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National Collaborating Centre for Women's and Children's Health (UK). Hypertension in Pregnancy: The Management of Hypertensive Disorders During Pregnancy. London: RCOG Press; 2010 Aug. (NICE Clinical Guidelines, No. 107.)

Appendix NSafety data for antihypertensives in pregnancy

Centrally acting drugs

Methyldopa (compatible) (Bm)

Crosses the placenta and achieves fetal concentrations similar to maternal serum concentration.

Collaborative Perinatal Project (CPP) – 1 infant exposure in 1st trimester – no abnormalities found.

Michigan Medicaid surveillance study – 242 infants exposed in 1st trimester – 11 (4.5%) major birth defects (10 expected). Does not support an association with methyldopa and congenital defects.

A decrease in intercranial volume has been reported after 1st trimester exposure to methyldopa. Children evaluated at 4 years of age showed no association between head size and retarded mental development.

A reduced systolic blood pressure of 4–5 mmHg in 24 infants for the first 2 days after delivery has been reported. This was not considered to be significant.

An infant born with oesophageal atresia with fistula, congenital heart disease, absent left kidney and hypospadias was exposed to methyldopa throughout pregnancy and clomiphene (in the 1st trimester).

Clonidine (Limited human data) (Cm)

No reports linking the use of clonidine with congenital defects or adverse fetal effects have been located. Clonidine has been used during all trimesters but experience in the 1st trimester is very limited.

Michigan Medicaid surveillance study – 59 infants exposed in 1st trimester – 3 (5.1%) major birth defects observed (3 expected). Number of exposures is too low to draw any conclusions.

Moxonidine

No information

Beta (β) blockers

Labetalol (Human data suggest low risk) (Cm)

Does not seem to pose a risk to the fetus, except possibly in the 1st trimester.

Michigan Medicaid surveillance study – 29 infants exposed in 1st trimester – 4 (13.8%) major birth defects (1 expected). May support an association with labetalol and congenital defects, but other factors (mother’s disease, concurrent drug use and chance) may be involved.

No published reports of fetal malformations with labetalol exposure located, but experience in the 1st trimester is limited. Most reports found no adverse effects on birthweight, head circumference, Apgar scores or blood glucose control after in utero exposure.

One case of neonatal hypoglycaemia has been mentioned but mother was also taking a thiazide diuretic.

Offspring of mothers treated with labetalol had significantly higher birthweight compared with those exposed to atenolol (3280 g versus 2750 g).

A study comparing hospitalisation with or without labetalol showed significantly higher rates of growth retardation in labetalol exposed infants (19.1% versus 9.2%).

Fetal heart rate is apparently unaffected by labetalol in utero exposure. However, 2 studies have observed neonatal bradycardia in 5 infants (one case this was marked - < 100bpm - and persistent). Hypotension was also noted in another infant born at 28 weeks by caesarean section.

In a study examining the effects of labetalol exposure on term neonates, mild transient hypotension which resolved within 24 hours was reported (maternal dose – 100–300 mg TDS). Heart rate, respiratory rate, palmar sweating, blood glucose control and metabolic and vasomotor responses to cold stress did not differ between groups.

Several studies have shown a lack of effect of labetalol treatment on uterine contractions. One study reported a higher incidence of spontaneous labour in labetalol treated mothers (compared with methyldopa), however because most studies do not show this, the effect on uterine contractility is questionable.

Follow-up studies in children at 6 months of age to 10 infants exposed in utero showed normal growth and development.

Atenolol (Human data suggest risk in 2nd and 3rd trimesters) (Dm)

Crosses the placenta and achieves fetal concentrations similar to maternal serum concentration.

Michigan Medicaid surveillance study – 105 infants exposed in 1st trimester – 12 (11.4%) major birth defects (4 expected). Possible association with hypospadias, but other factors (mother’s disease, concurrent drug use and chance) may be involved.

The use of atenolol has been described frequently in pregnancy, no fetal malformations have been reported in these, however treatment did not occur in the 1st trimester.

Atenolol induced decreased fetal heart rate, increased pulsatory indices (and peripheral vascular resistance) of the fetal thoracic descending aorta, abdominal aorta and umbilical artery and a decrease in umbilical venous blood flow has been reported in several sources.

Low birth and placental weights, low birth length and IUGR have been reported with the use of atenolol in pregnancy. Some case reports were also associated with other factors such as pre-eclampsia.

Several reports of intrauterine death are given but little other details are available.

A randomised double blind study looking at atenolol versus placebo started at 34 weeks gestation showed no statistical difference in mean gestational age at delivery, hypoglycaemia, respiratory distress syndrome, hyperbilirubinaemia, birthweight or placental weight. Atenolol exposed infants did have significantly more bradycardia (39% versus 10%), no infants required treatment.

1 report of retroperitoneal fibromatosis in a foetus exposed to atenolol 100 mg daily from the second month of pregnancy. Drug was attributed to this due to the location of the mass being similar to that of fibroids reported in adults exposed to atenolol.

Propranolol (Human data suggest risk in 2nd and 3rd trimesters) (Cm*)

Propranolol readily crosses the placenta

A number of fetal and neonatal adverse effects have been reported with propranolol use in pregnancy, but other factors (mother’s disease, concurrent drug use or a combination of these) may be involved. Doses of 160 mg daily (or more) seem to produce more serious complications but lower levels have been associated with toxicity.

Adverse effects seen in a meta-analysis of 23 reports included (n = 167):

Michigan Medicaid surveillance study – 274 infants exposed in 1st trimester – 11 (4%) major birth defects (12 expected).

Respiratory depression was noted in 4 of 5 infants born to mothers who were given 1 mg IV propranolol just before C-section.

Fetal bradycardia has been reported in women having 1 mg/minute propranolol for 4 minutes for dysfunctional labour.

An increase in perinatal mortality has been described in a small study when compared with a control; however mothers were also using multiple other antihypertensives and had more severe renal disease and higher blood pressures in the propranolol group.

There are conflicting studies that either do or do not show a link with premature labour with propranolol use.

Acebutolol (Limited human data) (Bm*)

No human malformations attributed to acebutolol have been observed, but experience in the first trimester is lacking.

There have been reports of reduced birthweight with acebutolol.

In a comparison of 20 pregnant women treated with either acebutolol or methyldopa for mild to moderate hypertension, no differences were found in: pregnancy duration, birthweight, Apgar scores or placental weight. No evidence of neonatal bradycardia, hypoglycaemia or respiratory problems were seen, however, blood pressures, heart rates and blood glucose were significantly lower in the acebutolol group.

Bisoprolol (Human data suggest risk in 2nd and 3rd trimesters) (Cm*)

A case describing a 24 year old woman who took bisoprolol 5 mg/day (and naproxen and sumatriptan) in the first 5 weeks of pregnancy. The infant was delivered at 37 weeks by C-section and had a wide bilateral cleft palate, marked hypertelorism, a broad nose and bilateral but asymmetric toe abnormalities.

Carvedilol (Human data suggest risk in 2nd and 3rd trimesters) (Cm*)

No reports of use in human pregnancy have been located

Carvedilol is thought to cross the placenta

Celiprolol (Human data suggest risk in 2nd and 3rd trimesters) (B*)

In a small study celiprolol was shown to cross the placenta and reach 25–50% of maternal serum concentration in the foetus.

Esmolol (Compatible – maternal benefit >> embryo/fetal risk) (Cm)

Hypotension with esmolol is common (up to 50% in some trials) the potential for decreased uterine blood flow and resulting fetal hypoxia should be considered.

A case report of reduced fetal heart rate (139–144bpm to 131–137bpm) in a 22 week gestation foetus has been described during an esmolol infusion – bolus up to 2 mg/kg then 200 mcg/kg/min - No long lasting effects were see on this infant after birth.

Another case in a woman at 38 weeks gestation received 0.5 mg/kg bolus followed by a continuous infusion of 50 mcg/kg/min. Fetal heart rate before drug was 150–160bpm and increased to 170–175bpm 20 minutes after, at 24 minutes fetal heart rate fell to 70–80bpm and persisted despite stopping the infusion. After emergency caesarean section the infant’s heart rate was 60bpm but recovered to 140bpm 60 seconds of age. Umbilical vein pH was 7.09.

Symptoms of β-blockade have been seen in an infant after delivery during maternal esmolol use; including: hypotonicity, weak cry, dusky appearance and apnoea with feeding (which resolved after 48 hours).

Symptoms of β-blockade have also been described in a foetus and neonate in which a mother was treated with 25 mcg/kg/minute esmolol during labour. Fetal bradycardia (100bpm) with loss of beat-to-beat variability was described. Apgar scores of 8 and 9 at 1 and 5 minutes respectively but neonate was hypotensive, mildly hypotonic, hypoglycaemic and fed poorly. All resolved at 36 hours of age. Fentanyl was also given during labour.

Metoprolol (human data suggest risk in 2nd and 3rd trimester) (Cm*)

Metoprolol readily crosses the placenta producing approximately equal maternal and fetal blood levels.

No fetal malformations attributable to metoprolol have been reported, but experience in the 1st trimester is limited.

Several reports are described were no fetal or neonatal complications were found.

Michigan Medicaid surveillance study – 52 infants exposed in 1st trimester – 3 (5.8%) major birth defects (2 expected).

A study compared 101 hypertensive pregnant women taking metoprolol (n = 57) or combined with hydralazine (n = 44) to 97 women taking hydralazine alone. Mean gestation was 34.1 weeks (13–41 weeks) for the metoprolol group and 32.5 weeks (12–40 weeks). The metoprolol group experienced a lower rate of perinatal mortality (2% versus 8%) and a lower incidence of IUGR (11.7% versus 16.3%). No signs or symptoms of β-blockade were seen in the foetuses or neonates.

There are several conflicting studies that either do or do not show IUGR and low birthweight.

Nadolol (Human data suggest risk in 2nd and 3rd trimester) (Cm*)

Michigan Medicaid surveillance study – 71 infants exposed in 1st trimester – 1 (1.4%) major birth defects (3 expected).

One published report describes nadolol use in a single mother throughout pregnancy (20 mg/day) for hypertension (plus a diuretic). An infant was delivered at 35 weeks by C-section that was growth retarded, exhibited tachypnea (68 breaths per minute) and mild hypoglycaemia. Depressed respiration, bradycardia and hypothermia occurred at 4.5 hours of age and persisted for 72 hours. The cause of this could have been attributed to β-blockade; however maternal condition and other drugs could not be excluded as causes.

Nebivolol

No information

Oxprenolol (Human data suggest risk in 2nd and 3rd trimester) (Cm*)

Oxprenolol crosses the placenta but only reaches 25–37% the serum concentration in the neonate compared with the mother.

No fetal malformations or other fetal adverse effects attributable to oxprenolol have been reported, but experience in the 1st trimester is limited.

When compared with methyldopa in pregnancy neonates are significantly larger (3051 g versus 2654 g), however the differences between these groups disappears after 10 weeks of treatment. Other studies have shown no difference in birth and placental weights, head circumference and Apgar scores.

Pindolol (Human data suggest risk in 2nd and 3rd trimester) (Bm*)

There are conflicting studies describing reduction in uterine artery vascular resistance.

No fetal malformations have been reported, but experience in the 1st trimester is lacking.

A study comparing pindolol to atenolol and acebutolol showed higher mean birthweights in the pindolol group. It is not known if this is linked to the drug potency, maternal condition or a combination of these or other factors.

Studies comparing pindolol to atenolol (started at 33 weeks) and hydralazine (started at 25 weeks) showed no difference in gestational length, birthweight, Apgar scores, caesarean section rates or umbilical cord blood glucose levels.

Alpha-blockers

Doxazosin (No human data) (Cm)

No reports of doxazocin in human pregnancy were located.

Indoramin

No information

Prazosin (Limited human data ) (Cm)

Transfer of prazocin to the foetus is likely.

In three studies where prazocin was added to oxprenolol, atenolol or minoxidil and metoprolol for severe essential hypertension, gestational hypertension or maternal hypertension secondary to chronic nephritis no adverse effects attributable to the drugs were noted.

Another case of prazosin use with a beta-blocker for pheochromocytoma was described in the 3rd trimester. A healthy male infant was delivered by C-section.

Terazosin (No human data) (Cm)

No reports of terazosin in human pregnancy were located.

Calcium-channel blockers

Nifedipine (Human data suggest low risk) (Cm)

Michigan Medicaid surveillance study – 37 infants exposed in 1st trimester – 2 (5.4%) major birth defects (2 expected).

Use in the 2nd and 3rd trimesters has shown no affect on fetal or neonatal heart rates.

One study showed possible increases in perinatal death (130/1000), a lowered gestational age at birth, increase in C-section rates and growth retardation. However no link could be made between the above and the drug due to the severity of maternal disease and concomitant drug therapy.

Nifedipine has been shown to have a tocolytic action and has been reported (1 case) of potentiating the neuromuscular blocking action of magnesium.

Amlodipine (No human data) (Cm)

Amlodipine is likely to cross the placenta.

No reports of amlodipine in human pregnancy were located.

Diltiazem (Limited human data) (Cm)

A case of diltiazem (60 mg QDS) use in the 1st month of pregnancy (with Isosorbide dinitrate 20 mg QDS) for symptomatic myocardial ischemia which were continued throughout pregnancy resulted in no adverse fetal effects.

Michigan Medicaid surveillance study – 27 infants exposed in 1st trimester – 4 (14.8%) major birth defects (1 expected). Although small numbers there may be an association with cardiovascular defects but maternal disease, concurrent drug use and chance cannot be excluded as causes.

A multi centre cohort study of 81 infants who were exposed to calcium-channel blockers (13% diltiazem) was reported. Compared with controls no increase in the risk of major malformations was found.

When 22 women were treated with diltiazem versus 23 women with nifedipine as a tocolytic, no differences were found in the outcomes or maternal effects.

Felodipine (Limited human data) (Cm)

A multi centre cohort study of 81 infants who were exposed to calcium-channel blockers (1% felodipine) was reported. Compared with controls no increase in the risk of major malformations was found.

Another study with use started before or during the 1st trimester for chronic essential hypertension in 3 women showed growth restriction in all 3 infants; however maternal disease and concomitant use of other antihypertensives (beta-blockers) were assigned as the cause.

Isradipine (Limited human data) (Cm)

Isradipine crosses the placenta

27 women in the 3rd trimester with pregnancy-induced hypertension were treated with 2.5 mg BD for 4 days then 5 mg BD showed significant reduction in MAP without significant change in the uteroplacental or fetal blood flow. No adverse fetal effects were observed.

Another study in 14 women with either essential hypertension (n = 3) or pre-eclampsia (n = 11) at 5 mg OD for 4 days then 5 mg BD in the 3rd trimester showed no adverse effects in the newborn except one who’s birthweight was below the 10th percentile and 2 who had transient hyperbilirubinaemia.

Several other studies are reported that show no fetal adverse effects.

Lacidipine

No information

Lercanidipine

No information

Verapamil (Compatible) (Cm)

Verapamil crosses the placenta.

There are several reports of verapamil use in the treatment of in utero supraventricular tachycardia (in conjunction with other agents) with no adverse fetal effects.

The use as antihypertensive and tocolytic in pregnancy has also been described without adverse fetal effects.

Michigan Medicaid surveillance study – 76 infants exposed in 1st trimester – 1 (1.3%) major birth defects (3 expected). This does not support an association between verapamil and congenital abnormalities.

A multi centre cohort study of 81 infants who were exposed to calcium-channel blockers (41% verapamil) was reported. Compared with controls no increase in the risk of major malformations was found.

The manufacturer also reports use in the 1st trimester without adverse fetal adverse effects, however hypotension has been reported with rapid IV boluses and may potentially cause reduced placental blood flow and fetal hypoxia.

Diuretics

Thiazide

Bendroflumethiazide (Limited human data) (Cm*) (D – for gestational hypertension)

See chlorothiazide

A study reported 1011 women who received 5 mg bendroflumethiazide a day from 30 weeks gestation until delivery (to prevent pre-eclampsia and eclampsia). No fetal adverse effects were noted.

Maternal hypovolaemia and diuretic use in pregnancy may be of concern.

Chlorothiazide (compatible) (Cm*)

Crosses the placenta – fetal levels are equal to that of the mother.

Published reports indicate that thiazides are infrequently used in the 1st trimester

Collaborative Perinatal Project (CPP) – 233 infants exposure in 1st trimester to thiazides (all mothers had cardiovascular disorders which may affect the results) – Increased risk of malformations for chlortalidone (20) and miscellaneous thiazides (35 – excluding chlorothiazide).

Michigan Medicaid surveillance study – 20, 48 and 567 infants exposed in 1st trimester to chlorothiazide, chlorthalidone and hydrochlorothiazide respectively:

Chlorothiazide - 2 (10%) major birth defects (1 expected)

Chlorthalidone - 2 (4.2%) major birth defects (2 expected)

Chlorothiazide - 24 (4.2%) major birth defects (22 expected)

Although the numbers are small it is not felt that these diuretics are linked to congenital malformations

When used in the 2nd and 3rd trimester adverse fetal effects are rare.

In 4035 women treated for oedema (drug not stated/hypertensive women excluded) significantly higher rates were found of: IOL, stimulation of labour, uterine inertia, meconium staining and perinatal mortality (not significant).

There are conflicting reports of neonatal thrombocytopenia

There are also concerns over possible: decrease in placental perfusion, neonatal hypoglycaemia, neonatal hypovolaemia and maternal/fetal serum electrolyte imbalances.

Chlortalidone

No information

Cyclopenthiazide

See chlorothiazide

Indapamide (Limited human data) (Bm*)

Michigan Medicaid surveillance study – 46 infants exposed in 1st trimester to indapamide – 3 (6.5%) major birth defects (2 expected).

Metolazone (Limited human data – Probably compatible) (Bm*)

See chlorothiazide

Xipamide

No information

Loop

Furosemide (Human data suggest low risk) (Cm*)

Crosses the placenta

Michigan Medicaid surveillance study – 350 infants exposed in 1st trimester – 18 (5.1%) major birth defects (15 expected). May support an association with furosemide and congenital defects (hypospadias), but other factors (mother’s disease, concurrent drug use and chance) may be involved.

Furosemide has been used in the 2nd and 3rd trimesters for oedema, hypotension and toxaemia without fetal or newborn adverse effects.

Vasodilator drugs

Hydralazine (Human data suggest risk in 3rd trimester) (Cm)

Hydralazine crosses the placenta leading to concentrations equal or greater than that of the mother in the neonate.

No reports linking hydralazine with congenital defects were located.

Collaborative Perinatal Project (CPP) – 8 infant exposures in 1st trimester/136 infant exposures throughout pregnancy – no abnormalities found with 1st trimester use. 8 (5.8%) infants had defects when used in the 2nd and 3rd trimesters which is higher than expected, however the severity of the maternal condition may be responsible for this.

Michigan Medicaid surveillance study – 40 infants exposed in 1st trimester – 1 (2.5%) major birth defects (2 expected).

Neonatal thrombocytopenia and bleeding secondary to hydralazine ingestion throughout the 3rd trimester have been reported in 3 infants. This however may have been due to maternal hypertension.

Bosentan (No human data) (Xm)

Bosentan and its metabolites are expected to cross the placenta

No reports in human pregnancy were located.

Diazoxide (Human data suggest risk in 3rd trimester) (Cm)

Diazoxide readily crossed the placenta reaching fetal levels similar to that of the mother.

In one study the decrease in maternal blood pressure was sufficient to produce a state of clinical shock and endanger placental perfusion. Transient fetal bradycardia has been reported in other studies following a rapid, marked decrease in maternal blood pressure. Fatal maternal hypotension has also been reported.

Rather than rapid IV boluses, small IV boluses at frequent intervals have successfully controlled maternal blood pressure without producing fetal toxicity.

Diazoxide is a potent relaxant of smooth muscle and may inhibit uterine contractions if given during labour (dose dependant effect); augmentation of labour with oxytocin may be required.

Neonatal hyperglycaemia has been reported after IV diazoxide use in the mother and can persist for 24–72 hours post delivery.

There are conflicting reports of alopecia, hypertrichosis and decreased ossification of the wrist in neonates exposed to diazoxide 19–69 days before delivery.

Copyright © 2011, Royal College of Obstetricians and Gynaecologists.

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Cover of Hypertension in Pregnancy
Hypertension in Pregnancy: The Management of Hypertensive Disorders During Pregnancy.
NICE Clinical Guidelines, No. 107.
National Collaborating Centre for Women's and Children's Health (UK).
London: RCOG Press; 2010 Aug.

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