LABETALOL IN PIH

CAN IT SUPPLANT ALPHA METHYL DOPA ?

DR KAVITA PRIYA M.D.(O &G) MEDICAL SUPERINTENDENT. CENTRAL HOSPITAL,DHANBAD

HYPERTENSION IN PREGNANCY

Hypertens ion can turn pregnancy into a

Historically, hypertension and pregnancy have intertwined, sometimes causing maternal death. At the turn of the 20th century, one in 100 live births resulted in maternal death, according to WHO.

Categories of Hypertension in Pregnancy

Chronic HTN

Gestational HTN HTN in Pregnancy Pre-eclampsia

Pre-eclampsia superimposed on Chronic HTN

American Family Physician. 2001 Jul 15;64(2):263-271

Chronic Hypertension
Pre-existing Hypertension Systolic pressure 140 mmHg, diastolic pressure 90 mmHg, or both. Presents before 20th week of pregnancy or persists longer than 12th weeks postpartum. Chronic hypertension is caused by Primary = Essential Hypertension Secondary HTN = Result of other medical conditions

American Family Physician.2004; 70(12 ):2317-2324

Systolic pressure 140 mmHg, diastolic pressure 90 mmHg, or both.

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Design: Retrospective, population-based cohort study

N= 29,842 women who delivered with chronic hypertension

Conclusion: Pregnant women with chronic hypertension have significantly increased risks of maternal and perinatal morbidity and mortality.

The Journal of Reproductive Medicine. 2007 Nov;52(11):1046-51

Gestational Hypertension
Mild hypertension without proteinuria or other signs of preeclampsia. Develops in late pregnancy, after 20th weeks gestation.

Resolves by 12th weeks postpartum.

Can progress in to pre-eclampsia.
* Often when hypertension develops <30 weeks gestation.

One fourth of women with gestational hypertension develop proteinuria and thus progress to pre-eclampsia.

American Family Physician.2004; 70(12 ):2317-2324

Pre-eclampsia
New onset of hypertension and proteinuria after 20th weeks gestation. Systolic blood pressure 140 mmHg OR diastolic blood pressure 90 mmHg Proteinuria of 0.3 g or greater in a 24-hour urine

Incidence: In India, pre-eclampsia occurs in 10% primigravidae (women pregnant for 1st time) and 5% in multigravidae (a woman who is pregnant and has been pregnant at least twice before) in hospital.
Dutta DC. Textbook of obstetrics. 5th edition. Central publication, 234-255

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BP = or > or 160mm Hg systolic or BP = or >

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Eclampsia, a severe complication of pre-eclampsia, is the new onset of seizures in a woman with pre-eclampsia. Eclampsia seizures are relatively rare and occur in <1% of women with pre-eclampsia.
Up to 40% of eclamptic seizures occur before delivery; approximately 16% occur more than 48hrs after delivery

American Family Physician.2004; 70(12 ):2317-2324

Risk factors for Pre-eclampsia

Pregnancy associated factors Chromosomal abnormalities Hydatidiform mole Hydrops fetalis Multifetal pregnancy Urinary tract infections New paternity First time father Previously fathered a pre-eclamptic pregnancy in another woman

Maternal-specific factors Age <20years & >35 years Family history of pre-eclampsia Nulliparity

Pre-eclampsia in previous pregnancy

Specific medical conditions: gestational diabetes, Type 1 diabetes, obesity, chronic hypertension, renal disease

American Family Physician.2004; 70(12 ):2317-2324

Pre-eclampsia superimposed upon Chronic Hypertension

Affects 10-25% of patients with chronic hypertension.

Pre-existing hypertension signs/symptoms:

with

the

following

additional

Hypertension and proteinuria beginning prior to 20th weeks of gestation. A sudden increase in blood pressure. Development of the HELLP (Hemolysis, Elevated liver enzymes, Low platelet count) syndrome.

American Family Physician.2004; 70(12 ):2317-2324

Gestational HTN
Systolic pressure 140 mmHg & diastolic pressure 90 mmHg, or both

Pre-eclampsia

Eclampsia
Severe grade of preeclampsia leads to seizures & dangerous to fetus & mother

BP + Proteinuria + Edema

American Family Physician.2004; 70(12 ):2317-2324

Differentiation Algorithm

American Family Physician.2004; 70(12 ):2317-2324

Etiology

American Journal of Physiology - Heart and Circulatory Physiology. 2008;294:H541H550

CNS Visual disturbance Seizures Thrombosis,

HEPATIC Periportal hemorrhagic necrosis AST ALT

Vasospasm Reduced flow

CARDIAC Cardiac output Plasma volume Pulmonary edema

KIDNEY Endotheliosis Proteinurea GFR Renal blood flow

VASCULAR Systemic vascular resistance Blood pressure Angiotensin II sensitivity

Systemic Diseases and the Kidney. Chapter 10

Uncontrolled hypertension leads to.

Intrauterine growth retardation (IUGR) Low birth weight Placental abruption (separation of placenta from uterus) Premature delivery

American Journal of Obstetrics & Gynecology .1999 Jan;180(1 Pt 1):207-13 Indian J Pediatr 2007; 74 (7) : 623-625

Management
Rest: Continued till all the pre-eclampsia manifestations subside.

Diet: Should contain adequate amount of protein.

Antihypertensive: The common oral drugs used are either Labetalol or Methyldopa.

Dutta DC. Textbook of obstetrics. 5th edition. Central publication, 234-255

(Oral Labetalol 100 mg)

(Labetalol 100 mg)

Labetalol is a popular first-line antihypertensive of choice in the treatment of hypertension. Most preferred antihypertensive drug among UK consultants in the management of severe pre-eclampsia and eclampsia. Useful in PIH because reduced placental transfer occurs, mainly due to low lipid solubility.

Obstetrics, Gynaecology & Reproductive Medicine.2009;19(5):136-141; Br J Obstet Gynaecol. 1992; 99:554-556 Ultrasound in Medicine and Biology.2011; 37 (1): 53-58

Labetalol: Mechanism of Action

Pharmacokinetics
Labetalol is completely absorbed.
Peak plasma concentrations is achieved within 2 hours. Relative bioavailability of oral labetalol is 100%. About 50% of the drug is bound in the plasma. Half-life of labetalol is 6 to 8 hours. Metabolized in liver and excreated through urine and bile.
Prac Diab Int.2011:28(3): 139-140 Lippincott . 5th edition.

Oral Labetalol Vs Placebo

Study Design: Prospective, Randomized, Double blind, Placebo controlled Multicentric trial. N =152 patients with non-proteinuric PIH Dose: Labetalol (100 mg t.i.d.), was increased to 200 mg t.i.d. where required

Significant reduction in maternal mean arterial pressure (MAP) was found with labetalol which was sustained over a 5 weeks period (P<0.01).
British Journal of Obstetrics and Gynaecology.1989 Jan; 96(1):38-43

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Some reduction in preterm delivery, neonatal respiratory distress syndrome and jaundice was observed in the labetalol treated group.

No perinatal deaths were observed.

Conclusion: Labetalol appeared to be an effective and safe agent in the management of mild to moderate pregnancy-induced hypertension.

British Journal of Obstetrics and Gynaecology.1989 Jan; 96(1):38-43

Oral Labetalol Vs Methyldopa

Study Design: Randomized comparative trial

N =104 primigravidas (a woman pregnant for the first time) with mild to moderate PIH
Group A: Labetalol (100 mg t.i.d.) n=54 Group B: Methyldopa (250 mg t.i.d.) ...n=50

Dose of both the drugs were doubled every 48 hrs to maintain MAP103.6 mmHg upto maximum dose of 900 mg labetalol and 2250 mg methyldopa per day.
International Journal of Gynecology & Obstetrics.1995 May;49(2):125-30

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MAP<103.6 mmHg (equivalent to BP 130/90 mmHg )

Labetalol demonstrated to have a quicker action, better control of blood pressure.

International Journal of Gynecology & Obstetrics.1995 May;49(2):125-30

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International Journal of Gynecology & Obstetrics.1995 May;49(2):125-30

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Hematological parameters Renal function

Oral Labetalol Methyldopa No abnormality was No abnormality was observed observed Beneficial effect on renal function by No beneficial effect was observed reducing incidence of proteinurea 48% 63%

Rate of induction of labor for uncontrolled PIH Rate of cesarean section for uncontrolled PIH

1%

5.6%

International Journal of Gynecology & Obstetrics.1995 May;49(2):125-30

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International Journal of Gynecology & Obstetrics.1995 May;49(2):125-30

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Labetalol safer than Methyldopa

Side effects Drowsiness Headache Nasal Congestion Postural hypotension Oral Labetalol None None None None Methyldopa 22.2% (12/50) 14.8% (8/50) 7.4% (4/50) 5.6% (3/50)

50 infants (100%) in labetalol group and 46 (85.2%) in methyldopa group were reviewed at 18 months of age. All had been developing normally, both physically and mentally.

Conclusion: Labetalol was better tolerated than methyldopa, gives more efficient control of blood pressure and may have a ripening effect on the uterine cervix.
International Journal of Gynecology & Obstetrics.1995 May;49(2):125-30

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In another comparative study between Labetalol and Methyldopa, a more satisfactory control of blood pressure was obtained with labetalol with minimal side-effects.

After 2 weeks labetalol treatment renal function had significantly improved with a markedly lower incidence of proteinuria.

No adverse effects attributable to labetalol were noted in the baby either ante- or post-natally.

Clinical and Experimental Hypertension.. 1980;2(5):865-95

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Blood pressure control was more frequently achieved in hypertensive pregnancies with labetalol than with methyldopa as a first line treatment.

Labetalol was safe to the fetus and newborn and might offer a better prevention of intrauterine

death than methyldopa.

Archives des Maladies du Cur et des Vaisseaux.1987;80(6):952-5

Safety
Labetalol was generally well tolerated but may cause fatigue, headache, postural hypotension, nasal stiffness, and gastrointestinal symptoms (if it is used in high doses).

Labetalol treatment was not related to any significant changes in fetal doppler.
No perinatal deaths were reported with labetalol treatment. Labetalol allows safe complicated by PIH. prolongation of pregnancies

International Journal of Gynecology & Obstetrics.1995 May;49(2):125-30; Dollery C. Therapeutic drugs.2nd edition: L1-L7 Ultrasound in Medicine and Biology.2011; 37 (1): 53-58

National Institute for Health and Clinical Excellence (NICE) guidance on the management of hypertensive disorders during pregnancy recommends oral labetalol as first line treatment to keep diastolic BP between 80100 mmHg and systolic BP <150 mmHg in the management of gestational hypertension and pre-eclampsia.

National Institute for Health and Clinical Excellence.2010

American college of obstetricians & Gynecologists (ACOG) and Royal college of obstetricians & Gynecologists (RCOG) also recommends labetalol as a first line treatment in the treatment of Pre-eclampsia.

National Institute for Health and Clinical Excellence.2010

Textbooks Recommending Labetalol

Danforths Obstetrics and Gynaecology. 2007;PN-264

Dutta DC. Textbook of Obstetrics. Central Publication. PN-544

Limitations of Available Anti-hypertensives

ACE Inhibitors & Angiotensin Receptor Blockers

Contraindicated in pregnancy because of adverse fetal effects.

Diuretics

Should be avoided in pregnancy, May interfere with aspects of fetal neurodevelopment.

Atenolol

Should be avoided due concerns with fetal growth.

to

Adv Chronic Kidney Dis. 2007;14(2):178-90; Semin Nephrol. 2011;31(1):70-85; Am J Psychiatry. 2003 ;160(3):464-8; CMA.1978;118:936; Rev Med Suisse. 2007 Sep 12;3(124):2012

Women should not become pregnant while taking an ACE inhibitor.

Methyldopa

Drowsiness, Nasal Congestion, Headache, Postural hypotension & Intrauterine death are reported.

Nicardipine

Tachycardia is reported.

Hydralazine

Associated with unpredictable hypotension.

Am J Obstet Gynecol. 2002 Oct;187(4):1046-50.; Intensive Care Med. 2002 Sep;28(9):1281-6; Am J Health Syst Pharm. 2009 Feb 15;66(4):337-44.

Labetalol may be preferred because of a lack

of reflex tachycardia, hypotension, or increased intracranial pressure.

American Journal of Health-System Pharmacy. 2009 Feb 15;66(4):337-44

Contraindications
Labetalol is contraindicated in women with a history of asthma. Labetalol should be used with caution in cardiac disease.

Lippincott. 5th edition

Dosage
Labetalol 100 mg twice or thrice in a day. If blood pressure control is unsatisfactory then dose can be doubled every 48 hrs up to maximum 900 mg per day.

OR
As directed by physician

(Oral Labetalol 100 mg)

First line treatment in the management hypertension and pre-eclampsia.

of

gestational

It is quicker and more efficient at controlling blood pressure. Better tolerated than Methyldopa. Improves renal function by reducing incidence of proteinurea. May help to ripen uterine cervix thus increase the rate of vaginal delivery.

(Oral Labetalol 100 mg)

Recommended by NICE guideline.

Does not adversely affect fetoplacental blood flow.

No perinatal deaths were reported with labetalol treatment.

Allows safe prolongation of pregnancies complicated by PIH.