| Study | Reason for exclusion |
|---|---|
| Argentina 1990 | Most women with severe chronic HT. Women with mild‐moderate HT not analysed separately. Methods: open, prospective, randomised, comparative 3‐arm trial. Participants: 90 women with severe chronic HT. Intervention: Atenolol (50 mg to 200 mg daily), vs methyldopa (500 mg to 2000 mg daily) vs ketanserin (80 mg to 120 mg daily). Outcomes: BP, gestational age at delivery, birthweight, 1‐min Apgar score, fetal and neonatal mortality. |
| Argentina 1994 | Not clearly randomised. Available as abstract only. Methods: 'divided into two groups'. No further information. Participants: 187 women with chronic HT (n = 66) or gestational HT (n = 121). Interventions: atenolol 40 mg/day to 100 mg/day vs methyldopa 250 mg/day to 2000 mg/day. Outcomes: superimposed PE, maternal BP, birthweight. |
| Australia 1985b | Comparison of 2 alpha agonists. Methods: quote "prospective, double blinded". Women entered in a numerical sequence. No numbers missed or used a second time. Participants: 100 women with BP > 130/85 mmHg or a rise of 30/15 mmHg from previous values. Intervention: clonidine 150 mcg/day to 1200 mcg/day vs methyldopa 250 mg/day to 2000 mg/day. If additional treatment needed, hydralazine. Outcomes: severe HT, need for additional drug, stopped treatment due to side‐effects, stillbirth, neonatal death, preterm delivery, birthweight (mean), SGA, 5‐min Apgar. |
| Australia 1991 | Entry criteria was DBP greater than 1 SD above the reported mean for gestational age. Mean BP of recruited women was 129/84 mmHg at entry to the trial (122 to 136 mmHg/79 to 89 mmHg) for the placebo group, and 126/82 mmHg (118‐134/79‐85) for the treatment group. Participants: 52 nulliparous with singleton pregnancies between 28 and 34 weeks of gestation, without proteinuria. Intervention: clonidine from 200 mcg to 800 mcg a day plus hydralazine from 50 mg to 200 mg a day, and placebo. Outcomes: severe HT, imminent eclampsia, eclampsia, severe proteinuria, antepartum haemorrhage, HELLP syndrome, fetal distress, fetal death, IUGR. |
| Belgium 1988 | Comparison of 2 beta blockers. Available as abstract only. Methods: 'randomised', no further information. Participants: 23 women with BP at least 140/90 mmHg x 2 and no proteinuria. Intervention: atenolol 100 mg a day vs pindolol 15 mg a day. Outcomes: umbilical PI, maternal BP, birthweight, Apgar score. |
| Brazil 1997 | Single‐dose intervention. No clinical outcomes studied (effect of nifedipine in placental blood flow). Article in Portuguese. Only abstract translated into English. Methods: double‐blind, placebo‐controlled, RCT. Participants: 65 women with PE. Intervention: nifedipine 20 mg orally (only dose) vs placebo. Outcomes: placental blood flow prior and 30 mins after the intervention. |
| Brazil 2000b | Quasi‐random design. Main paper in Portuguese. Methods: alternated allocation (data extracted from original thesis). 11 women (10.5%) excluded after trial entry. Participants: 105 women with singleton pregnancies diagnosed with PE, chronic HT, and PE superimposed to chronic HT. Intervention: isradipine (slow release), 5 mg every 12 hrs vs atenolol 50 mg every 12 hrs. Outcomes: BP, maternal heart rate, proteinuria, maternal side‐effects, mode of delivery, gestational age, birthweight, SGA babies, Apgar score. |
| Brazil 2000c | 40 women (24%) excluded after randomisation. Reasons for exclusion were: missed appointment for Doppler (70%), non‐compliance (20%), side‐effects (7.5%), preterm delivery (2.5%). Data were not presented by treatment arm. Main paper in Portuguese. Methods: randomised, double‐blind, placebo‐controlled trial. Participants: 123 pregnant women with chronic hypertension. Intervention: verapamil 240 mg/day vs placebo during 30 days. Outcomes: Doppler PI, RI and S/D ratio, incidence of PE, birthweight, gestational age at delivery, SGA. |
| China 1991 | Herbal medicine vs magnesium sulphate. No clinical data available. Article in Chinese. Only abstract translated into English. Methods: not reported. Authors state: "...randomly designed to...". Participants: 75 women with 'hypertension syndrome of pregnancy'. Intervention: Magnesium sulphate 20 g/day to 25 g/day vs ligustrazine 120 mg/day. to 160 mg/day. Outcomes: MAP, proteinuria, haematocrit, side‐effects, positive rate of NST, Apgar score. |
| China 1993 | Only dose intervention. Sublingual nifedipine previous to caesarean section. Article in Chinese. Only abstract translated into English. Methods: not reported. Indexed as publication type: RCT. Participants: 33 women with PE undergoing emergent caesarean section. Intervention: sublingual nifedipine, 16 mg (only dose). Control group not reported in abstract. Outcomes: MAP, systolic and DBP, maternal heart rate, postoperative haematocrit, side‐effects. |
| China 1998 | Single‐dose intervention. No clinical outcomes studied (effect of nimodipine in retinal blood flow). Article in Chinese. Only abstract translated into English. Methods: not stated. Indexed as publication type: RCT. Participants: 28 women with PIH. Intervention: nimodipine 30 mg orally (only dose) vs IV magnesium sulphate. Outcomes: retinal PI. |
| China 1999 | Herbal medicine + nifedipine vs nifedipine. No clinical outcomes studied. Article in Chinese. Only abstract translated into English. Methods: not stated. Indexed as publication type: RCT. Participants: 95 women with PIH. Intervention: prepared rhubarb + nifedipine vs nifedipine. Outcomes: serum lipids, and other blood tests. |
| China 2000 | Less than 7 days treatment. Treatment was given only during labour. Article in Chinese. Only abstract translated into English. Methods: quote "64 cases of PIH were randomly divided into...". Participants: 64 women with PIH. Interventions: Nifedipine orally given every 6 hrs during labour vs no treatment. Outcomes: postpartum haemorrhage. |
| China 2014 | Not mild‐moderate HT. Only women with pulmonary HT. Article in Chinese. Only abstract translated into English. Methods: "...randomly divided into group and control group..." Participants: 64 pregnant women with pulmonary arterial HT. Interventions: Sildenafil 25 mg three times daily vs low‐flow oxygen and low‐salt diet. Outcomes: variation of the blood oxygen saturation, pulmonary artery systolic pressure, haemodynamic parameters and pregnancy outcomes, including delivery modes, neonatal weight, morbidity of mother and fetus. |
| China 2017 | Intervention (Celastrol, traditional Chinese herbal medicine) is not an antihypertensive. Severe PE. Methods: stratified permuted‐block randomisation method with DBP as a factor. Participants: 522 pregnant women with severe HT and no history of use of antihypertensive drugs; no history of heart failure during the course of the pregnancy; no history of HELLP syndrome or chronic HT; and no history of smoking or diabetes. Interventions: oral nifedipine (10‐mg capsule, up to 5 doses) and celastrol (10‐mg capsule, up to 5 doses) every 15 mins until BP was no higher than 150/100 mmHg vs oral nifedipine (10‐mg capsule, up to 5 doses) plus glucose (10‐mg capsule, up to 5 doses) as placebo every 15 mins until BP was no higher than 150/100 mmHg. Outcomes: time required to control HT; time before another hypertensive crisis, number of dosages required to control HT; maternal and neonatal adverse effects. |
| Cuba 1994 | Quasi‐random design. Article in Spanish. Methods: alternate allocation (data provided by author). Participants: 90 pregnant women with chronic HT. Intervention: methyldopa (1 g/day to 2 g/day) or hydralazine (100 mg/day to 200 mg/day) vs no treatment. Outcomes: BP, superimposed PE, abruption, preterm delivery, LBW, Apgar score, RDS, hypoxia, fetal death. |
| Czech Republic 1993 | Comparison of 2 beta blockers. Article in Czech. Only abstract translated into English. Methods: 'divided at random'. No further information. Participants: 40 women with DBP 95 mmHg to 105 mmHg. Intervention: atenolol 50 mg/day to 100 mg/day vs bisoprolol 5 mg/day to 10 mg/day. Outcomes: BP, maternal heart rate, side‐effects. |
| Denmark 1991 | Intervention is not an antihypertensive: magnesium vs placebo. Methods: quote "...patients were allocated in a double‐blind and randomised manner, based in a computer‐generated list of numbers...". Participants: 61 women with PIH. Chronic HT excluded. Withdrawals: 3 women (2 from intervention group, 1 from control group) excluded after randomisation. Intervention: 48‐hrs of either IV magnesium or placebo infusion followed by daily oral magnesium or placebo tablets. Outcomes: MAP, caesarean section, induction of labour, side‐effects, gestational age, birthweight, Apgar score, admission to SCBU and days of stay. |
| Denmark 2000 | Intervention is not an antihypertensive: magnesium vs methyldopa. Methods: RCT. Allocation concealment by numbered sealed opaque envelopes. Participants: 33 women with PIH. Chronic HT excluded. Intervention: magnesium, 48‐hrs IV infusion followed by daily oral magnesium vs methyldopa 250 mg x 4/day. Outcomes: BP, gestational age, birthweight, admission to SCBU and length of stay, serum magnesium. |
| Dominican Republic 1992a | Not a RCT. Article in Spanish. Only abstract translated into English. Methods: not stated. Authors only state "...divided into 2 groups...". Women known as given the drugs under study were also included. Participants: 50 pregnant women with chronic HT + superimposed PE. Intervention: slow‐release nifedipine 20 mg every 8 hrs vs methyldopa 500 mg every 12 hrs. Outcomes: BP, Apgar score. |
| Dominican Republic 1992b | Not a RCT. Article in Spanish. Only abstract translated into English. Methods: not stated. Authors only state"...divided into 2 groups...". Participants: 30 pregnant women with severe PE. Intervention: methyldopa 250 mg to 500 mg every 5 hrs vs hydralazine 20 mg to 50 mg every 8 hrs. Outcomes: BP, maternal side‐effects. |
| Egypt 1988 | No relevant clinical outcomes studied. Available as abstract only. Methods: quote "patients were randomly allocated to three treatment groups". No further information. Participants: 50 primigravidae with pre‐eclamptic toxaemia and 20 multigravidae with essential HT in their late pregnancy. Interventions: 3‐arm trial: bromocriptine 5 mg, methyldopa 1 g, and placebo, in different combinations. No further information. Outcomes: serum prolactin and serum placental lactogen, BP. 1‐year follow‐up reported. |
| Egypt 1993 | 1‐week intervention. Outcomes measured at 30 mins, 3 and 7 days. Methods: 'randomly allocated'. Participants: 30 women with PE in the third trimester. 25 women had mild PE with DBP 100 mmHg to 109 mmHg and 5 had severe PE with DBP >/= 110 mmHg. Intervention: nifedipine 20 mg every 8 hrs for 7 days or placebo in the same time and duration. Outcomes: BP and fetal heart rate measured at 30 mins, 3 and 7 days. Renal function tests and Doppler scans of umbilical cord. |
| Egypt 1997 | The intervention is not an antihypertensive. Naltrexone vs placebo. Available as an abstract only. Methods: quote "...were randomly allocated to either naltrexone (...) or placebo". Participants: 20 women with PIH at 30 to 36 weeks' gestation. Intervention: naltrexone (opioid receptor antagonist), 50 mg every 12 hrs vs placebo. Outcomes: BP, proteinuria, oedema, prolactin levels, gestational age, status of the baby at birth. |
| Egypt 2009 | The intervention is not an antihypertensive. Ozone therapy (rectal insufflations). Methods: quote "...were randomly assigned into two groups in equal numbers as follow...". Participants: 30 hypertensive pregnant women at 24 weeks' gestation. Intervention: ozone therapy by rectal Insufflations 3 sessions/week for 7 weeks + methyldopa vs methyldopa. Outcomes: BP, resistance and PI, dose of methyldopa required. |
| Egypt 2017 | The intervention is not an antihypertensive. Ezomeprazole vs placebo. Protocol registration of an ongoing study. ClinicalTrials.gov: NCT03213639 Methods: RCT. Double‐blind, placebo‐controlled. Participants: target 390 pregnant women with early onset PE at 28 to 31 weeks' gestation. Intervention: esomeprazole single dose of 40 mg orally once a day vs identical placebo. Outcomes: HELLP syndrome, change in serum level of sFlt‐1 and endoglin, prolongation of gestation, side‐effects. |
| Finland 1988a | Comparison of 2 beta blockers. Methods: quote "according to randomisation table". No further information. Participants: 51 women with BP > 149/94 mmHg x 2 in sitting position after 2 days bed rest in hospital. Intervention: atenolol 50 mg/day to 100 mg/day vs pindolol 10 mg/day to 20 mg/day. If needed, hydralazine 150 mg/day added. Outcomes: stillbirths, side‐effects, need for additional drug, caesarean section, gestation at delivery (mean), birthweight (mean), 5‐min Apgar. |
| Finland 1995 | Comparison of 2 beta blockers. Less than 7 days treatment, single‐dose study. Women with mild HT not reported separately from severe HT. Methods: 'randomly chosen'. No further information. Participants: 24 women with a singleton pregnancy at 28 to 40 weeks, and either mild or severe PE (BP > 160/110 mmHg plus proteinuria > 5 g/24 hrs, or BP 140/90 mmHg to 160/110 mmHg plus proteinuria < 5 g/24 hrs). Intervention: atenolol 0.15 mg/kg IV vs pindolol 0.006 mg/kg IV in 100 mL of Ringer's solution. Infusion time 15 to 20 mins. Outcomes: utero and umbilico‐placental vascular impedance, fetal haemodynamics and cardiac function. |
| Finland 1999 | Main outcomes were assessed only at 5‐7 days of inclusion. 29% of women were excluded from the analysis. Methods: randomised, double‐blind, double‐dummy study. Participants: 24 women with singleton pregnancies between 29 and 39 weeks with BP > 140/90 mmHg x2, 6 hrs apart, and proteinuria > 0.3 g in 24‐hr urine collection. Intervention: isradipine 2.5 mg twice daily or placebo vs metoprolol 50 mg twice daily or placebo (double‐dummy study). Outcomes: insulin sensitivity, uric acid, degree of proteinuria, lipids and lipoproteins, BP, umbilical artery RI, birthweight, placental weight, caesarean section, Apgar scores. |
| France 1986 | Severe HT in hospitalised patients. Methods: 'Randomised'. No further details Participants: 35 women with severe HT induced by pregnancy. Intervention: labetalol vs clonidine orally Outcomes: BP, need for additional treatment, blood uric acid, duration of pregnancy, birthweight, neonatal Apgar score, neonatal hypoglycaemia, neonatal hypocalaemia. |
| France 1988b | No clinical outcomes studied. Outcomes assessed at 4 weeks after trial entry. Available as abstract only. Methods: 'randomised' no further information. 3‐arm study. Participants: 29 women with isolated HT after quote: "a mean period of 18 weeks of pregnancy". Intervention: pindolol vs atenolol vs methyldopa. Outcomes: BP, maternal heart rate, serum sodium, potasium, uric acid, creatinine, plasma renin activity and aldosterone. |
| Germany 2012 | Not mild‐moderate HT. Prevention study. Methods: randomised, placebo‐controlled, double‐blind study. Participants: 111 pregnant women with abnormal placental perfusion at 19 to 24 weeks' gestation. Intervention: NO‐donor penterythriltetranitrat (n = 54) vs placebo (n = 57). Outcomes: utero‐placental perfusion, preterm birth, IUGR, PE, fetal deaths. |
| Hungary 1999 | 28% of women excluded after randomisation (7 because of treatment duration not exceeding 10 days and 2 dropped out). Methods: allocation 'according to randomisation list'. No further information. Participants: 32 healthy primigravidae with BP at least 140/90 mmHg x 2 at least 6 hrs apart. Interventions: calcium dobesilate 2 g a day vs placebo. Outcomes: new proteinuria, caesarean section, placental abruption, preterm delivery. |
| India 1999 | Intervention is an antiplatelet agent. Available as abstract only. Methods: randomised, placebo‐controlled trial. Participants: 163 women with PIH of 20 to 32 weeks' gestation. Intervention: aspirin 60 mg a day vs placebo from 22 until 38 weeks of gestation. Outcomes: prevention of PIH grade B (BP 160/110 mmHg x 2, 4 hrs apart), proteinuria 2+ or more, perinatal mortality, maternal mortality, eclampsia, SGA (< 10th centile). |
| India 2012a | Includes women with severe HT. IV labetalol given to this subgroup, not analysed separately. Methods: prospective, randomised controlled parallel‐group study. Participants: 90 women with singleton, vertex pregnancies at 20 to 40 weeks' gestation with BP >/= 140/90, with and without proteinuria. Intervention: oral or IV Labetalol vs oral methyldopa. Outcomes: serum urea and creatinine, significant proteinuria, severe maternal complications, induction of labour, caesarean section, lactation, gestational age at delivery, Apgar score, admission to NICU, RDS, bradycardia, jaundice, hypoglycaemia. |
| India 2012b | Intervention is not an antihypertensive: magnesium sulphate vs placebo. No clinical outcomes studied. 27% women (18/66) excluded after randomisation. Methods: women were randomly allocated by sealed envelopes containing computer‐generated random numbers. Double‐blind, placebo‐controlled. Participants: 66 women with mild PE or PIH after 34 weeks' gestation. Intervention: 24‐hrs of either IV magnesium sulphate or placebo infusion. Outcomes: umbilical artery and fetal middle cerebral artery PI. |
| India 2013d | Severe HT. Protocol registration of an ongoing study. ClinicalTrials.gov: NCT01912677. CTRI/2013/08/003866 Methods: open‐label RCT. Participants: target 671 pregnant women with severe HT. Intervention: 3‐arm trial. Oral nifedipine vs oral labetalol vs oral methyldopa. Outcomes: number of hourly BP's in severe range. No other outcomes listed. |
| India 2015c | Severe HT. Pilot feasibility study of Protocol registered as India 2013b. ClinicalTrials.gov: NCT01912677. CTRI/2013/08/003866 Methods: open‐label RCT. Participants: 30 pregnant women in India with a sustained SBP P160 mmHg or DBP P110 mmHg. Intervention: oral nifedipine (10 mg up to 3 total doses in 6 hrs) vs oral labetalol (200 mg up to 3 total doses in 6 hrs) vs a single dose of oral methyldopa 1000 mg. Outcomes: achievement of the targeted BP within 6 hrs, use of additional antihypertensives, adverse maternal and neonatal effects, and side‐effect profile. |
| India 2015d | Severe HT. No clinical outcomes measured. Available as abstract only. Methods: RCT Participants: 30 women with severe PE having acute HT (more than or equal to 160/105 mmHg) Intervention: IV labetalol vs oral nifedipine Outcomes: Doppler vascular PI, RI, S/D ratio of umbilical (UA), middle cerebral artery (MCA), maternal uterine and renal artery flow. |
| India 2016 | No clinical outcomes measured. Methods: single‐blind RCT. Participants: 60 primiparous pregnant women with PE (BP > 140/90 mmHg and proteinuria or oedema). Intervention: 4‐arm trial. Methyldopa vs Methyldopa + vit C vs nifedipine vs nifedipine + vit C. Outcomes: serum levels of malondialdehyde (MDA) Superoxide Dismutase (SOD) before and after treatment in the 4 groups. No other clinical outcomes reported. |
| Iran 2000 | Quasi‐random design (data from personal communication). Available as abstract only. Methods: quote: "patients were sequentially assigned to one of two randomised group"'. Alternate allocation (data obtained from personal communication). Participants: 37 pregnant women over 26 weeks' gestation with BP over 140/90 mmHg (after 24 to 48 hrs resting) + proteinuria or generalised oedema. Intervention: nifedipine 10 mg three times daily. vs hydralazine 10 mg three times daily. Outcomes: BP, termination of pregnancy, side‐effects. |
| Iran 2005 | Intervention is not an antihypertensive: IV magnesium sulphate vs oral magnesium chloride. No clinical outcomes studied. Methods: randomised controlled open clinical trial. Participants: 68 women with mild PE. Intervention: IV magnesium sulphate (2 g/hrs) or oral magnesium chloride (4 g/2hrs). Outcomes: serum Mg levels at 3, 6 and 12 hrs after administration. |
| Iran 2012 | 7‐day treatment. No clinical outcomes proposed. Protocol registration of an ongoing study. ClinicalTrials.gov: NCT01674127 Methods: placebo‐controlled RCT. Participants: 50 women with mild PE (no further details). Intervention: methyldopa 500 mg day vs placebo. Outcomes: uterine artery diameter, uterine artery blood flow, umbilical artery and fetal middle‐cerebral artery by Doppler ultrasound. |
| Iran 2016 | Not a RCT. Protocol for an observational single‐arm study. Irct registration number: IRCT201602067676N5 Methods: observational. Participants: target 80 pregnant women with chronic HT. Intervention: sequential use of methyldopa 250 mg twice daily 4g/day, Hydralazine 5 mg to 10 mg IV every 20 mins 30 mg, Nifidipine 10 mg twice daily and diltiazem 120 mg to 180 mg every day. Outcomes: superimposed PE, acute kidney injury, placental abruption, fetal death. |
| Israel 1988 | Comparison of 2 beta blockers. Published as abstract only. Methods: quote: "allocated in blind and randomised manner". No further information. Participants: 30 women with SBP 140 mmHg to 170 mmHg and DBP 90 mmHg to 110 mmHg x 2, 6 hrs apart. Intervention: Atenolol 100 mg plus 2 placebo tablets vs pindolol 5 mg x 3/day. Outcomes: gestation at delivery (mean). |
| Israel 1992b | Comparison of 2 beta blockers. Methods: quote: "randomly allocated to double blind treatment". No further information. Participants: 20 women with mild PE, BP >/= 140/90 mmHg. Interventions: propranolol 40 mg x 3/day vs pindolol 5 mg x 3/day, for 7 days. Outcomes: BP, umbilical artery Doppler. |
| Israel 1999 | Single‐dose intervention. Methods: double‐blind, placebo‐controlled RCT. Participants: 23 women with PIH. Intervention: sublingual tablet of Isosorbide dinitrate (5 mg) or placebo (single dose). Outcomes: maternal BP and heart rate, umbilical artery Doppler. |
| Italy 1986 | Not an RCT (matched controls). Available as abstract only. Methods: 'randomised protocol', no further information, for group A (nifedipine or atenolol), control group (B) was matched by age and parity with group A. Results in group A were not presented separately. Participants: 10 women with mild‐moderate HT in the third trimester (group A). Interventions: atenolol 100 mg a day or slow‐release nifedipine 20 mg x 2/day (group A) vs diuretics or bed rest (group B). Outcomes: BP, gestational age, birthweight, Apgar score, serum bilirubin, preterm delivery, RDS, side‐effects. |
| Italy 1988 | Quasi random design. Study abandoned (5 women recruited) Personal communication. Methods: quasi‐random design. Participats: pregnant women with mild‐moderate HT (BP = or > 140/90). Intervention: pharmacological treatment vs bed rest. Outcomes: pregnancy outcomes (no further details). |
| Italy 1990a | Quasi‐randomised design. 2 trials with same methods reported in 1 paper (1) 44 women (2) 50 women. Methods: allocation by quote: "order of attendance at clinic or department". Participants: women with BP =/> 140/90 mmHg x 2 over 8 hrs, normal BP before pregnancy. Intervention: (1) slow‐release verapamil 360 mcg/day to 480 mcg/day vs pindolol 15 mg/day to 20 mg/day. (2) slow‐release verapamil 360 mcg/day to 480 mcg/day vs atenolol 100 mg/day to 150 mg/day. Outcomes: caesarean section, baby death, Apgar (mean), gestation at delivery (mean). |
| Italy 1990b | Intervention is an antiplatelet agent. No clinical outcomes reported. Available as abstract only. Methods: quote: "...using a random selection...". No further information. Participants: 20 women with PIH before 36 weeks' gestation. Intervention: picotamide (no dose reported) vs no treatment. Outcomes: platelet aggregation, ADP‐threshold values, collagen concentration thresholds. |
| Italy 2000a | Women had chronic HT or history of HT or IUGR (results were not presented separately). Methods: quote "...patients were randomly allocated to two treatments...". Participants: 68 women with either chronic HT or with previous history of PE or IUGR. Intervention: glyceryl trinitrate transdermal patch (5 mg/24 hrs) for 14 to 16 hrs/day from 16 to 38 weeks' gestation vs observation. Outcomes: hypertensive syndrome, preterm delivery, abruptio, birthweight, IUGR, Apgar score, admission to SCBU, RDS, neonatal death, umbilical and cerebral artery PI. |
| Italy 2001 | Not clearly randomised. No clinical data studied. Available as congress abstract only. Methods: not stated. Participants: 24 women with PIH. Intervention: isosorbide dinitrate sublingual every 6 hrs (n = 12) vs nifedipine 20 mg daily (n = 12). Outcomes: apoptosis in placental tissues. |
| Italy 2004 | Intervention is not an antihypertensive: acupuncture + methyldopa vs. methyldopa. Protocol for a future RCT. Available as abstract only. Methods: planned RCT Participants: 60 women with chronic HT at 16 to 20 weeks' gestation. Intervention: acupuncture + methyldopa vs. methyldopa. Outcomes:need for antihypertensives. |
| Italy 2006 | Intervention is not an antihypertensive. Single‐dose treatment. Methods: double‐blind, randomised, cross‐over design. Participants: 15 pregnant women at 30 to 34 weeks' gestation with mild/moderate PIH. Intervention: L‐Arginine 20 g/500 mL vs placebo infusion. Outcomes: systolic and DBP, fetal heart rate and fetal movements. |
| Italy 2008 | Intervention is not an antihypertensive. Available only as an abstract. Methods: double‐blind, randomised, placebo‐controlled trial. Participants: 20 pregnant women with PE. Intervention: L‐Arginine 1.66g 3 times a day vs placebo. Outcomes: Serum L‐arginine levels, adverse maternal and fetal outcomes. |
| Italy 2010 | Intervention is not an antihypertensive. Methods: double‐blind, randomised, placebo‐controlled trial. Participants: 80 pregnant women with mild chronic HT. Intervention: L‐Arginine vs placebo. Outcomes: BP, need for additional antihypertensives, superimposed PE, adverse maternal and fetal outcomes. |
| Italy 2012 | Not a RCT. Sequential allocation. Methods: sequential allocation. Participants: 400 pregnant women with early‐onset (20 to 27 weeks’ gestation) mild GH (systolic and DBP < 170/110 mmHg). Intervention: 4‐arm trial. nifedipine (Group A) vs nifedipine and NO donors vs nifedipine and oral fluids vs nifedipine, NO donors and oral fluids. Outcomes: total peripheral vascular resistance, severe maternal and fetal complications (placental abruption, HELLP syndrome, fetal growth restriction, severe RDS; and perinatal death. |
| Japan 1997 | Single‐dose intervention. No clinical outcomes studied. Methods: quote "...randomly allocated into two groups using sealed envelopes...". Participants: 18 pregnant women with SBP = or > 140 mmHg and DBP = or > 90 mmHg, with or without proteinuria and oedema. Intervention: isosorbide dinitrate patches (40 mg, only dose) and bed rest vs bed rest alone. Outcomes: systolic and DBP, uterine and umbilical Doppler velocimetry. |
| Japan 2016b | Intervention is not an antihypertensive (statin therapy for PE). Protocol for an ongoing study. UMIN‐CTR: UMIN000020686 Methods: open‐‐label RCT. Participants: target 50 pregnant women with PE with hyperlipaemia. Intervention: pravastatin 10 mg/day vs no treatment. Outcomes: maternal BP, body weight, oedema, liver function, kidney function, serum lipids, urinary protein, postpartum BP, extend the period of pregnancy, maternal serum soluble fms‐like tyrosine kinase 1, maternal serum tumour necrosis factor alfa, maternal urine F2‐Isoprostanes. |
| Japan 2017 | Not mild‐moderate HT. Prevention trial. Protocol of an ongoing trial. UMIN ID: UMIN000027270 Methods: open‐RCT. Participants: target 20 pregnant women with history of severe hypertensive disorders of pregnancy that required delivery prior to 34 weeks' gestation at 12‐16 weeks' gestation. Intervention: tadalafil (20 mg/day) vs conventional management. Outcomes: recurrence rate of hypertensive disorders of pregnancy, completion rate of the treatment regimen, Efficacy monitoring, US estimated fetal weight (g), fetal head circumference (cm), Doppler imaging of umbilical arterial, middle cerebral arterial, uterine arterial blood flow, deep est amniotic fluid pocket (cm), prolongation of gestational age at birth (days), birthweight (g), gestational age, Apgar score, umbilical artery pH and base excess values, incidence of PE, neonatal morbidity, rate of obstetric complications, perinatal mortality, neonatal mortality. |
| Kuwait 1995 | Not clearly randomised. Methods: 'randomly allocated in sequence'. No further information. Participants: 120 primigravid women > 26 weeks' gestation, with SBP 120 mmHg to 140 mmHg and DBP 95 mmHg to 105 mmHg persisting for 3 days. Intervention: labetalol 100 mg to 300 mg x 3/day vs methyldopa 250 mg to 750 mg x 3/day. Outcomes: maternal MAP, proteinuria (undefined), placental abruption, caesarean section, elective delivery, side‐effects, 1‐min Apgar score < 5, days on SCBU, birthweight (mean). |
| Mexico 2008 | Intervention is not an antihypertensive. Available only as an abstract. Methods: randomised, placebo‐controlled trial. Participants: 100 pregnant women with PE. Intervention: L‐Arginine vs placebo. Outcomes: birthweight, SGA babies. |
| Netherlands 2014 | Post‐partum HT. Protocol of an ongoing trial. EudraCT Number: 2014‐002524‐27. Methods: double‐blind RCT. Participants: target 30 women with postpartum HT after a pre‐eclamptic pregnancy. Intervention: 4‐arm trial. Placebo vs losartan vs low sodium diet vs moxonidine. Outcomes: mean 24‐hr BP, RAAS‐activity, SNS‐activity, endothelial function, arterial stiffness, lipid metabolism, insulin sensitivity, oxidative stress and systemic inflammation. |
| Pakistan 1994 | Intervention is an antiplatelet agent. Methods: 'randomly divided into two groups'. No further information. Participants: 200 women, 1 group with previous history of PIH (100 women) and other with mild essential HT or those developing BP 140/90 mmHg x 2 at least 15 days apart (100 women). Intervention: aspirin 75 mg twice daily vs routine antihypertensive treatment with beta blockers or calcium channel blockers when DBP exceeded 100 mmHg. Outcomes: development of PE. No other relevant outcomes reported. |
| Panama 2012 | Severe HT. Ongoing trial. Methods: randomised, open‐label trial. Participants: 284 (estimated) women with at > 24 weeks' gestation with severe HT (SBP > 160 mmHg/DBP > 110 mmHg). Intervention: 5 mg IV hydralazine every 15 min until BP controlled vs. IV labetalol ant increasing doses until BP controlled. Outcomes: BP control. |
| Philippines 2000 | 3 days treatment. No relevant clinical outcomes studied. Available as abstract only. Methods: randomised, double‐blind, placebo‐controlled trial. Participants: 16 pre‐eclamptics (no further details). Intervention: nitrol patch 5 mg for 16 hrs for 3 consecutive days vs the same regimen using a gauze only. Outcomes: uterine and umbilical Doppler velocimetry. |
| Russia 1993 | Possibly not a RCT. Full text awaiting translation from Russian. Abstract only in English. Participants: 92 women with slight and medium‐severe HT at 24 to 39 weeks' gestation. Interventions: venodilators, prazosin and cordafen are all mentioned. Not clear how the groups were constructed. |
| Singapore 1996 | More than 20% of women excluded, 6 women (22%) excluded because delivered in the week after trial entry. Methods: 'by opening a sealed envelope'. Participants: 27 women with singleton pregnancies, DBP 90 mmHg or above and proteinuria. Interventions: isradipine (slow release) 5 mg a day vs methyldopa 750 mg a day. Outcomes: MAP, side‐effects, caesarean section, perinatal mortality, birthweight, admission to SCBU, Apgar score, maternal and fetal haemodynamics (by Doppler). |
| Singapore 1998 | No relevant clinical outcomes studied. Methods: 'randomised', no further information. Participants: 30 women with PE, DBP >/= 90 mmHg and proteinuria >/= 300 mg/24 hrs. Interventions: methyldopa 250 mg x 3/day to 500 mg x 3/day vs isradipine 5 mg to 10 mg once/day. Outcomes: haemostatic parameters only (thrombelastography, fibrinogen, antithrombin III, thrombin‐antithrombin‐complex, beta‐thromboglobulin, plasminogen activators, plasminogen activators inhibitors, and plasminogen). |
| Slovakia 2002 | Not a RCT. Methods: cohort study. Participants: women with HT during pregnancy. Interventions: acebutolol vs other antihypertensives. Outcomes: maternal and perinatal adverse events. |
| South Africa 1988 | Quasi‐random design. Less than 7 days treatment, single‐dose study. No clinical outcomes reported. Methods: quasi‐random design, using last digit of the hospital number. Participants: 18 women in the last trimester of pregnancy with HT +/‐ proteinuria. Interventions: nifedipine 5 mg vs placebo (single dose). Outcomes: measures of uteroplacental blood flow. |
| South Africa 1990 | Included women with severe HT (DBP 100 mmHg to 120 mmHg). Methods: 'randomly allocated', no further information. Participants: 60 women at 28 to 36 weeks' gestation with mean 24‐hr DBP 100 mmHg to 120 mmHg +/‐ proteinuria. Intervention: indoramin 50 mg twice daily vs methyldopa 1 g twice daily vs placebo 1 tablet daily. Outcomes: MAP, need for additional antihypertensive. |
| South Africa 1991b | Quasi‐random design. Single‐dose intervention. Methods: allocation quote: "by virtue of the last digit of their folder number". Participants: 19 women at > 28 weeks' gestation, singleton pregnancy and HT (defined as mean DBP >/= 90 mmHg). Intervention: sublingual nifedipine 5 mg vs placebo (single dose). Outcomes: DBP (mean), maternal and fetal heart rate, gestational age, side‐effects. |
| South Africa 1997 | Most women did not have HT. Eligibility criteria DBP >/= 80 mmHg, before 20 weeks' gestation. Of 138 recruited women, less than half had DBP >/= 90 mmHg. Results for this group were not presented separately. Methods: sequentially‐numbered sealed boxes containing drug or placebo. Participants: 138 women between 12 to 20 weeks' gestation with DBP 80 mmHg to 109 mmHg, without antihypertensive therapy. Intervention: ketanserin 40 mg to 80 mg a day vs placebo. Outcomes: severe HT, proteinuria, placental abruption, other drugs needed, perinatal deaths, SGA (< 10th centile), birthweight. |
| South Africa 2004 | Less than 7 days treatment. Available as abstract only. Methods: 'randomised'. No further details. Participants: preliminary data of 177 pre‐eclamptic women being delivered. Intervention: IV magnesium sulphate vs labetalol (20 mg IV then 200 mg orally every 6 hours). Outcomes: incidence of eclampsia, additional anti‐ HT therapy, side‐ effects (flushing), intrapartum complications, neonatal outcomes. |
| South Africa 2015 | Intervention (ezomeprazole) is not an antihypertensive. Protocol of an ongoing trial. Pan African Clinical Trial Registry: PACTR201504000771349. Methods: double‐blind, placebo‐controlled RCT. Participants: target 120 pregnant women with early onset PE at a gestational age between 26 + 0 and 31 + 6 weeks. Intervention: 40 mg of esomeprazole vs identical placebo tablet orally once a day. Outcomes: prolongation of pregnancy, maternal, fetal and neonatal mortality and morbidity, maternal serum biomarkers (including sFlt, sEng and endothelin 1) and biomarkers in placental samples. |
| South Africa 2016 | Intervention (metformin) is not an antihypertensive. Protocol of an ongoing trial. Pan African Clinical Trial Registry: PACTR201608001752102. Methods: double‐blind RCT. Participants: target 120 pregnant women with early onset PE at a gestational age between 26 + 0 and 31 + 6 weeks. Intervention: metformin 3g/day vs identical placebo tablets. Outcomes: prolongation of pregnancy, maternal, fetal and neonatal mortality and morbidity, maternal serum biomarkers (including sFlt, sEng and endothelin 1). |
| Sri Lanka 1994 | Quasi‐random design. Methods: quote: "patients were alternately allocated". Participants: 126 women with PIH. Interventions: nifedipine 30 mg/day to 90 mg/day vs methyldopa 750 mg/day to 2000 mg/day. Outcomes: severe HT, gestation at delivery (mean), birthweight (mean). |
| Sweden 1992 | Comparison of 2 beta blockers. Methods:quote: "'randomly allocated" using "double‐blind dummy technique". No further information. Participants: 32 women admitted to hospital with PIH in the third trimester (BP >/= 140/90 mmHg x 2 at least 4 hrs apart) and normotensive in the first trimester. Intervention: atenolol 50 mg x 2/day vs pindolol 5 mg x 2/day, for at least 1 week. Outcomes: side‐effects, caesarean section, maternal haemodynamics, fetal haemodynamics, admission to SCBU, birthweight (mean), 5‐min Apgar score. |
| Sweden 1993 | It is not clear from papers whether reported data represent only a subgroup of women. Methods: not stated. Authors state "allocated at random". Participants: 20 women at 26 to 37 weeks' gestation with 'persistent' DBP >/= 100 mmHg and proteinuria. Intervention: labetalol 300 mg/day to 1000 mg/day orally (if necessary, IV 25 mg bolus followed by 25 mg/hr to 65 mg/hr infusion), vs hydralazine 75 mg/day to 400 mg/day orally (if necessary, 1.5 mg/hr to 6.0 mg/hr infusion). Outcomes: severe HT, additional antihypertensive, caesarean section, neonatal death, birthweight (mean), gestation at delivery (mean), SGA (2 SD below mean), bradycardia, hypotension, hypoglycaemia, 5‐min Apgar < 7, RDS, cord pH (< 7.20). |
| Uganda 1992 | Status unknown. Personal communication of a planned RCT of aspirin and methyldopa in moderate HT during pregnancy. No further data. |
| UK 1978 | Included women with severe HT. Methods: 'randomly allocated'. No further information. Participants: 74 women with singleton pregnancy with DBP > or = to 170/100 mmHg x 2 at up to 36 weeks' gestation. Intervention: labetalol 100 mg (max 1200 mg daily) vs methyldopa 250 mg (up to 4000 mg daily). Outcomes: severe HT, proteinuria ('greater than trace'), additional antihypertensive therapy, changed drugs due to maternal side‐effects, caesarean section, perinatal mortality, SGA infants (< 10th centile), intubated, umbilical cord pH. |
| UK 1991 | Less than 7 days treatment, single‐dose study. Methods: sequentially‐numbered, sealed envelopes. Participants: 30 women with singleton pregnancy and HT, defined as BP >/= 140/90 mmHg. Intervention: 10 mg hydralazine IV vs or 100 mg labetalol IV, as single dose. Outcomes: MAP, maternal and fetal heart rate, side‐effects, umbilical artery PI. |
| UK 2015 | Not mild‐moderate HT. Protocol of an ongoing prevention trial in high‐risk women. Intervention is not an antihypertensive (statins). EUCTR2016‐005206‐19‐BE. ISRCTN17787139. Methods: double‐blind, placebo‐controlled RCT. Participants: target 1684 pregnant women at high risk for preterm‐PE at 11 to 13 weeks by the algorithm combining maternal history and characteristics, biophysical findings (MAP and uterine artery Dopplers) and biochemical factors (placental growth factor). Intervention: pravastatin 20 mg vs placebo, orally once a day. Outcomes: incidence of preterm PE < 37 weeks, < 34 weeks, birthweight, fetal and neonatal weight, NICU admission, composite measure of neonatal mortality and morbidity, placental abruption, spontaneous preterm delivery < 34 weeks and < 37 weeks. |
| USA 1957 | Not randomised. Although a group of women received placebo, results are presented together with a group of matched controls. Included women with severe HT. Methods: not stated. Participants: 106 pregnant women with chronic HT and 28 women with severe PE. In addition, 671 women with chronic HT were included as controls. Intervention: oral reserpine 0.25 mg/day to 3 mg/day (n = 80) vs placebo (n = 26). 28 women received IV reserpine. Outcomes: status at birth, birthweight. |
| USA 1981 | Study included 63 women, but only 21 randomised. Outcomes not reported separately for randomised women. Methods: 'randomly and blindly assigned'. No further information. Participants: 21 women with BP 140/90 mmHg or above in a seated position or at rest, x 2, 6 or more hrs apart. Intervention: hydralazine 25 mg x 3/day vs methyldopa 250 mg x 3/day vs placebo x 3/day. Outcomes: MAP, caesarean section, induction of labour, birthweight. |
| USA 1990b | Status unknown. Personal communication of a planned RCT of oral hypotensive agents in early onset PE. No further data. |
| USA 1991 | Not a randomised trial. No clinical outcomes reported. Methods: placebo group were matched as controls. Participants: 16 women at 17 to 22 weeks' gestation. Intervention: 10 mg sublingual nifedipine vs placebo. Outcomes: S/D ratio of the uterine artery, maternal BP, maternal heart rate. |
| USA 2005 | Intervention is not an antihypertensive. Protocol of an ongoing trial. Study NCT00194974. Methods: RCT. Sequentially numbered opaque envelopes. Participants: 50 pregnant women with chronic HT. Intervention: target BP of 120 to 130/80‐85 mmHg vs target BP 140 to 150/90‐100 mmHg. Outcomes: BP, superimposed PE, worsening HT, HELLP syndrome, gestational age, birthweight, serious perinatal complications. |
| USA 2006 | Study abandoned (2 women recruited). Personal communication. ClinicalTrials.gov Identifier: NCT00329511 Methods: open‐label RCT. Participants: pregnant women between 14 to 28 weeks of gestation with chronic HT requiring antihypertensive therapy (BP < 180/110). Intervention: methyldopa 250 mg to 750 mg in 4 doses vs clonidine patch 0.1 mg to 0.4 mg once a week. Outcomes: patient compliance, change in mean arterial BP at weeks 1,2,3,4 in comparison to baseline BP at the initial visit, side‐effects to each medication as reported by the patients. |
| USA 2016b | Not mild‐moderate HT. Prevention trial in high‐risk women. Intervention is not an antihypertensive (statins). Methods: pilot, multicentre, double‐blind, placebo‐controlled, RCT. Participants: 20 pregnant women at high risk of PE at 12.0 to 16.6 weeks. Intervention: pravastatin 10 mg vs placebo, orally once a day. Outcomes: number and type of maternal and fetal/neonatal adverse events, pharmacokinetic parameters of the drug. |
| Venezuela 1985 | Not randomised. Included women with severe HT. Article in Spanish. Methods: alternated allocation (personal communication). Participants: 32 pregnant women at > 25 weeks' gestation with severe PE (defined as BP 160/110 or 140/90) and symptoms as headache, epigastric pain, blurred vision or hyperreflexia. Intervention: labetalol 200 mg/day to 800 mg/day vs methyldopa 750 mg/day to 2000 mg/day. Outcomes: maternal MAP, maternal pulse rate, gestational age at delivery, birthweight, 1‐min Apgar, fetal and neonatal death. |
| Venezuela 1997 | Not a RCT. Matched controls. Article in Spanish. Methods: controls were women treated with methyldopa in the same study period, with the same characteristics than the study group. Participants: 20 women with PIH. Intervention: labetalol 200 mg to 300 mg orally given every 12 hrs vs methyldopa from 500 mg/day to 1500 mg/day Outcomes: BP, severe HT, gestational age, induction of labour, caesarean section, birthweight. |
| Venezuela 2001 | No relevant clinical outcomes studied. Less than 7 days of treatment. Available as abstract only. Methods: Authors state"...were randomly assigned to..." No further information. Participants: 30 pre‐eclamptic. No further information. Intervention: transdermal nitroglycerin (7 mg for 12 hrs for 2 consecutive days) vs placebo. Outcomes: umbilical S/D ratio, PI and RI by Doppler ultrasound. |
| Venezuela 2007 | Mixed control group. Available only as an abstract. Method: quote: "...were randomly assigned to two study groups...". Participants: 30 women with pre‐eclampsia and gestational HT. Intervention: carvedilol vs traditional antihypertensive drugs (methyldopa and/or nifedipine). Outcomes: BP control, additional antihypertensives, maternal and fetal complications, Apgar score, fetal heart rate. |
ADP: adenosine diphosphate BP: blood pressure DBP: diastolic blood pressure HELLP: syndrome of haemolysis, elevated liver enzymes and low platelets hr(s): hour(s) HT: hypertension IUGR: intrauterine growth retardation IV: intravenous LBW: low birthweight min(s): minute(s) MAP: mean arterial pressure mg: magnesium NICU: neonatal intensive care unit NO‐donor: nitric oxide donor NST: non‐stress test PIH: pregnancy‐induced hypertension PI: pulsatility index PE: pre‐eclampsia RAAS: Renin‐Angiotensin‐Aldosterone System RCT: randomised controlled trial RDS: respiratory distress syndrome RI: resistance index SBP: systolic blood pressure SCBU: special care baby unit SD: standard deviation S/D ratio: ratio between peak systolic to end‐diastolic flow velocity SGA: small‐for‐gestational age SNS: sympathetic nervous system US: ultrasound vs: versus