Kavita Priya Labetalol in Pih - i

LABETALOL IN PIH CAN IT SUPPLANT

ALPHA METHYL DOPA ?

DR KAVITA PRIYA M.D.(O &G) MEDICAL

SUPERINTENDENT.CENTRAL

HOSPITAL,DHANBAD

HYPERTENSION IN PREGNANCY

Hypertension can turn pregnancy into a nightmare.

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.

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

Categories of Hypertension in Pregnancy

HTN in Pregnancy

Pre-eclampsia superimposed on

Chronic HTN

Pre-eclampsia

Gestational HTN

Chronic HTN

Chronic Hypertension

• “Pre-existing Hypertension”

• Chronic hypertension is caused by Primary = “Essential Hypertension” Secondary HTN = Result of other medical conditions

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

Presents before 20th week of pregnancy or persists longer than 12th weeks postpartum.

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

• Mild hypertension without proteinuria or other signs of pre-eclampsia.

Gestational Hypertension

• Develops in late pregnancy, after 20th weeks gestation.

• Resolves by 12th weeks postpartum.

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

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


• New onset of hypertension and proteinuria after 20 th weeks gestation.

Pre-eclampsia

• 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.

Systolic blood pressure ≥140 mmHg OR diastolic blood pressure ≥90 mmHg

Proteinuria of 0.3 g or greater in a 24-hour urine

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

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BP = or > or 160mm Hg systolic or BP = or > 110mmHg diastolic

• 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.

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Up to 40% of eclamptic seizures

occur before delivery;

approximately 16% occur more than

48hrs after delivery


Risk factors for Pre-eclampsia

Pregnancy associated factors

Chromosomal abnormalities

Hydatidiform mole

Hydrops fetalis

Multifetal pregnancy

Urinary tract infections

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

New paternity

First time father

Previously fathered a pre-eclamptic pregnancy in another woman


• Affects 10-25% of patients with chronic hypertension.

Pre-eclampsia superimposed upon Chronic Hypertension

• Pre-existing hypertension with the following additional signs/symptoms:

Hypertension and proteinuria beginning prior to 20 th weeks of gestation.

A sudden increase in blood pressure.

Development of the HELLP (Hemolysis, Elevated liver enzymes, Low platelet count) syndrome.


Gestational HTN Pre-eclampsia Eclampsia

↑BP + Proteinuria + Edema

Systolic pressure ≥ 140 mmHg & diastolic pressure ≥90

mmHg, or both

Severe grade of pre-eclampsia leads to

seizures & dangerous to fetus & mother


Differentiation Algorithm


Etiology

American Journal of Physiology - Heart and Circulatory Physiology. 2008;294:H541–H550

VasospasmReduced flow

KIDNEY Endotheliosis Proteinurea↓GFR↓ Renal blood flow

VASCULAR↑ Systemic vascular resistance↑ Blood pressure↑ Angiotensin II sensitivity

CARDIAC↓ Cardiac output↑ Plasma volumePulmonary edema

CNSVisual disturbanceSeizures Thrombosis,

HEPATICPeriportal hemorrhagic necrosis ↑ AST↑ ALT

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):207-13Indian J Pediatr 2007; 74 (7) : 623-625

Management

• Diet: Should contain adequate amount of protein.

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

• 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 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.

(Labetalol 100 mg)

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

Labetalol: Mechanism of Action

Pharmacokinetics

• Labetalol is completely absorbed.

• About 50% of the drug is bound in the plasma.

• Half-life of labetalol is 6 to 8 hours.

• Peak plasma concentrations is achieved within 2 hours.

• Relative bioavailability of oral labetalol is 100%.

• Metabolized in liver and excreated through urine and bile.

Prac Diab Int.2011:28(3): 139-140Lippincott . 5th edition.

CLINICAL EVIDENCE

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

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

• No perinatal deaths were observed.

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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 MAP≤103.6 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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• Labetalol demonstrated to have a quicker action, better control of blood pressure.

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


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Oral Labetalol MethyldopaHematological

parametersNo abnormality was observed

No abnormality was observed

Renal functionBeneficial effect on renal function by reducing incidence of proteinurea

No beneficial effect was observed

Rate of induction of labor for uncontrolled PIH

48% 63%

Rate of cesarean section for uncontrolled PIH

1% 5.6%


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

Conclusion: Labetalol was better tolerated than methyldopa, gives more efficient control of blood pressure and may have a ripening effect on the uterine cervix.

• 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.

Labetalol safer than Methyldopa


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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 Cœur 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 prolongation of pregnancies complicated by PIH.

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 80-100 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

Danforth’s 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 to

concerns with fetal growth.

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.

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.

Nicardipine • Tachycardia is reported.

Hydralazine• Associated with unpredictable

hypotension.

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.

• As directed by physician

OR

• If blood pressure control is unsatisfactory then dose can be doubled every 48 hrs up to maximum 900 mg per day.


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

• It is quicker and more efficient at controlling blood pressure.

• Improves renal function by reducing incidence of proteinurea.

• May help to ripen uterine cervix thus increase the rate of vaginal delivery.

• Better tolerated than Methyldopa.


• Allows safe prolongation of pregnancies complicated by PIH.

• Recommended by NICE guideline.

• No perinatal deaths were reported with labetalol treatment.

• Does not adversely affect fetoplacental blood flow.

THANK YOU

Kavita Priya Labetalol in Pih - i

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