The document summarizes 3 journal articles on the treatment of severe hypertension during pregnancy. The first article recommends intravenous labetalol and hydralazine as first-line therapies. It also recommends oral nifedipine and close monitoring of maternal and fetal status. The second article finds that low-dose aspirin initiated before 16 weeks of gestation reduces the risk of severe preeclampsia but not mild preeclampsia. The third article finds that oral nifedipine is as effective as intravenous antihypertensives for treating severe hypertension during pregnancy and postpartum, with similar safety profiles.

1. Dr Girija Ashok Kumar

2. Journal 1
 The American College of Obstetricians and
Gynaecologists
 Committee opinion – No.623, february 2015
 Reaffirmed 2016
 EMERGENT THERAPY FOR ACUTE ONSET, SEVERE
HYPERTENSION DURING PREGNANCY AND THE
POST-PARTUM PERIOD

3. AIM
 To introduce standardized care
 To reduce adverse maternal outcomes
Hypertensive emergencies
 Acute onset, severe hypertension accurately measured,
persistent for 15 miutes
 Can cause central nervous system injury (cerebral
hemorrhage or infarct)
 Goal – not to normalize BP but to achieve a BP 140-150/90-
100 mmHg to prevent loss of cerebral vascular
autoregulation after prolonged exposure to severe HTN

4. Do’s
 Maternal stabilization before delivery
 BP to be stabilzed and other appropriate measures like
Magnesium sulphate initiated before transfer to
tertiary centre
 Before intubation & induction of GA, undertake steps
to minimize the hypertensive response to intubation
 Close maternal and foetal monitoring
 Judicious fluid administration even in oliguria

5. Recommendations – First-Line
therapy
 IV labetalol and hydralazine
 Oral nifidipine also – it lowered BP more quickly and
had significant increase in urine output.
 Nifidipine with MgSO4 – both are calcium antagonists
but concern about neuromuscular blockade & severe
hypotension not substantiated in large retrospective
review.
 MgSO4 for seizure prophylaxis and treatment, not as
anti-hypertensive

6. IV Labetalol IV Hydralazine Oral Nifedipine
Loading dose 20mg over 2 min 5/10mg over 2 min 10mg
Repeat BP After 10 min After 20 min After 20 min
Still high 40mg over 2 min 10mg over 2 min 20mg
After 10 min After 20 min After 20 min
80mg over 2 min 20mg over 2 min IV Labetalol 40mg
over 2 min
After 10 min After 10 min Multi -disciplinary
IV Hydralazine 10
mg over 2 min
IV Labetalol 40mg
over 2 min
After 20 min Multi -disciplinary
Multi- disciplinary

7. Drug Labetalol Hydralazine Nifedipine
Dose 20 – 80 mg, max
300mg
5-10mg Max 20 mg/dose
Maternal Side
effects
Neonatal
bradycardia
Hypotension/tachyc
ardia(propranolol)/
epigastric pain
tachycardia/
overshoot
hypotension
Foetal/neonatal tachycardia nil
Contra-indications Asthma,heart
disease/CCF
Angina/MI/CCF/
Elevated LFT
(relative )
Duration of action 3-6 hrs 3-5 hrs 4-8hrs

8. Recommendation – second line
therapy
 Labetalol or nicardipine by infusion pump
 Sodium nitrprusside –extreme emergencies/only for
short term ( ICT, cyanide and thiocyanate toxicity in
mother/foetus/newborn)
 Oral labetalol till IV access

9. Journal 2
 Early Administration of Low-Dose Aspirin for the
Prevention of Severe and Mild Preeclampsia: A Systematic
Review and Meta-Analysis
 Stéphanie Roberge1, Yves Giguère2, Pia Villa3, Kypros Nicolaides4,
Merja Vainio5, Jean-Claude Forest2, Peter von Dadelzen6, Daniel
Vaiman7, Sylvie Tapp1, Emmanuel Bujold8
 Amer J Perinatol 2012; 29(07): 551-556
DOI: 10.1055/s-0032-1310527
 Methods
 Sources Relevant citations were extracted from Embase,
PubMed, the Cochrane Central Register of Controlled Trials
(CENTRAL), and Web of Science from 1965 to October 2011

10. Study Selection/outcomes
 Study Selection
 This meta-analysis includes only prospective, randomized, controlled trials.
 The population involved pregnant women at risk of preeclampsia treated with
low-dose aspirin initiated at or before 16 weeks of gestation. No restrictions
were applied to risk criteria for preeclampsia. Low-dose aspirin was defined as
50 to 150 mg of acetylsalicylic acid daily, alone or in combination with 300 mg
of dipyridamole or less, another antiplatelet agent. The control group had to be
allocated to placebo or no treatment. Studies' qualities were evaluated using
Cochrane Handbook Criteria for judging risk of bias tool
 Outcomes
 The primary outcome was the occurrence of severe or mild preeclampsia.
 Statistical Analysis
 Individual risk ratios (RRs) were calculated for each study, and pooled for
global analysis with 95% confidence intervals (CIs).
 Analysis of preeclampsia was divided into severe preeclampsia and mild
preeclampsia.

11. Results
 The literature search identified 7941 potentially
eligible studies, and 352 were reviewed. The inclusion
criteria were met by 15 studies but only four were
included (392 women) for the final analysis because
information on severe and mild preeclampsia were
available. In three studies, women randomized to the
control received placebo, and in the fourth study, they
received no treatment.

13. Discussion
 High effectiveness of early onset, low-dose aspirin in
the prevention of severe preeclampsia but not of mild
disease is that the pathophysiology of the two
conditions is different and only the former is
susceptible to the effects of aspirin
 Impedance to flow in the uterine arteries is
increased.[33] Such increased impedance to flow is
thought to be a consequence of inadequate
trophoblastic invasion of the maternal spiral arteries
and their conversion from narrow muscular vessels to
wide nonmuscular channels
 Early onset, low-dose aspirin improves placentation
and, therefore, reduces the risk of severe preeclampsia.

14. Draw backs/conclusion
Draw backs
 small number of studies included
 the absence of very large trials
 the possibility of publication bias.
Conclusion
 our meta-analysis confirms that low-dose aspirin initiated between
7 and 16 weeks' gestation is associated with a significant reduction
in severe preeclampsia, in a population of women identified at high
risk for preeclampsia.
 References
 1 World Health Organization International Collaborative Study of Hypertensive Disorders of
Pregnancy.Geographic variation in the incidence of hypertension in pregnancy. Am J Obstet Gynecol
1988; 158: 80-83
 2 Magee LA, Helewa M, Moutquin JM, von Dadelszen P. ; Hypertension Guideline Committee;
Strategic Training Initiative in Research in the Reproductive Health Sciences (STIRRHS)
Scholars. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. J
Obstet Gynaecol Can 2008; 30 (3, Suppl) S1-S48
 3 Bujold E, Roberge S, Lacasse Y , et al. Prevention of preeclampsia and intrauterine growth
restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010; 116 (2 Pt 1)
402-414

15. Journal 3
 Oral antihypertensive therapy for severe
hypertension in pregnancy and postpartum: a
systematic review
 Authors T Firoz,LA Magee, K MacDonell, BA Payne, R
Gordon, M Vidler, P von Dadelszen, and for the
Community Level Interventions for Pre-eclampsia
(CLIP) Working Group
 First published: 16 May 2014
 BJOG, International Journal of Obstetrics and
Gynaecology

16.  Background
 Pregnant and postpartum women with severe hypertension are
at increased risk of stroke and require blood pressure (BP)
reduction. Parenteral antihypertensives have been most
commonly studied, but oral agents would be ideal for use in busy
and resource-constrained settings.
 Objectives
 To review systematically, the effectiveness of oral
antihypertensive agents for treatment of severe
pregnancy/postpartum hypertension.
 Search strategy
 A systematic search of MEDLINE, EMBASE and the Cochrane
Library was performed.
 Selection criteria
 Randomised controlled trials in pregnancy and postpartum with
at least one arm consisting of a single oral antihypertensive agent
to treat systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 110 mmHg.

17.  Data collection and analysis
 Cochrane REVMAN 5.1 was used to calculate relative risk (RR) and
weighted mean difference by random effects.
 Main results
 We identified 15 randomised controlled trials (915 women) in
pregnancy and one postpartum trial. Most trials in pregnancy
compared oral/sublingual nifedipine capsules (8–10 mg) with another
agent, usually parenteral hydralazine or labetalol. Nifedipine achieved
treatment success in most women, similar to hydralazine (84% with
nifedipine; relative risk [RR] 1.07, 95% confidence interval [95% CI]
0.98–1.17) or labetalol (100% with nifedipine; RR 1.02, 95% CI 0.95–
1.09). Less than 2% of women treated with nifedipine experienced
hypotension. There were no differences in adverse maternal or fetal
outcomes. Target BP was achieved ~ 50% of the time with oral labetalol
(100 mg) or methyldopa (250 mg) (47% labetelol versus 56%
methyldopa; RR 0.85 95% CI 0.54–1.33).
 Conclusions
 Oral nifedipine, and possibly labetalol and methyldopa, are suitable
options for treatment of severe hypertension in pregnancy/postpartum

19.  Twelve RCTs compared oral/sublingual nifedipine
capsules or tablets (5–10 mg, 724 women) with another
agent. Most compared nifedipine with intravenous
hydralazine (5–20 mg, seven trials, 350 women) or
intravenous labetalol (20 mg, two trials, 100 women).
Other trials compared short-acting nifedipine with
oral nifedipine 10 mg prolonged action (PA) tablets
(one trial), oral prazosin 1 mg (one trial) or
intravenous/intramuscular chlorpromazine 12.5 mg
(one trial). The postpartum RCT (38 women)
compared sublingual nifedipine with intravenous
hydralazine.

20.  Discussions
 Based on RCTs in pregnancy and postpartum, we found that a single
oral agent can adequately lower BP when compared with parenteral
agents. In particular, oral nifedipine (10 mg), compared with parenteral
hydralazine or labetalol, is a suitable oral agent for treatment of severe
hypertension in pregnancy or postpartum, with: similar and high
treatment success rates (of at least 84%); low rates of maternal
hypotension (< 2%, 3/158 women in six trials comparing nifedipine
with either intravenous hydralazine or labetalol); and similar maternal
and perinatal outcomes.
 Strengths
 a large number of studies included
 first systematic review to specifically examine oral antihypertensive
therapy for severe hypertension in pregnancy and postpartum
 The 2010 UK National Institute for Health and Clinical Excellence (NICE) Hypertension
in Pregnancy guideline recommends oral labetalol or nifedipine for the treatment of
severe hypertension in women during pregnancy or after birth
 Disadvantages
 Few RCTs underpowered to find important between-group differences
in outcomes given the limited number and size of trials. Second, our
results are limited by poor to fair study quality.

21. Conclusion
 Severe hypertension in pregnancy and postpartum should be treated to
decrease the risk of maternal stroke. Oral agents appropriate in the
outpatient setting while transfer to hospital or in resource-constrained
institutions, any maternity care facility in low- and middle-income
countries where the vast majority of HDP-related maternal
complications occur.
 The oral antihypertensive agent with most evidence for treatment of
severe hypertension in pregnancy/postpartum is nifedipine (10 mg).
Labetalol (100 mg) and methyldopa (250 mg) are reasonable second-
line options
 Future trials should focus on head to head comparisons of oral agents,
particularly nifedipine, labetalol and methyldopa; one such trial is
underway (http://gynuity.org). Studies should also focus on early
treatment of severe hypertension in the community, particularly in
low- and middle-income countries where delays in triage and transport
could make antihypertensive treatment extremely important for stroke
prevention.

22. Journal 4
 The nitric oxide pathway and possible therapeutic options
in pre-eclampsia
 Authors Tamanrit Johal, Christoph C. Lees, Thomas R. Everett,
Ian B. Wilkinson
First published: 21 July 2014
 British journal of clinical pharmacology
 Abstract : Although not causal, endothelial dysfunction and
reduced nitric oxide bioavailability are likely to play an
important role in the maternal and fetal pathophysiology of pre-
eclampsia. Lack of treatment modalities that can target the
underlying pathophysiological changes and reverse the
endothelial dysfunction and pre-eclampsia by itself frequently
leads to iatrogenic preterm delivery of the fetus. The purpose of
this review is to outline the current status of clinical research
involving these therapeutic modalities in the context of pre-
eclampsia, with the focus being on the nitric oxide donors.

23. The nitric oxide pathway and possible therapeutic options in pre‐eclampsia
British Journal of Clinical Pharmacology
Volume 78, Issue 2, pages 244-257, 21 JUL 2014 DOI: 10.1111/bcp.12301
http://onlinelibrary.wiley.com/doi/10.1111/bcp.12301/full#bcp12301-fig-0001

24.  A study of intravenous GTN infusion in 15 women with
abnormal uterine artery Doppler velocimetry at 24–
26 weeks gestation showed a dose-dependent
reduction in uterine artery resistance without any
effect on the maternal cardiovascular parameters or
the fetal circulation. Further studies, however, have
shown a significant reduction in the maternal blood
pressure and umbilical artery resistance without any
significant adverse effects after intravenous infusion of
GTN.

25.  A randomized, placebo-controlled trial of low-dose
transdermal GTN patches in women with abnormal uterine
artery Doppler velocimetry at 24–26 weeks showed no
change in the incidence of pre-eclampsia, growth
restriction or preterm delivery, but GTN increased the
likelihood of a complication-free pregnancy, with a
significant reduction in hazard ratio in the GTN-treated
group. There was no effect on maternal cardiovascular
parameters or on uterine and fetal Doppler velocimetry.
 Studies of both transdermal and sublingual GTN in women
affected by pre-eclampsia consistently showed a significant
reduction in blood pressure and resistance in the uterine
artery without an adverse effect on fetal Doppler
parameters.

26. Conclusion
 Organic nitrates have been the obvious first line of investigation.
However, the evidence for their effectiveness in the prevention
and treatment of pre-eclampsia is currently limited.
 S-Nitrosoglutathione has also been infused in women with pre-
eclampsia, but current data are limited to only a few small
studies.
 Dietary supplementation with L-arginine and treatment with
sildenafil citrate have been investigated in the prevention and
treatment of pre-eclampsia, respectively. However, further
studies are warranted
 Extensive research is, however, needed before NO donors can be
incorporated into the existing treatment protocols for pre-
eclampsia. There is currently very limited evidence for the
preventative role of any of these drugs in women at risk of
developing pre-eclampsia. Nonetheless, NO donors may hold
potential for improving outcomes

27. Journal 5
 The effect of nitroglycerin infusion versus hydralazine infusion
as antihypertensive therapy in acute management of patients
with severe pre-eclampsia
Rania M Ali MD 1, Dina Salah1, Dina Y Mansour
 Year : 2015 | Volume : 8 | Issue : 4 | Page : 499-504
 Patients and methods - prospective study conducted at the ICU of
the Obstetrics and Gynecology Hospital of Ain-Shams University over a
period of 2 years
A total of 180 patients with severe PE admitted to Ain Shams Obstetric
ICU to stabilize blood pressure before delivery were randomly assigned
to one of two equal groups: group H and group N. Group H received
hydralazine infusion (1 mg/ml) and group N received nitroglycerin
infusion (1 mg/ml). The infusion rate (5 ml/h) was adjusted to maintain
systolic blood pressure at 130-140 mmHg and diastolic blood pressure
at 80-100 mmHg.

28.  Inclusion criteria
 Age – 20-40 years
 Gestation age - > 34 weeks
 Uncomplicated severe pre-eclampsia
 Exclusion criteria included patients with chronic
hypertension or other chronic diseases, fetal compromise
diagnosed before the start of the study, or any known
allergy to one of the study drugs.
 Drugs : H group – IV Hydralazine (two ampoules of 20 mg
each of hydralazine to a volume of 40 ml of sodium
chloride 0.9% to obtain a concentration of 1 mg/ml)
N group – IV NTG ( at a concentration of 1 mg/ml;
thus, 1 mg/kg/min equals to 4.8 ml/h for an 80 kg patient).
Sample size determination significance level was a =
0.05

29.  Statistical analysis
P-values less than 0.05 were considered significant.

30. Conclusion
 The choice of antihypertensive for the acute management of patients
with severe PE should depend on the clinician's experience, familiarity
with a particular drug, and what is known about adverse effects.
Nitroglycerin could be a good alternative option. It is an effective
antihypertensive with minimal side effects. However, more studies are
necessary to confirm this conclusion and it is suggested to perform
more randomized clinical trials on this significant issue.
 References
1.World Health Organization. WHO international collaborative study of
hypertensive disorders of pregnancy. Geographic variation in the incidence of
hypertension in pregnancy. Am J Obstet Gynecol 1988; 158:80-83.
 2.Arulkumaran N, Lightstone L. Severe pre-eclampsia and hypertensive crises. Best
Pract Res Clin Obstet Gynaecol 2013; 27:877-884.
 3.Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure during
pregnancy. Cochrane Database Syst Rev 2013; 7:CD001449.
 4.NICE Clinical Guideline. Hypertension in pregnancy: the management of
hypertensive disorders during pregnancy. August 2010. Royal College of
Obstetricians and Gynaecologists

31.  Hydralazine is a peripheral vasodilator , but it crosses the placenta, causes
reflex tachycardia, and has unpredictable pharmacodynamics [4] . Nitroglycerin
is a nitric oxide (NO) donor with a potent venodilator effect in low doses and
an arteriolar dilator in high doses [5] . There are no sufficient data regarding the
use of intravenous infusion of nitroglycerin as an antihypertensive agent in the
management of patients with PE.
 Results
As regards hemodynamic parameters, the time to achieve blood pressure
control was significantly shorter in the N group compared with the H group.
However, the number of cases of severe persistent hypertension and the
number of attacks of hypotension were comparable between the two groups.
Maternal side effects and fetal and neonatal complications were comparable
between the two groups, except for maternal headache and tachycardia, which
were significantly higher in the H group compared with the N group. The rate
of cesarean section delivery was significantly higher than the rate of vaginal
delivery in both groups. Meanwhile, the rate of cesarean section after induction
of labor was significantly higher in the N group compared with the H group.
Conclusion
Nitroglycerin could be a good alternative option for the acute management of
patients with severe PE. It is an effective antihypertensive with minimal side
effects.

32. RCOG Guideline No. 10(A)
 Antihypertensive treatment should be started in women with a systolic
blood pressure over 160 mmHg or a diastolic blood pressure over 110
mmHg. In women with other markers of potentially severe disease,
treatment can be considered at lower degrees of hypertension.
 Labetalol, given orally or intravenously, nifedipine given orally or
intravenous hydralazine can be used for the acute management of
severe hypertension.
 In moderate hypertension, treatment may assist prolongation of the
pregnancy. Clinicians should use agents with which they are familiar.
 Atenolol, angiotensin converting enzyme (ACE) inhibitors, angiotensin
receptor-blocking drugs (ARB) and diuretics should be avoided.
 Nifedipine should be given orally not sublingually)
 Labetalol should be avoided in women with known asthma.

33.  Magnesium sulphate should be considered for women with pre-
eclampsia for whom there is concern about the risk of eclampsia. This
is usually in the context of severe pre-eclampsia once a delivery
decision has been made and in the immediate postpartum period. In
women with less severe disease the decision is less clear and will
depend on individual case assessment.
 Magnesium sulphate is the therapy of choice to control seizures. A
loading dose of 4 g should be given by infusion pump over 5–10
minutes, followed by a further infusion of 1 g/hour maintained for 24
hours after the last seizure. Recurrent seizures should be treated with
either a further bolus of 2 g magnesium sulphate or an increase in the
infusion rate to 1.5 g or 2.0 g/hour.
 Fluid restriction is advisable to reduce the risk of fluid overload in the
intrapartum and postpartum periods. In usual circumstances, total
fluids should be limited to 80 ml/hour or 1 ml/kg/hour.