Hypertensive disorders of pregnancy are an important cause of severe morbidity, long-term disability and death among both pregnant women and their babies, and account for approximately 14% of all maternal deaths worldwide. Improving care for women around the time of childbirth is a necessary step towards achievement of the health targets of the Sustainable Development Goals (SDGs). Efforts to prevent and reduce morbidity and mortality during pregnancy and childbirth could also help address the profound inequities in maternal and perinatal health globally. To achieve these goals, healthcare providers, health managers, policy makers and other stakeholders need up-to-date and evidence-based recommendations to inform clinical policies and practices.
In 2017, the Executive Guideline Steering Group (GSG) on WHO maternal and perinatal health recommendations prioritized the updating of the existing WHO recommendations on antihypertensive drugs for severe hypertension in pregnancy in response to important new evidence on these interventions. These recommendations are a revalidation of the previous recommendations issued in 2011 in the WHO recommendations on prevention and treatment of pre-eclampsia and eclampsia.

# Target audience
The primary audience of these recommendations includes healthcare providers who are responsible for developing national and local health protocols (particularly those related to hypertensive disorders of pregnancy) and those directly providing care to pregnant women and their newborns, including midwives, nurses, general medical practitioners, obstetricians, managers of maternal and child health programmes, and relevant staff in ministries of health, in all settings.

# Guideline development methods
The updating of these recommendations was guided by standardized operating procedures in accordance with the process described in the WHO handbook for guideline development. The recommendations were initially developed using this process, namely:
(i) identification of the priority question and critical outcomes;
(ii) retrieval of evidence;
(iii) assessment and synthesis of evidence;
(iv) formulation of the recommendations; and
(v) planning for the dissemination, implementation, impact evaluation and updating of the recommendations.
The scientific evidence supporting the recommendations was synthesized using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.
The systematic review was used to prepare evidence profiles for the prioritized question.
WHO convened an online meeting on 2 May 2018 where an international group of experts -the Guideline Development Group (GDG) -reviewed and approved the recommendations.

# The recommendations
The GDG reviewed the balance between the desirable and undesirable effects and the overall quality of supporting evidence, values and preferences of stakeholders, resource requirements and cost-effectiveness, acceptability, feasibility and equity. The GDG revalidated the WHO recommendations published in 2011 with minor revisions to the remarks and implementation considerations.
To ensure that the recommendations are correctly understood and applied in practice, guideline users should refer to the remarks, as well as to the evidence summary, if there is any doubt as to the basis of the recommendations and how best to implement them. 1. Women with severe hypertension during pregnancy should receive treatment with antihypertensive drugs (strong recommendation, very low certainty evidence)
- The guideline development group considered that there is no clinical uncertainty over whether treatment of severe hypertension during pregnancy is beneficial. This recommendation was made based on expert opinion; the group considered that most maternal deaths related to hypertensive disorders are associated with complications of uncontrolled severe high blood pressure. Based on that, the group agreed that antihypertensive treatment should be recommended in all cases of severe hypertension.
- The choice and route of administration of an antihypertensive drug for severe hypertension during pregnancy, in preference to others, should be based primarily on the prescribing clinician's experience with that particular drug, its cost and local availability (conditional recommendation, very low certainty evidence)
- In terms of the choice and route of administration of an antihypertensive drug for severe hypertension during pregnancy, the guideline development group noted that not only is the evidence base for this recommendation limited, but also some antihypertensive drugs may not be feasible options in many settings.
- The group acknowledged that hydralazine, alpha methyldopa, beta blockers (including labetalol) and nifedipine have been extensively used, and therefore, these agents would seem to be reasonable choices until further evidence becomes available.
- The group noted that there was no evidence to suggest that nifedipine interacts adversely with magnesium sulfate. In addition, the group considered that the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and sodium nitroprusside should be avoided due to safety concerns.
An estimated 303 000 women and adolescent girls died as a result of pregnancy and childbirthrelated complications in 2015, around 99% of which occurred in low-resource settings (1).
Haemorrhage, hypertensive disorders and sepsis are responsible for more than half of all maternal deaths worldwide. Thus, improving the quality of maternal healthcare for women is a necessary step towards the achievement of the health targets of the Sustainable Development Goals (SDGs). International human rights law includes fundamental commitments by states to enable women and adolescent girls to survive pregnancy and childbirth as part of their enjoyment of sexual and reproductive health and rights and living a life of dignity (2). The World Health Organization (WHO) envisions a world where "every pregnant woman and newborn receives quality care throughout the pregnancy, childbirth and the postnatal period" (3).
There is evidence that effective interventions exist at reasonable cost for the prevention or treatment of virtually all life-threatening maternal complications (4). Almost two-thirds of the global maternal and neonatal disease burden could be alleviated through optimal adaptation and uptake of existing research findings (5). To provide good quality care, healthcare providers at all levels of maternal healthcare services (particularly in low and middle-income countries) need to have access to appropriate medications and training in relevant procedures. Healthcare providers, health managers, policymakers and other stakeholders also need up-to-date, evidence-based recommendations to inform clinical policies and practices in order to optimize quality of care and enable improved healthcare outcomes. Efforts to prevent and reduce morbidity and mortality in pregnancy and childbirth could reduce the profound inequities in maternal and perinatal health globally.
Hypertensive disorders of pregnancy are an important cause of severe morbidity, long-term disability and death among both mothers and their babies. Worldwide, they account for approximately 14% of all maternal deaths (6). In 2011, WHO published 22 recommendations for the prevention and treatment of pre-eclampsia and eclampsia, including two recommendations on the use and choice of antihypertensive drugs for the treatment of severe hypertension during pregnancy (7). These recommendations were developed according to the WHO guideline development standards, including synthesis of available research evidence, use of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, and formulation of recommendations by a guideline panel of international experts.

# Rationale and objectives
In 2017, WHO established a new process for prioritizing and updating maternal and perinatal health recommendations whereby an Executive Guideline Steering Group (GSG) oversaw a systematic prioritization of maternal and perinatal health recommendations in most urgent need of updating (8). Recommendations were prioritized on the basis of changes or important, new uncertainties in the underlying evidence base on benefits, harms, values placed on outcomes, acceptability, feasibility, equity, resource use, cost-effectiveness or factors affecting implementation. The Executive GSG prioritized the updating of the existing WHO recommendations on antihypertensive drugs for severe hypertension during pregnancy in response to new, potentially important evidence.
The primary goal of these recommendations is to improve the quality of care and outcomes for pregnant women, particularly those related to the treatment of hypertensive disorders of pregnancy. These recommendations provide a foundation for the sustainable implementation of drug treatment for severe hypertension in pregnancy globally.

# Target audience
The primary audience of these recommendations includes healthcare providers who are responsible for developing national and local health guidelines and protocols (particularly those related to hypertensive disorders of pregnancy) and those directly providing care to women during labour and childbirth, including midwives, nurses, general medical practitioners, obstetricians, managers of maternal and child health programmes and relevant staff in ministries of health, in all settings.
The recommendations will also be of interest to professional societies involved in the care of pregnant women, nongovernmental organizations concerned with promoting people-centred maternal care and implementers of maternal and child health programmes.

# Scope of the recommendations
Framed using the Population (P), Intervention (I), Comparison (C), Outcome (O) (PICO) format, the question directing these recommendations was:
- For women with severe hypertension in pregnancy (P), does treatment with one antihypertensive drug (I), compared with another (C), improve maternal and perinatal outcomes (O)?

# Persons affected by the recommendations
The population affected by the recommendations includes pregnant women in low-, middle-or high-income settings, particularly those who experience severe hypertension during pregnancy.
The recommendations were first developed using standardized operating procedures in accordance with the process described in the WHO handbook for guideline development (9). In summary, the process included:
(i) identification of the priority question and critical outcomes;
(ii) retrieval of evidence;
(iii) assessment and synthesis of evidence;
(iv) formulation of the recommendations; and
(v) planning for the dissemination, implementation, impact evaluation and updating of the recommendations.
WHO recommendations on the use of antihypertensive drugs for severe hypertension in pregnancy were identified by the Executive GSG as a high priority for updating in response to new, potentially important evidence on this question. Six main groups were involved in this process, with their specific roles described in the following sections.

# Contributors to the guideline

# Executive Guideline Steering Group (Executive GSG)
The Executive GSG is an independent panel of 14 From the MPH-GDG pool, 16 external experts and relevant stakeholders were invited to constitute the Guideline Development Group (GDG) for updating these recommendations. Those selected were a diverse group of individuals with expertise in research, guideline development methods, and clinical policy and programmes relating to maternal and perinatal health.
In accordance with WHO guidelines, the GDG members were selected in a way that ensured geographic representation and gender balance and there were no important conflicts of interest The Group appraised the evidence that was used to inform the recommendations, advised on the interpretation of this evidence, formulated the final recommendations based on the draft prepared by the Steering Group, and reviewed and approved the final document. The members of this Group are listed in Annex 1.

# External Review Group
This Group included eight technical experts with interest and expertise in the provision of evidence-based obstetric care. None of its members declared a conflict of interest. The Group reviewed the final document to identify any errors of fact and commented on the clarity of the language, contextual issues and implications for implementation. The Group ensured that the decision-making processes have considered and incorporated contextual values and preferences of potential users of the recommendations, healthcare providers and policy makers. They did not change the recommendations that were formulated by the GDG. The members of the External Review Group are presented in Annex 1.

# Systematic review team and guideline methodologists
A Cochrane systematic review on this question was updated, supported by the Cochrane Pregnancy and Childbirth Group. The WHO Steering Group reviewed and provided input into the protocol and worked closely with the Cochrane Pregnancy and Childbirth Group to appraise the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.
Representatives of the Cochrane Pregnancy and Childbirth Group attended the GDG meeting to provide an overview of the available evidence and GRADE tables and to respond to technical queries from the GDG.

# External partners and observers

# Identification of critical outcomes
The critical and important outcomes were aligned with the prioritized outcomes from the WHO recommendations on prevention and treatment of pre-eclampsia and eclampsia (7). These outcomes were initially identified through a search of key sources of relevant, published, systematic reviews and a prioritization of outcomes by the 2011 GDG panel. All outcomes were included in the scope of this document for evidence searching, retrieval, grading and formulation of the recommendations. The list of outcomes is provided in Annex 2.

# Evidence identification and retrieval
A Cochrane systematic review was updated by the Cochrane Pregnancy and Childbirth Group. This systematic review was the primary source of evidence for these recommendations.
Randomized controlled trials (RCT) relevant to the key question were screened by the review authors, and data on relevant outcomes and comparisons were fed into Review Manager (RevMan) software. The RevMan file was retrieved from the Cochrane Pregnancy and Childbirth Group and customized to reflect the key comparisons and outcomes (those that were not relevant to the recommendations were excluded).
Then the RevMan file was exported to GRADE profiler software (GRADEpro) and GRADE criteria were used to critically appraise the retrieved scientific evidence. Finally, evidence profiles (in the form of GRADE tables) were prepared for comparisons of interest, including the assessment and judgements for each outcome and the estimated risks.

# Certainty assessment and grading of the evidence
The certainty assessment of the body of evidence for each outcome was performed using the GRADE approach (11). Using this approach, the certainty of evidence for each outcome was rated as 'high', 'moderate', 'low' or 'very low' based on a set of established criteria. The final rating of certainty of evidence was dependent on the factors briefly described below.

# Study design limitations:
The risk of bias was first examined at the level of individual study and then across studies contributing to the outcome. For randomized trials, certainty was first rated as 'high' and then downgraded by one ('moderate') or two ('low') levels, depending on the minimum criteria met by the majority of the studies contributing to the outcome.

# Inconsistency of the results:
The similarity in the results for a given outcome was assessed by exploring the magnitude of differences in the direction and size of effects observed in different studies. The certainty of evidence was not downgraded when the direction of the findings were similar and confidence limits overlapped, whereas it was downgraded when the results were in different directions and confidence limits showed minimal or no overlap.
Indirectness: The certainty of evidence was downgraded when there were serious or very serious concerns regarding the directness of the evidence, that is, whether there were important differences between the research reported and the context for which the recommendations were being prepared. Such differences were related, for instance, to populations, interventions, comparisons or outcomes of interest.
Imprecision: This assessed the degree of uncertainty around the estimate of effect. As this is often a function of sample size and number of events, studies with relatively few participants or events, and thus wide confidence intervals around effect estimates, were downgraded for imprecision.

# Publication bias:
The certainty rating could also be affected by perceived or statistical evidence of bias to underestimate or overestimate the effect of an intervention as a result of selective publication based on study results. Downgrading evidence by one level was considered where there was strong suspicion of publication bias.
Certainty of evidence assessments are defined according to the GRADE approach:
- High certainty: We are very confident that the true effect lies close to that of the estimate of the effect

# Formulation of recommendations
The WHO Steering Group used the evidence profiles to summarise evidence on effects on the pre-specified outcomes. The evidence summary and corresponding GRADE tables, other related documents for assessment of values and preferences, resource requirements and costeffectiveness, acceptability, feasibility and equity were provided in advance to meeting participants, who were invited to submit their comments electronically in advance of the meeting.
The GDG members and other participants were then invited to attend an online GDG meeting (see Annex 1 for the list of participants) organized by the Steering Group on 2 May 2018. During the meeting, the GDG members reviewed and discussed the balance between the desirable and undesirable effects of the intervention and the overall certainty of supporting evidence, values and preferences of stakeholders, resource requirements and cost-effectiveness, acceptability, feasibility and equity, before finalizing the recommendations and remarks.

# Declaration of interests by external contributors
According to WHO regulations, all experts must declare their interests prior to participation in WHO guideline development processes and meetings. All GDG members were therefore required to complete a standard WHO Declaration of Interest (DOI) form before engaging in the guideline development process and before participating in the guideline-related meeting. The WHO Steering Group reviewed each declaration before finalizing the experts' invitations to participate. Where any conflict of interest was declared, the Steering Group determined whether such conflicts were serious enough to affect the expert's objective judgement on the guideline development process. To ensure consistency, the Steering Group applied the criteria for assessing the severity of conflict of interests in the WHO Handbook for Guideline Development to all participating experts. All findings from the received DOI statements were managed in accordance with the WHO DOI guidelines on a case-by-case basis and communicated to the experts. Where a conflict of interest was not considered significant enough to pose any risk to the guideline development process or reduce its credibility, the experts were only required to openly declare such conflict of interest at the beginning of the GDG meeting, and no further actions were taken.
Annex 3 shows a summary of the DOI statements, and how the conflicts of interest declared by the experts were managed by the Steering Group.

# Decision-making during the Guideline Development Group meeting
During the meeting, the GDG reviewed and discussed the evidence summary and sought clarification. In addition to evaluating the balance between the desirable and undesirable effects of the intervention and the overall certainty of the evidence, the GDG applied additional criteria based on the GRADE evidence-todecision framework to determine the direction and strength of the recommendations. These criteria included stakeholders' values, resource implications, acceptability, feasibility and equity. Considerations were based on the experience and opinions of members of the GDG and supported by evidence from a literature search where available. Evidence-to-decision tables were used to describe and synthesize these considerations.
Decisions were made based on consensus defined as the agreement by three quarters or more of the participants. None of the GDG members expressed opposition to the recommendations.

# Document preparation
Prior to the online meeting, the WHO Steering Group prepared a draft version of the GRADE evidence profiles, evidence summary and other documents relevant to the deliberation of the GDG. The draft documents were made available to the participants of the meeting two weeks before the meeting for their comments. During the meeting, these documents were modified in line with the participants' deliberations and remarks. Following the meeting, members of the WHO Steering Group drafted a recommendation document to accurately reflect the deliberations and decisions of the participants. The draft document was sent electronically to GDG members and the External Review Group for final review and approval.

# Peer review
Following review and approval by GDG members and the External Review Group, the final document was sent to eight external independent experts who were not involved in the guideline panel for peer review. The WHO Steering Group evaluated the inputs of the peer reviewers for inclusion in this document. After the meeting and external peer review, the modifications made by the WHO Steering Group to the document consisted only of correcting factual errors and improving language to address any lack of clarity.

# Recommendations and supporting evidence
The following section outlines the recommendations and the corresponding narrative summary of evidence for the prioritized question. The evidence-to-decision table, summarizing the balance between the desirable and undesirable effects and the overall certainty of the supporting evidence, values and preferences of stakeholders, resource requirements, cost-effectiveness, acceptability, feasibility and equity that were considered in determining the strength and direction of the recommendations, is included in the evidence-todecision framework (Annex 4).
The following recommendations were adopted by the GDG. Evidence on the effectiveness of the intervention was derived from one systematic review and was summarized in GRADE tables (Annex 5). The certainty of the supporting evidence was rated as 'very low' for most critical outcomes. To ensure that the recommendations are correctly understood and appropriately implemented in practice, additional 'remarks' reflecting the summary of the discussion by the GDG are included under each recommendation.
- The guideline development group considered that there is no clinical uncertainty over whether treatment of severe hypertension during pregnancy is beneficial. This recommendation was made based on expert opinion; the group considered that most maternal deaths related to hypertensive disorders are associated with complications of uncontrolled severe high blood pressure. Based on that, the group agreed that antihypertensive treatment should be recommended in all cases of severe hypertension.
- The choice and route of administration of an antihypertensive drug for severe hypertension during pregnancy, in preference to others, should be based primarily on the prescribing clinician's experience with that particular drug, its cost and local availability (conditional recommendation, very low certainty evidence)
- In terms of the choice and route of administration of an antihypertensive drug for severe hypertension during pregnancy, the guideline development group noted that not only is the evidence base for this recommendation limited, but also some antihypertensive drugs may not be feasible options in many settings.
- The group acknowledged that hydralazine, alpha methyldopa, beta blockers (including labetalol) and nifedipine have been extensively used, and therefore, these agents would seem to be reasonable choices until further evidence becomes available.
- The group noted that there was no evidence to suggest that nifedipine interacts adversely with magnesium sulfate. In addition, the group considered that the use of angiotensinconverting enzyme inhibitors, angiotensin receptor blockers and sodium nitroprusside should be avoided due to safety concerns.

# Dissemination and implementation of the recommendations
Dissemination and implementation of the recommendations is to be considered by all stakeholders and organizations involved in the provision of care for pregnant women at the international, national and local levels. There is a vital need to increase access and strengthen the capacity of health centres to provide high quality services to all women giving birth. It is therefore crucial that these recommendations are translated into antenatal and intrapartum care packages and programmes at country and health-facility levels (where appropriate).

# Recommendation dissemination and evaluation
A shorter document containing the recommendations, remarks, implementation considerations and research priorities will be formulated for public dissemination. This document will have annexes (also made publicly available) containing all the information in this document, including methods, evidence-todecision frameworks and GRADE tables.
The recommendations will be disseminated through WHO regional and country offices, ministries of health, professional organizations, WHO collaborating centres, other United Nations agencies and nongovernmental organizations, among others. These recommendations will be also available on the WHO website and in the WHO Reproductive Health Library. Updated recommendations are also routinely disseminated during meetings or scientific conferences attended by relevant WHO staff.
The recommendations document will be translated into the six UN languages and disseminated through the WHO regional offices. Technical assistance will be provided to any WHO regional office willing to translate the full recommendations into any of these languages.

# Implementation considerations
- The successful introduction of these recommendations into national programmes and healthcare services depends on well-planned and participatory consensus-driven processes of adaptation and implementation. The adaptation and implementation processes may include the development or revision of existing national guidelines or protocols.
- The recommendations should be adapted into a locally appropriate document that can meet the specific needs of each country and health service. Any changes should be made in an explicit and transparent manner.
- A set of interventions should be established to ensure that an enabling environment is created for the use of the recommendations (including, for example, the availability of antihypertensive drugs), and that the behaviour of the healthcare practitioner changes towards the use of this evidence-based practice.
- In this process, the role of local professional societies is important and an allinclusive and participatory process should be encouraged.
- Healthcare providers should discuss with women the risks, benefits and treatment options in the management of severe hypertension during pregnancy, to facilitate informed decision-making.
- Guidance on the management of severe hypertension in pregnancy, including doses and routes of administration, is available in the WHO handbook Managing complications of pregnancy and childbirth (Second edition) (17).

# Research implications
The GDG identified important knowledge gaps that need to be addressed through primary research, which may have an impact on these recommendations. The following issues were identified as high priorities for further research:
- The relative effectiveness of available drugs for severe acute hypertension, including effects on the fetus and newborn;
- Conducting further research to understand the relative importance that women with hypertension during pregnancy place on health outcomes, and their preferences regarding treatment options;
- The evaluation of interventions on how women can manage their own blood pressure during pregnancy (including diet, exercise and other interventions);
- The management of severe hypertension in pregnancy at primary and secondary level care (prior to referral to higher-level facility) in low-resource settings; and
- The evaluation of health education interventions for communicating with women who experience hypertension during pregnancy.

# Applicability issues

# Anticipated impact on the organization of care and resources
Implementing these evidence-based recommendations will require resources to ensure it is done safely, including staff time for monitoring of women undergoing drug treatment for severe hypertension in pregnancy. The GDG noted that updating training curricula and providing training would increase impact and facilitate implementation. Standardization of care by including recommendations into existing maternity care packages and protocols can encourage healthcare provider behaviour change.

# Monitoring and evaluating guideline implementation
Implementation should be monitored at the health-service level as part of broader efforts to monitor and improve the quality of maternal and newborn care. For example, interrupted time series, clinical audits or criterion-based clinical audits can be used to obtain relevant data related to induction of labour. Clearly defined review criteria and indicators are needed; these could be associated with locally agreed targets. These can be aligned with the standards and indicators described in the WHO document Standards for improving quality of maternal and newborn care in health facilities (18).

# Updating the recommendations
The Executive GSG convenes regularly to review WHO's current portfolio of maternal and perinatal health recommendations and to advise WHO on prioritization of new and existing questions for recommendation development and updating. Accordingly, these recommendations will be reviewed and prioritized by the Executive GSG. In the event that new evidence (that could potentially impact the current evidence base) is identified, the recommendations may be updated. If no new reports or information are identified, the recommendations may be revalidated.
Following publication and dissemination of the updated recommendations, any concern about the validity of the recommendations will be promptly communicated to the guideline implementers, in addition to plans to update the recommendations.
WHO welcomes suggestions regarding additional questions for inclusion in the updated recommendations. Please email your suggestions to mpa-info@who.int. The antihypertensive drugs investigated in these trials were hydralazine, calcium channel blockers (nifedipine, nimodipine, nicardipine and isradopine), labetalol, methyldopa, diazoxide, prostacyclin, ketanserin, urapidil, magnesium sulfate, prazosin, atenolol, and isosorbide. All drugs were administered intravenously, except for chlopromazine (intravenous  and intramuscular, nifedipine (oral and sublingual) and prazosin (oral). In two older trials in which women were given atenolol, ketanserin, labetalol and methyldopa, routes of administration were not reported although the dosing regimens are suggestive of oral route. Hydralazine was compared with another drug in 6 out of the 17 comparisons in the review. There were considerable variations between the studies regarding antihypertensive drug dosages.
In summary, the analysis of the evidence related to the multiple comparisons of antihypertensive drugs for very high hypertension during pregnancy is complicated by the evidence's low quality which is due primarily to the small samples used in the trials, rare events as outcomes and variations in the administered drug regimens. Hydralazine is the most studied drug, though in the comparison with calcium channel blockers (nifedipine and isradipine) the latter have been associated with a greater reduction in the risk of persistent high blood pressure.

# IV labetalol versus IV hydralazine Maternal outcomes
There were no events in either labetalol or hydralazine groups for several outcomes, that were all very low certainty evidence: maternal death, eclampsia, serious morbidities in women (including acute renal insufficiency and disseminated intravascular coagulation).
Persistent high blood pressure: It is uncertain whether labetalol reduces persistent high blood pressure when compared with hydralazine because the certainty of the evidence is very low.
HELLP syndrome: It is uncertain whether labetalol reduces the incidence of haemolysis, elevated liver enzymes, low platelet (HELLP) syndrome when compared with hydralazine because the certainty of this evidence is very low.
Serious morbidity in women: oliguria: It is uncertain whether labetalol reduces the incidence of oliguria when compared with hydralazine because the certainty of the evidence is very low.
Serious morbidity in women: pulmonary oedema: It is uncertain whether labetalol reduces the incidence of pulmonary oedema when compared with hydralazine because the certainty of the evidence is very low.
Placental abruption: It is uncertain whether labetalol reduces the incidence of placental abruption when compared with hydralazine because the certainty of the evidence is very low.
Hypotension: It is uncertain whether labetalol reduces hypotension when compared with hydralazine because the certainty of the evidence is very low.
Side effects in women: It is uncertain whether labetalol reduces the incidence of any side effects when compared with hydralazine because the certainty of the evidence is very low, including headaches, visual symptoms, epigastralgia, palpitations, nausea, flushing and emesis.

# Infant outcomes
Fetal or neonatal deaths: It is uncertain whether labetalol reduces the incidence of fetal or neonatal death when compared with hydralazine because the certainty of the evidence is very low.
Apgar score less than 7 at one minute: It is uncertain whether labetalol improves Apgar scores at one minute when compared with hydralazine because the certainty of the evidence is very low.
Apgar score less than 7 at five minutes: It is uncertain whether labetalol improves Apgar scores at five minutes when compared with hydralazine because the certainty of the evidence is very low.
Fetal heart rate decelerations: It is uncertain whether labetalol reduces fetal heart rate decelerations when compared with hydralazine because the certainty of the evidence is very low.
Admission to special care baby unit: It is uncertain whether labetalol reduces admissions to special care baby units when compared with hydralazine because the certainty of the evidence is very low.

# Calcium channel blockers (oral or sublingual nifedipine, or IV isradipine) versus IV hydralazine Maternal outcomes
Maternal death: There were no maternal deaths in either group (one trial, 60 women; 0/30 vs 0/30; effect not estimable; low-certainty evidence).
Persistent high blood pressure: Moderate certainty evidence suggests that calcium channel blockers probably reduce persistent high blood pressure at a greater rate than hydralazine (six trials, 313 women; 13/160 vs 34/153; RR 0.37, 95% CI 0.21 to 0.66).
Further episodes of very high blood pressure: It is uncertain whether calcium channel blockers reduce further episodes when compared with hydralazine because the certainty of the evidence is very low.
Hypotension: It is uncertain whether calcium channel blockers reduce hypotension when compared with hydralazine because the certainty of the evidence is very low.
Side-effects in women: It is uncertain whether calcium channel blockers reduce any side effects when compared with hydralazine because the certainty of the evidence is very low, as for headaches, nausea, vomiting or both, palpitations and flushing. Low-certainty evidence suggests little or no difference in the incidence of dyspnoea between the calcium channel blocker and hydralazine groups (one trial, 37 women; 1/20 vs 1/17; RR 0.85, 95% CI 0.06 to 12.59; low-certainty evidence), and little or no difference in the incidence of tachycardia between the calcium channel blocker and hydralazine groups (one trial, 60 women; 2/30 vs 0/30; RR 5.00, 95% CI 0.25 to 99.95; low-certainty evidence).

# Infant outcomes
Fetal or neonatal death: It is uncertain whether calcium channel blockers reduce the incidence of fetal or neonatal death when compared with hydralazine because the certainty of the evidence is very low.
Apgar scores less than 7 at 5 minutes: Low-certainty evidence suggests little or no difference between the calcium channel blocker and hydralazine groups (two trials, 110 infants; 2/55 vs 1/55; RR 2.00, 95% CI 0.19 to 20.90).
Fetal heart rate decelerations: It is uncertain whether labetalol reduces fetal heart rate decelerations when compared with hydralazine because the certainty of the evidence is very low (four trials, 274 infants; 9/141 vs 10/133; RR 0.80, 95% CI 0.13 to 4.95).
Admission to neonatal intensive care unit: Low-certainty evidence suggests little or no difference between the calcium channel blocker and hydralazine groups (one trial, 60 infants; 2/30 vs 1/30; RR 2.00, 95% CI 0.19 to 20.90).

# IV prostacyclin versus IV hydralazine Maternal outcomes
Persistent high blood pressure: It is uncertain whether prostacyclin reduces persistent high blood pressure when compared with hydralazine because the certainty of the evidence is very low.
Side-effects in women: It is uncertain whether prostacyclin reduces side effects when compared with hydralazine because the certainty of the evidence is very low.

# Infant outcomes
Neonatal death: It is uncertain whether prostacyclin reduces neonatal death when compared with hydralazine because the certainty of the evidence is very low.

# IV ketanserin versus IV hydralazine Maternal outcomes
Maternal death: It is uncertain whether ketanserin reduces maternal death when compared with hydralazine because the certainty of the evidence is very low.
Eclampsia: It is uncertain whether ketanserin reduces eclampsia when compared with hydralazine because the certainty of the evidence is very low.
Persistent high blood pressure: Low-certainty evidence suggests that ketanserin may increase the incidence of persistent high blood pressure (four trials, 210 women; 37/111 vs 7/99; RR 4.99, 95% CI 2.37 to 10.48).
Severe maternal morbidity: It is uncertain whether ketanserin reduces severe maternal morbidity when compared with hydralazine because the certainty of the evidence is very low.
HELLP syndrome: It is uncertain whether ketanserin reduces the incidence of HELLP syndrome when compared with hydralazine because the certainty of the evidence is very low.
Serious morbidity in women: disseminated intravascular coagulation: It is uncertain whether ketanserin reduces disseminated intravascular coagulation when compared with hydralazine because the certainty of the evidence is very low.
Serious morbidity in women: pulmonary oedema: It is uncertain whether ketanserin reduces pulmonary oedema when compared with hydralazine because the certainty of the evidence is very low.
Hypotension: Low-certainty evidence suggests ketanserin may slightly reduce hypotension when compared with hydralazine (three trials, 106 women; 4/57 vs 11/49; RR 0.34, 95% CI 0.12 to 0.93).
Placental abruption: It is uncertain whether ketanserin reduces placental abruption when compared with hydralazine because the certainty of the evidence is very low.
Side-effects for woman: Low-certainty evidence suggests ketanserin may reduce side-effects when compared with hydralazine (three trials, 120 women; 13/64 vs 36/56; RR 0.32, 95% CI 0.19 to 0.53).
Low-certainty evidence suggests little or no difference between the ketanserin and hydralazine groups for specific side-effects: headaches (one trial,

# Infant outcomes
Perinatal death: It is uncertain whether ketanserin reduces perinatal death when compared with hydralazine because the certainty of the evidence is very low.
Side-effects -neonatal hypotension: Low certainty evidence suggests little or no difference between the ketanserin and hydralazine groups (one trial, 27 infants; 4/12 vs 1/15; RR 5.00, 95% CI 0.64 to 39.06).

# IV urapidil versus IV hydralazine Maternal outcomes
Eclampsia: There were no eclampsia cases in either group (one study, 26 women; 0/13 vs 0/13; effect not estimable; very low certainty evidence).
Persistent high blood pressure: It is uncertain whether urapidil reduces persistent high blood pressure when compared with hydralazine because the certainty of the evidence is very low.
Hypotension: It is uncertain whether urapidil reduces hypotension when compared with hydralazine because the certainty of the evidence is very low.
Side-effects in women: It is uncertain whether urapidil is associated with fewer side-effects when compared with hydralazine because the certainty of the evidence is very low.
Placental abruption: It is uncertain whether urapidil reduces placental abruption when compared with hydralazine because the certainty of the evidence is very low.

# Infant outcomes
Stillbirth: There were no stillbirths in either group (one study, 26 infants; 0/13 vs 0/13; effect not estimable; very low certainty evidence).
Neonatal death: It is uncertain whether urapidil reduces neonatal death when compared with hydralazine because the certainty of the evidence is very low.

# IV labetalol versus calcium channel blockers (oral nifedipine or IV nicardopine) Maternal outcomes
Maternal death: There were no maternal deaths in either group (one trial, 100 women; 0/50 vs 0/50; effect not estimable; low-certainty evidence).
Eclampsia: It is uncertain whether labetalol reduces eclampsia when compared with calcium channel blockers because the certainty of the evidence is very low.
Stroke: Low certainty evidence suggests little or no difference between the labetalol and calcium channel blocker groups (one trial, 100 women; 2/50 vs 1/50; RR 2.00, 95% CI 0.19 to 21.36).
Persistent high blood pressure: It is uncertain whether labetalol reduces persistent high blood pressure when compared with calcium channel blockers because the certainty of the evidence is very low.
Any serious morbidity: heart failure: Low-certainty evidence suggests little or no difference between the labetalol and calcium channel blocker groups (one trial, 100 women; 1/50 vs 1/50; RR 1.00, 95% CI 0.06 to 15.55).
Hypotension: There were no cases of hypotension in either group (five studies, 337 women; 0/168 vs 0/169; effect not estimable; very low certainty evidence).
Side-effects for woman: It is uncertain whether labetalol is associated with fewer side-effects when compared with calcium channel blockers because the certainty of the evidence is very low, including for mild headache, nausea, vomiting or both, moderate tachycardia, tachycardia, and dizziness.
There were no incidences of palpitations (one study, 60 women; 0/30 vs 0/30; effect not estimable; very low certainty evidence), chest pain (one study, 147 women; 0/73 vs 0/74; effect not estimable; very low certainty evidence), or shortness of breath (one study, 147 women; 0/73 vs 0/74; effect not estimable; very low certainty evidence).
Postpartum haemorrhage (500ml or more): Low-certainty evidence suggests that labetalol may reduce postpartum haemorrhage when compared with calcium channel blockers (one trial, 120 women; 2/60 vs 15/60; RR 0.13, 95% CI 0.03 to 0.56).
Admission to intensive care: Low-certainty evidence suggests little or no difference between the labetalol and calcium channel blocker groups (one trial, 50 women; 2/25 vs 0/25; RR 5.00, 95% CI 0.25 to 99.16).

# Infant outcomes
Perinatal death: Low-certainty evidence suggests little or no difference between the labetalol and calcium channel blocker groups (one trial, 60 infants; 2/30 vs 0/30; RR 5.00, 95% CI 0.25 to 99.95).
Apgar score less than 7 at 5 minutes: Low certainty evidence suggests little or no difference between the labetalol and calcium channel blocker groups (four trials, 427 infants; 24/213 vs 25/214; RR 1.02, 95% CI 0.40 to 2.62).
Side-effects associated with the drug -fetal heart rate (FHR) abnormality: Low certainty evidence suggests little or no difference between the labetalol and calcium channel blocker groups (one trial, 100 infants; 3/50 vs 6/50; RR 0.50, 95% CI 0.13 to 1.89).
Admission to special care baby unit: Low-certainty evidence suggests little or no difference between the labetalol and calcium channel blocker groups (three trials, 210 infants; 11/105 vs 6/105; RR 1.83, 95% CI 0.71 to 4.75).
Labetalol versus methyldopa (route unclear but dosing regimens suggestive of oral route)

# Maternal outcomes
Persistent high blood pressure: It is uncertain whether labetalol reduces persistent high blood pressure when compared with methyldopa because the certainty of the evidence is very low.
Changed drugs due to side-effects: It is uncertain whether labetalol is associated with changes in drugs due to side effects when compared with methyldopa because the certainty of the evidence is very low.

# Infant outcomes
Stillbirth: There were no stillbirths in either group (one study, 72 infants; 0/38 vs 0/34; effect not estimable; very low certainty evidence).
Neonatal death: It is uncertain whether labetalol reduces neonatal death when compared with methyldopa because the certainty of the evidence is very low.
Admission to special care baby unit: It is uncertain whether labetalol reduces admissions to special care baby units when compared with methyldopa because the certainty of the evidence is very low.

# IV labetalol versus IV diazoxide Maternal outcomes
Persistent high blood pressure: It is uncertain whether labetalol reduces persistent high blood pressure when compared with diazoxide because the certainty of the evidence is very low.
Hypotension: It is uncertain whether labetalol reduces hypotension when compared with diazoxide because the certainty of the evidence is very low.

# Infant outcomes
Perinatal deaths: It is uncertain whether labetalol reduces perinatal death when compared with diazoxide because the certainty of the evidence is very low.

# Nitrates versus magnesium sulfate Maternal outcomes
Eclampsia: There were no cases of eclampsia in either group (one trial, 36 women; 0/18 vs 0/18; effect not estimable; very low certainty evidence).
Persistent high blood pressure: It is uncertain whether nitrates reduces persistent high blood pressure when compared with magnesium sulfate because the certainty of the evidence is very low.

# Oral or IV nimodipine versus IV magnesium sulfate Maternal outcomes
Eclampsia: Low-certainty evidence suggests little or no difference between the nimodipine and magnesium sulfate groups (two trials, 1683 women; 21/837 vs 9/846; RR 1.03, 95% CI 0.07 to 16.03).
Stroke: There were no cases of stroke in either group (one trial, 1650 women; 0/819 vs 0/831; effect not estimable; low-certainty evidence).
Persistent high blood pressure: Moderate certainty evidence suggests that nimodipine probably slightly reduces persistent high blood pressure compared with magnesium sulfate (one trial, 1650 women; 374/819 vs 451/831; RR 0.84, 95% CI 0.76 to 0.93).

# Coagulopathy in women:
It is uncertain whether nimodipine reduces coagulopathy when compared with magnesium sulfate because the certainty of the evidence is very low.
Serious morbidity in women: oliguria: Low certainty evidence suggests little or no difference between the nimodipine and magnesium sulfate groups (one trial, 1650 women; 47/819 vs 55/831; RR 0.87, 95% CI 0.59 to 1.26).
Hypotension: It is uncertain whether nimodipine reduces hypotension when compared with magnesium sulfate because the certainty of the evidence is very low.
Postpartum haemorrhage: Low-certainty evidence suggests nimodipine may slightly reduce the incidence of postpartum haemorrhage when compared with magnesium sulfate (one trial, 1650 women; 8/819 vs 20/831; RR 0.41, 95% CI 0.18 to 0.92).
Placental abruption: It is uncertain whether nimodipine reduces placental abruption when compared with magnesium sulfate because the certainty of the evidence is very low.
Respiratory difficulty in women: Low certainty evidence suggests nimodipine may slightly reduce the incidence of respiratory difficulty when compared with magnesium sulfate (one trial, 1650 women; 3/819 vs 11/831; RR 0.28, 95% CI 0.08 to 0.99).
Side-effects in women: Moderate certainty evidence suggests nimodipine probably slightly reduces all (unspecified) side-effects when compared with magnesium sulfate (one trial, 1650 women; 109/819 vs 162/831; RR 0.68, 95% CI 0.55 to 0.85) and flushing is probably also reduced by nimodipine (one trial, 1650 women; 13/819 vs 59/831; RR 0.22, 95% CI 0.12 to 0.40).
There was little or no difference between the nimodipine and magnesium sulfate groups in nausea, vomiting or both (one trial, 1650 women; 49/819 vs 58/831; RR 0.86, 95% CI 0.59 to 1.24; low certainty evidence), and it is uncertain whether nimodipine reduces headaches when compared with magnesium sulfate because the certainty of the evidence is very low (one trial, 1650 women; 47/819 vs 45/831; RR 1.06, 95% CI 0.71 to 1.58).

# Infant outcomes
Side-effects in babies -low blood pressure: It is uncertain whether nimodipine reduces low blood pressure when compared with magnesium sulfate because the certainty of the evidence is very low.

# Oral nifedipine versus oral prazosin Maternal outcomes
Maternal death: It is uncertain whether nifedipine reduces maternal death when compared with prazosin because the certainty of the evidence is very low.
Eclampsia: There were no cases of eclampsia in either group (one trial, 145 women; 0/74 vs 0/71; effect not estimable; very low certainty evidence).
HELLP syndrome: It is uncertain whether nifedipine reduces the incidence of HELLP syndrome when compared with prazosin because the certainty of the evidence is very low.
Renal failure: It is uncertain whether nifedipine reduces the incidence of renal failure when compared with prazosin because the certainty of the evidence is very low.
Pulmonary oedema: It is uncertain whether nifedipine reduces pulmonary oedema when compared with prazosin because the certainty of the evidence is very low.
Placental abruption: It is uncertain whether nifedipine reduces the incidence of placental abruption when compared with prazosin because the certainty of the evidence is very low.
Admission to intensive care: It is uncertain whether nifedipine reduces admissions to intensive care when compared with prazosin because the certainty of the evidence is very low.

# Infant outcomes
Stillbirth: It is uncertain whether nifedipine reduces the incidence of stillbirth when compared with prazosin because the certainty of the evidence is very low.
Admission to special care baby unit: It is uncertain whether nifedipine reduces admissions to special care baby units when compared with prazosin because the certainty of the evidence is very low.

# Sublingual nifedipine versus IV and IM chlorpromazine Maternal outcomes
Eclampsia: It is uncertain whether nifedipine reduces the incidence of eclampsia when compared with chlorpromazine because the certainty of the evidence is very low.
Persistent high blood pressure: It is uncertain whether nifedipine reduces the incidence of persistent high blood pressure when compared with chlorpromazine because the certainty of the evidence is very low.

# IV hydralazine versus IV diazoxide Infant outcomes
Perinatal death: It is uncertain whether hydralazine reduces the incidence of perinatal death when compared with diazoxide because the certainty of the evidence is very low.
Stillbirth: It is uncertain whether hydralazine reduces the incidence of stillbirth when compared with diazoxide because the certainty of the evidence is very low.
Neonatal death: It is uncertain whether hydralazine reduces the incidence of neonatal death when compared with diazoxide because the certainty of the evidence is very low.
Apgar score less than 7 at 5 minutes: It is uncertain whether hydralazine is associated with fewer babies with Apgar scores of less than 7 at 5 minutes when compared with diazoxide because the certainty of the evidence is very low.

# Methyldopa versus atenolol (routes unclear but dosing regimens suggestive of oral route) Maternal outcomes
Side-effects in women: somnolence: Low-certainty evidence suggests methyldopa might slightly increase the incidence of somnolence (one trial, 60 women; 10/30 vs 0/30; RR 21.00, 95% CI 1.29 to 342.93).

# Infant outcomes
Stillbirth: It is uncertain whether methyldopa reduces the incidence of stillbirth when compared with atenolol because the certainty of the evidence is very low.
Neonatal death: It is uncertain whether methyldopa reduces the incidence of neonatal death when compared with atenolol because the certainty of the evidence is very low.
Side-effects in babies: There were no cases of neonatal side-effects in either group (one trial, 60 infants; 0/30 vs 0/30; effect not estimable; very low certainty evidence).

# Methyldopa versus ketanserin (routes unclear but dosing regimens suggestive of oral route) Maternal outcomes
Side-effects in women: somnolence: Low-certainty evidence suggests methyldopa might slightly increase the incidence of somnolence (one trial, 60 women; 10/30 vs 0/30; RR 21.00, 95% CI 1.29 to 342.93).

# Infant outcomes
Stillbirth: It is uncertain whether methyldopa reduces the incidence of stillbirth when compared with ketanserin because the certainty of the evidence is very low.

# Undesirable effects
How substantial are the undesirable anticipated effects of antihypertensive drug treatment for severe hypertension in pregnancy?

# Additional considerations
Is there important uncertainty about, or variability in, how much women value the main outcomes associated with the choice of an antihypertensive drug treatment for severe hypertension in pregnancy?

# Research evidence
No direct evidence.

# Additional considerations
Evidence from a qualitative systematic review of what women want from antenatal care showed that healthy pregnant women from high-, medium-and low-resource settings valued maintenance of optimal health for mother and baby (13). No studies were identified on the values and preferences of pregnant women with severe hypertension, with regards to the choice of antihypertensive drugs.
A diagnosis of severe hypertension in pregnancy can increase the risk of adverse outcomes to mother and baby, as well as increase the need for of additional interventions and hospital admission. Considering these risks, the GDG considers it unlikely that there would be important variability in how women value this outcome.
How large are the resource requirements (costs) of antihypertensive drug treatment for severe hypertension in pregnancy?

# Research evidence
The Cochrane review had pre-specified economic outcomes, however none of the studies included reported data on these outcomes. No direct evidence on the cost-effectiveness of antihypertensive drug treatments for severe hypertension in pregnancy was identified.

# Main resource requirements
What would be the impact of antihypertensive drug treatment for severe hypertension in pregnancy on health equity?

# Research evidence
No direct evidence identified.

# Additional considerations
In LMICs, women who are poor, least educated, and residing in rural areas have lower health intervention coverage and worse health outcomes than more advantaged women. In the 2015 WHO State of Inequalities Report, antenatal care coverage of at least four visits differed by at least 25% between the most and least educated, and the richest and poorest in half the LMICs studied (14). It is therefore likely that adverse consequences of severe hypertension in pregnancy are worse in women living in disadvantaged circumstances. Effective, equitable implementation of this intervention could therefore reduce health inequities.

# Judgement Don't know
Varies Reduced Probably reduced

# Probably no impact
Probably increased Increased
Is the intervention acceptable to key stakeholders?

# Research evidence
No direct evidence was identified in relation to this question, for women or healthcare providers.

# Additional considerations
A 2012 qualitative evidence synthesis provided indirect evidence with regards to patient understanding and experiences of hypertension and drug taking (15). The review findings related to management of chronic hypertension; pregnancy-related hypertension was specifically excluded. In total, 53 qualitative studies from 16 high, middle and low-income countries were identified. Participants reported intentionally reducing or stopping treatment without consulting their doctor, and commonly perceived that their blood pressure improved when symptoms abated or when they were not stressed, and that treatment was therefore not needed. Participants disliked treatments and side effects and feared addiction. These findings were consistent across countries and ethnic groups.
Is the intervention feasible to implement?

# Research evidence
No direct evidence was identified.

# Additional considerations
A mixed-methods study of multi-stakeholder groups in Uganda and Tanzania on implementation of the WHO pre-eclampsia and eclampsia guidelines (16) identified key factors affecting implementation: at the health system level (access to resources, drugs, equipment and supplies, and adequate drug procurement, distribution and management mechanisms); health provider level (the need for buy-in, improving knowledge and skills through training and mentorship) and woman and community level (including traditional beliefs and perceptions of healthcare services, knowledge and awareness of illnesses and interventions, and engaging community healthcare workers).