HTN in Pregnancy

Hypertension in Pregnancy and Women of Childbearing Age American Journal of Medicine 2009

林小姐
33 y/o woman with essential HTN
Regularly f/u at your OPD
BP currently well controlled with ACEI + CCB
She tells you today that she plans on getting pregnant this year
我要去度蜜月了，哈哈！！ What do you do??

呂太太
34 y/o woman with no past Hx
G1P0, GA8wks
BP 145/95 incidentally found on health checkup
Denied other specific discomfort
What do you do?? 什麼？我有高血壓？

Women…
Women tend to have lower BP then men
Age delay in developing HTN in women  most women do not require HTN Rx during childbearing years
↑ of obesity & metabolic syndrome  ↑ number of young women with HTN

Joint National Committee 7 (JNC7) classification of HTN and Rx goals: same regardless of age or gender

Challenge in Rx HTN in the woman of childbearing age: selection of medications
many drugs have potential teratogenicity
Several clinical hypertensive disorders are associated with pregnancy
Appropriate diagnosis and timely intervention needed to reduce fetal and maternal M&M

Rx of essential HTN in women of childbearing age Part 1

If fresh case, workup for secondary causes of HTN: endocrine, renal…
Ask about contraceptive use: hormonal contraceptive use – common cause of HTN!

Women of childbearing age with Class I HTN likely need no medical Rx
Try lifestyle modification and exercise Rx
Most preg. women can tolerate some degree of exercise
Exercise can ↓ gestational HTN and risk of preeclampsia / eclampsia

FDA pregnancy drug categories A Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy B Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester. C Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans , but potential benefits may warrant use of the drug in pregnant women despite potential risks. D There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. X Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

In choosing the medication…
Caution! In women who may be or who are planning to become pregnant
FDA guidelines regarding safety
Drugs with significant risk for fetal effects are classified as class D or have a black box recommendation – should be avoided!

Many drugs fall into ambiguous category
American Heart Association, American College of Cardiology, American College of ObGyn have developed recommendations
Minimal risk in pregnancy  good option!

ACEI & ARB 不要用
Associated with renal agenesis & fetal demise
If pregnancy occurs during Rx with ACEI/ARB  stop immediately
Counseling and contraceptive education beforehand

林小姐
33 y/o woman with essential HTN
Regularly f/u at your OPD
BP currently well controlled with ACEI + CCB
She tells you today that she plans on getting pregnant this year
我要去度蜜月了，哈哈！！

Normal hemodynamic changes in Pregnancy Part 2

First 20 wks of pregnancy: intravascular volume ↑ 30~40%
Red cell mass also ↑ by 20%
↑ intravascular vol & neurohormone changes  relative vasodilation  ↑ placental perfusion
Maternal HR ↑ 10beats/min
Cardiac output ↑ 30%
O2 consumptoion ↑ 30%
GA20wks, uterus may impinge on inf. vena cava  position dependent ↓ pre-load

因 relative vasodilation 的緣故，原本懷孕前血壓偏高的病人懷孕後反而血壓正常了！
BP control in p’t with essential HTN does not ↓ risk for preeclampsia/eclampsia
No successful intervention for prevention of preeclampsia

Approach to HTN during pregnancy Part 3

Pregnant women should receive regular BP monitoring
Comparison of classification:
When to start HTN Rx: varies internationally
JNC7 ACOG Stage I 140~159/90~99 Mild 140~159/ 90~109 Stage II >160/100 Severe > 160/110

Little evidence to support aggressive Rx for BP <160/110mmHg
Individualized Rx for the patient’s condition
P’t with chronic HTN may tolerate higher BP without complication
Marked ↑ in arterial hemorrhagic events occurs when BP>160/110mmHg  assoc. with mortality rate of 50%

Evaluation and Rx of severe HTN
Similar to that of HTN urgency/emergency
If end-organ damage or neurological compromise  aggressive & rapid Rx
Safety of the mother comes first
Early delivery may be considered, esp. in eclampsia

Goal of Rx
目標是希望可以快速把血壓降下來：
25% ↓ in mean arterial pressure within 2 hrs of presentation
160/110 mmHg within next couple of hours
也不能降太快： Reduction of >25% BP may cause
maternal end-organ hypoperfusion (CVA, MI)
placental ischemia  fetal compromise

Medical treatment
First-line agents: L-methyldopa (Aldomet), Labetalol (Trandate), Nifedipine (Adalat)
Methyldopa : The only Class B drug for HTN often the 1 st med used
Labetalol use ↑ but some studies show association with fetal growth restriction

Beta-blockers: 安全的
esp. Labetalol
Selective beta-blockers can also be used, but due to less vasodilatory activity  ↑ risk of bradycardia
High dose of BB associated with transient neonatal hypoglycemia

CCB: 應該是安全的！
Likely safe during pregancy
Most data regarding Nifedipine (Adalat), but also some reports w/ Nicardipine, Isradipine, Verapamil, Felodipine

CCB:
Theoretical concerns in early pregnancy: many embryogenesis processes are Ca dependent
Largest randomized trial to date: no significant risk
Adjust starting dose & frequency (due to ↑renal & hepatic clearance)
Case reports of neuromuscular blockage with CCB + MgSO4 use… 要注意

Diuretics: 應該是安全的！但是…
? Plasma volume↓  ↓ uteroplacental perfusion?
uteroplacental perfusion ↓ less likely if p’t prev treated with Thiazide diuretics
Not usually first choice medication

ACEI & ARB 不要用
Associated with renal agenesis & fetal demise
IUGR, IUFD
Oligohydramnios
PDA
Pulmonary hypoplasia

HTN drugs for use during pregnancy Apresolin 0.5 amp IM PRN Q20~30min if SBP>170mmHg or DBP>110mmHg Trandate Adalat Aprezin Apresolin Hydrochlorothiazide

Hypertensive disorders of pregnancy Part 4

Classification: Working Group of the NHBPEP (2000)
Platelets < 100,000/mm 3
Microangiopathic hem
olysis (↑eased LDH)
Elevated ALT or AST
Persistent headache or other cerebral or visual disturbance
Persistent epigastric pain
Final diagnosis made only postpartum
May have other signs or symptoms of preeclampsia, e.g. epigastric discomfort or thrombocytopenia

徐小姐
29 y/o woman
G1P0, GA33wks
No HTN noted on previous checkups
BP 142/100 found on routine checkup
Dipstick: 1+ proteinuria
What do you do?? 徐小姐你血壓有點高喔…

Development of HTN after GA 20wks without evidence of preeclampsia (no proteinuria)
Occurs in 6% of pregnancies
Progesses to preclampsia 15~45% of cases
Final diagnosis made only postpartum

HTN present before GA20wks
HTN persistent after 12wks postpartum
Occurs in 3% of all pregnancies
Essential HTN most common
More prevalent in African Americans, the obese, advanced maternal age (>35yrs)

New-onset HTN (>GA20wks) with proteinuria
Proteinuria:
≥ 300mg/24hrs or dipstick ≥ 1+
Can occur anytime during gestation or postpartum
Up to 1/3 cases occur in 6wks after delivery
4% of all pregnancies

Pathophysiology of preeclampsia
Abnormal placental implantation  placental hypoperfusion
Image source: Medscape - Pathophysiology of preeclampsia and resulting symptoms

Severity of preeclampsia:
Mild preeclampsia
Severe preeclampsia
Hypertension (> 160/100mmHg)
Proteinuria (>5g/24hrs)
Neurological Sx (seizures, headache)
Renal compromise (oliguria, ↑ Cr)
HELLP syndrome
Fetal growth restriction (< 10 th percentile)

HELLP syndrome
H epatic dysfunction or hemolysis
E levated L iver enzymes
L ow P latelet count

Eclampsia. Subcapsular hematoma dissecting under Glisson's capsule in a fatal case of eclampsia
Kumar: Robbins and Cotran Pathologic Basis of Disease, Professional Edition , 8th ed. 2009

Treatment of preeclampsia
Ultimate therapy for preeclampsia/ eclampsia: delivery of the baby
Development of HTN is related to placental hyperperfusion  placental response to hypoperfusion  Not directly related to BP  Rx of BP will not prevent sequalae of preeclampsia/eclampsia!

Management plan for patients with mild preeclampsia
Gabbe: Obstetrics: Normal and Problem Pregnancies, 5th ed. 2007

Management plan for patients with severe preeclampsia

MgSO4 prevents seizure
Alter membrane permeability  ↑ seizure threshold
P’t with sev. preeclampsia should be Rx with MgSO4 during labor ~ 24hrs after delivery (majority of seizures occur during this period)
MgSO4 may also ↓ BP (transient)
MgSO4 (2g) x 2 Amps + D5W 1 Amp IV push slowly > 15' (Loading Dose)
MgSO4 (2g) x 5 Amps + D5W 400ml IVD (maintain dose) 60 cc/hr (1.2g/hr)
Check BP and DTR Q4H

Narrow safety range, beware of intoxication
Monitor p’t DTR, RR, and blood Mg level
Use Ca gluconate in case of intoxication
Valium (Phenytoin) 10~15 mg/kg IV slow push may also be used
May cause fetal acidosis & low Apgar score
Mg response 1~2 mg/dl Normal range during pregnancy 4~8 mg/dl Therapeutic range 9~12 mg/dl DTR gone 15~17 mg/dl Respiratory depression 30~35 mg/dl Cardiac arrest

Preeclampsia + seizure = eclampsia
Usually grand mal, generalized tonic-clonic seizure
大部分 postpartum eclampsia 發生在產後 24hrs 內

New-onset proteinuria ≥ 300 mg/24 hrs in HTN women but no proteinuria before GA 20wks
sudden ↑ proteinuria or BP or platelet count < 100,000/mm 3 in women with HTN & proteinuria before GA 20wks

Most p’ts w/ severe preeclampsia will require BP Rx for at least 6 wks
Ask about reproductive & breastfeeding plans
P’t w/ preeclampsia Hx have ↑ risk of
x2 risk of developing HTN
x2~5 risk of ischemic stroke
May also have ↑ risk of CAD

徐小姐
29 y/o woman
G1P0, GA33wks
No HTN noted on previous checkups
BP 142/100 found on routine checkup
Dipstick: 1+ proteinuria
Preeclampsia 徐小姐你血壓有點高喔…

本院作法 : 收入院 indication
在門診用口服藥物血壓仍控制不佳
出現 severe preeclampsia  收入院打 MgSO4
可能需要 termination or 催生 ( 先收進來打 betamethasone)
Fetal compromise (e.g. IUGR, oligohydramnios, S/D ratio >3, biophysical profile 不好 , non-reassuring FHB ）  收進來 fetal monitoring

Rx of HTN during breastfeeding Part 5

Hemodynamics return to normal within 3~5 wks of delivery
If BP still ↑ 3~5days after delivery  Rx should be continued/initiated

Drugs often prescribed during lactation

Take Home Messages

In the pregnant patient…
Regular screening for HTN is needed
Rx is aimed at avoiding intracranial hemorrhage & stroke ( BP: 160/110mmHg )
First-line agents: L-methyldopa (Aldomet), Labetalol (Trandate), Nifedipine (Adalat), Apresolin (Aprezin)
Development of preeclampsia may affect risk of developing HTN, stroke, and CAD
Only cure for preeclampsia: delivery!

Thank You
References
Hypertension in Pregnancy & Women of Childbearing Age Am J Med. 2009 Oct;122(10)890-5
Hypertensive Disorders of Pregnancy Am Fam Physician. 2008 Jul 1;78(1):93-100
Hypertensive Pregnancy Disorders - Current Concepts J Clin Hypertens (Greenwich). 2007 Jul;9(7)560-6
MedScape website
Obstetrics and Gynecology at a Glance

Conditions mimicking preeclampsia / eclampsia
Similar presentation
Acute fatty liver of pregnancy
TTP-HUS
SLE with flare-up

Autosomal recessive inheritance
1/10,000 pregnancies
Presents in late pregnancy (GA 27~40wks)
Susp due to fetal 3-hydoxyacyl-coenzyme A dehydrogenase, defect in mitochondrial function
Acute fatty liver of pregnancy 1

Presenation
Progressive fatigue, malaise, anorexia, nausea/vomiting, mid-epigastric or RUQ pain, jaundice
Mental status change, fever, HTN, proteinuria, severe hyperglycemia, coagulopathy are common
U/S, CT, MRI  fatty infiltration of liver
CT diagnostic only in 50% cases
Biopsy not usually performed

Pentad has significant overlap w/ eclampsia
Thrombocytopenia
Migcroangiopathic hemolytic anemia
Neurologic abnormalities
Fever
Renal dysfunction
Suggestive of TTP-HUS if: Early onset HTN or HELLP before GA20wks
Thrombotic thrombocytopenic purpura and Hemolytic uremic syndrome 2

Women with SLE may have underlying HTN, proteinuria & microscopic hematuria
Flares occur in 25~30% of pregnant women
Present with thrombocytopenia, ↓ renal function, severe HTN, fever, skin lesions
Lupus cerebritis occurs seldomly  Sx similar to eclampsia
May exhibit HELLP lab data
DDx: ↓ complement levels, antiphospholipid Ab (30~40%)
SLE with flare-up 3

P’ts with SLE should receive baseline renal function testing & 24-hr urine test early in pregnancy & if Sx develop
P’t with early-onset (< 32 wks) severe preeclampsia should be tested for underlying autoimmune Dz (SLE, antiphospholipid syndrome, inherited/acquired thrombophilia)

HTN in Pregnancy

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