2010 Oct; 104(4): 771)

Role of Calcium Systematic review of 13 RCT evaluating Calcium supplementation with at least 1 gm/day in 15,730 pregnant women. Systematic review of 13 RCT evaluating Calcium supplementation with at least 1 gm/day in 15,730 pregnant women. Reduced rate of preeclampsia, NNT assuming pre-eclapmsia in 6% placebo group. Reduced rate of preeclampsia, NNT assuming pre-eclapmsia in 6% placebo group. Almost all women were low risk and had a low calcium diet. Almost all women were low risk and had a low calcium diet. Cochrane Database Syst Rev 2010 Aug 4; (8): CD001059

Role of Vitamin D Cochrane review of 5 trials involving 623 women compared effects of Vitamin D alone versus no supplement/placebo. Cochrane review of 5 trials involving 623 women compared effects of Vitamin D alone versus no supplement/placebo. Only one trial(400 women) reported: women who received 1200 IU Vit. D along with 375 mg of elemental Calcium were as likely to develop preeclampsia as women who received no supplementation(RR0.67; 95% CI ). Only one trial(400 women) reported: women who received 1200 IU Vit. D along with 375 mg of elemental Calcium were as likely to develop preeclampsia as women who received no supplementation(RR0.67; 95% CI ). Cochrane Database of Systematic Reviews; 2011 in Press.

Vitamin D level: Preeclampsia Risk Canadian Prospective cohort study. Canadian Prospective cohort study. 221 pregnant patients attending specialty clinic due to the risk of preeclapmsia. Serum Vitamin D level measured between 10 and 20 wks of gestation. 221 pregnant patients attending specialty clinic due to the risk of preeclapmsia. Serum Vitamin D level measured between 10 and 20 wks of gestation. 78% were Vitamin D insufficient(<75 nmol/l) and 53% were deficient (<50). There was no difference in the rates of preeclampsia, GHTN, preterm birth or composite adverse pregnancy outcomes by 25 OHD concentration. 78% were Vitamin D insufficient(<75 nmol/l) and 53% were deficient (<50). There was no difference in the rates of preeclampsia, GHTN, preterm birth or composite adverse pregnancy outcomes by 25 OHD concentration. BJOG: 2010: 117(13): 1593

Antioxidants 9969 nulliparous women at low risk for preeclampsia randomized to begin Vitamin C and E vs. placebo between 9-16 wks pregnancy nulliparous women at low risk for preeclampsia randomized to begin Vitamin C and E vs. placebo between 9-16 wks pregnancy. Preeclampsia in 7.2% vs. 6.7% Preeclampsia in 7.2% vs. 6.7% PIH in 29.2% vs. 26.6% NNH 38 PIH in 29.2% vs. 26.6% NNH 38 Medically indicated delivery due to HTN in 10.3% vs. 9.6% Medically indicated delivery due to HTN in 10.3% vs. 9.6% Am J Obstet Gynecol 2011 Jun; 204(6): 503.e1

Fish Oil Prospective trial enrolled 386 pregnant women with h/o PIH in previous pregnancy and randomly assigned to a fish oil or olive oil supplement beginning after 16 wks of gestation. Prospective trial enrolled 386 pregnant women with h/o PIH in previous pregnancy and randomly assigned to a fish oil or olive oil supplement beginning after 16 wks of gestation. Fish oil had no effect on PIH prevention (OR 0.98; 95% CI 0.63 to 1.53) Fish oil had no effect on PIH prevention (OR 0.98; 95% CI 0.63 to 1.53) Possible higher risk for hypertensive disorder. Possible higher risk for hypertensive disorder. BJOG. 2000;107(3):382.

L-Arginine 672 pregnant women at high risk of preeclampsia. 672 pregnant women at high risk of preeclampsia. Supplementation with medical food bar containing L-Arginine plus antioxidant vs. antioxidant vs. placebo between wks and followed until delivery. Supplementation with medical food bar containing L-Arginine plus antioxidant vs. antioxidant vs. placebo between wks and followed until delivery. Adverse effects are common with medical food bar like nausea, dyspepsia, dizziness, palpitations, headache. Adverse effects are common with medical food bar like nausea, dyspepsia, dizziness, palpitations, headache. BMJ 2011 May 19; 342: d2901 Full-text

Results OutcomePlaceboAntioxidantAlone Arginine + Antioxidant Preeclamp /Eclampsia 30% 23% (p=0.052) 13%, NNT-6 Preterm Delivery 20%23% 11%, NNT- 11 Spont. Preterm del 6%7%5% Cesarean Delivery 68.4%66.6%67.9% BMJ 2011 May 19; 342: d2901 Full-text

Salt Restriction Cochrane review of 2 RCTs involving 603 women on restricted Sodium on diet in Netherlands. Cochrane review of 2 RCTs involving 603 women on restricted Sodium on diet in Netherlands. Preeclampsia (two trials, 603 women; RR % CI ) Preeclampsia (two trials, 603 women; RR % CI ) Peri-natal death (two trials, 409 women; RR 1.92, 9% CI ) Peri-natal death (two trials, 409 women; RR 1.92, 9% CI ) APGAR score <7 at 5 min (one trial, 361 women; RR 1.37, 95% CI ) APGAR score <7 at 5 min (one trial, 361 women; RR 1.37, 95% CI ) The Cochrane Library, Issue 1, 2010.

Anti-hypertensive: Mild to Mod HTN 46 studies (4282 women) 46 studies (4282 women) 28 studies (3200 women) compared anti-HTN drug with placebo or no anti-HTN drug. 28 studies (3200 women) compared anti-HTN drug with placebo or no anti-HTN drug. ½ of the risk of developing severe HTN ½ of the risk of developing severe HTN No difference in the risk of developing preeclampsia/ proteinuria. No difference in the risk of developing preeclampsia/ proteinuria. No difference in the rates of preterm birth, prenatal death and SGA. No difference in the rates of preterm birth, prenatal death and SGA. Cochrane Database of Systematic Review 2007

LCC Data Total Number of Patients with h/o preeclampsia: 45 (Logician) Total Number of Patients with h/o preeclampsia: 45 (Logician) Total Number of Patients with h/o preeclampsia: >300 (St. Luke’s Hospital; ) Total Number of Patients with h/o preeclampsia: >300 (St. Luke’s Hospital; ) Number of patients on prophylactic low dose aspirin: 2 Number of patients on prophylactic low dose aspirin: 2 Number of patients on calcium: 2 Number of patients on calcium: 2 Documented instruction for weight reduction in post- partum visit: 0 Documented instruction for weight reduction in post- partum visit: 0

Conclusions Aspirin(81 mg) for moderate to high risk of preeclampsia. Aspirin(81 mg) for moderate to high risk of preeclampsia. Calcium for low intake in diet or high risk patients. Calcium for low intake in diet or high risk patients. Inter-pregnancy weight loss recommended. Inter-pregnancy weight loss recommended. Proper documentation and overall quality improvement in practice. Proper documentation and overall quality improvement in practice.

Pretest Questionnaire 26 yo African American female G2 P1 10 wks pregnant with her 7 wks US is in LCC for OB work up. She had C/S at 32 wks due to severe preeclampsia. Today on physical examination BP 120/84, FHR 150/min and trace protein on urine dipstick. Patient is concerned about the risk of preeclampsia and would like to know the measures to reduce during this pregnancy. Which of the following is true? 26 yo African American female G2 P1 10 wks pregnant with her 7 wks US is in LCC for OB work up. She had C/S at 32 wks due to severe preeclampsia. Today on physical examination BP 120/84, FHR 150/min and trace protein on urine dipstick. Patient is concerned about the risk of preeclampsia and would like to know the measures to reduce during this pregnancy. Which of the following is true?

A. Strict bed rest. A. Strict bed rest. B. Low Molecular Weight Heparin B. Low Molecular Weight Heparin C. Fish Oil C. Fish Oil D. Vitamin C and E D. Vitamin C and E E. Aspirin E. Aspirin

Questionnaire Cont’d…… A 20 yo G3 P2 14 wks (by her LMP) pregnant Caucasian female was for meet and greet at LCC on December 12, She is single, currently lives with her children at Heart of Iowa and is unemployed. She was induced at 37 wks due to severe HELLP syndrome during her last pregnancy. She is not taking prenatal vitamin due to swallowing issue and has h/o lactose intolerance. What are the medications you are going to prescribe today? A 20 yo G3 P2 14 wks (by her LMP) pregnant Caucasian female was for meet and greet at LCC on December 12, She is single, currently lives with her children at Heart of Iowa and is unemployed. She was induced at 37 wks due to severe HELLP syndrome during her last pregnancy. She is not taking prenatal vitamin due to swallowing issue and has h/o lactose intolerance. What are the medications you are going to prescribe today?

A. Aspirin A. Aspirin Gummy Vitamin Gummy Vitamin Calcium Calcium All of the above All of the above

Questionnaire Cont’d… 22 yo G4 P3 Caucasian female at LCC is for her 6 wks post-partum visit. She smokes ½ PPD. Her last pregnancy was complicated with mild preeclampsia and was induced at 39 wks. Her BMI is 38 and blood pressure in the clinic today is 120/70. She is planning to have another child in coming few years and is interested in knowing how she can lower the risk of preeclampsia during next pregnancy? 22 yo G4 P3 Caucasian female at LCC is for her 6 wks post-partum visit. She smokes ½ PPD. Her last pregnancy was complicated with mild preeclampsia and was induced at 39 wks. Her BMI is 38 and blood pressure in the clinic today is 120/70. She is planning to have another child in coming few years and is interested in knowing how she can lower the risk of preeclampsia during next pregnancy?

A. Smoking cessation A. Smoking cessation B. Weight reduction B. Weight reduction C. Antioxidants C. Antioxidants D. Both A and B D. Both A and B