Arterial hypertension and pregnancy

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Different kinds of arterial hypertension should be distinguished from one another as follows (for pulmonary hypertension, see section 2.8.14):

m Chronic hypertension (with or without proteinuria) which was diagnosed before, during or after pregnancy

■ Pre eclampsia, eclampsia that is proteinuria (>300mg/d), and newly diagnosed hypertension (edemas are no longer necessary symptoms)

■ Pre-eclampsia in a pregnant woman with pre-existing chronic hypertension, which occurs in 20-25 percent of all pregnancies with chronic hypertension

■ Pregnancy-induced hypertension (PIH) that occurs beyond 20 weeks without proteinuria and returns to normal 12 weeks after delivery; approximately half of these pregnant women develop pre-eclampsia.

Blood pressure of 140/90 mmHg is the threshold for hypertension in pregnancy. Treatment should only be initiated at levels higher than 160/110 mmHg, because below that there are no advantages in treatment for the outcome of mother and child. If a patient has no proteinuria, a blood pressure at threshold level, normal ECG and echocardiography, and no abnormalities at the examination, the outcome is usually favorable.

Complications of severe hypertension in pregnant women may include intracerebral bleeding, cardiac problems, and placental dysfunction. Placental detachment, prematurity, intrauterine growth restriction, and perinatal death are problems that may occur due to placental dysfunction. The risk for mother and child in any case of pre-eclampsia is high. It has been suggested that there is a deranged interaction between invasion of the trophoblast and dccidua, followed by insufficient dilatation of the uterine spiral arteries, which leads to placental hypoperfusion. There is no other causal therapy in this case, except delivery. A conservative option for therapy is antihypertensive therapy at diastolic values beyond 110 mmHg, plus 100 mg per day acetylsalicylic acid, if there is to be strict control of this pregnancy. The HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count) can be a life-threatening condition for mother and fetus.

A prospective study with almost 2000 pregnant women confirmed that the risk is strikingly higher in pre-eclampsia compared with other forms of hypertension {Ray 2001). A meta-analysis concerning antihypertensive drugs and the possible changes of fetal and neonatal heart rate stated that the data concerning nifedipine, hydalazine, labetalol, and methyldopa are insufficient for any conclusion to be drawn (Waterman 2004).

The drugs of choice for the treatment of hypertension in pregnancy are different from those used to treat non-pregnant patients, but despite many studies and experiences there are still no uniform recommendations for pregnant women. Controlled systematic large studies are rare. Drugs that have been on the market a long time tend to be used in preference to newer drugs because of lack of safety data for the fetus in the latter group.

In cases of chronic hypertension, the drug of first choice is methyldopa, followed by metoprolol, dihydralazine/hydralazine, and nifedipine.

If a prcgnancy is complicated by any form of pre-eclampsia, dihy-dralazine, nifedipine and urapidil show good results, i-blockers are also acceptable, of which labetalol is the best proven one.

Hypertensive diseases in pregnancy require good control and diagnostic procedures in order to decide on the optimum therapy.

2.8.2 a-methyldopa

Pharmacology

Methyldopa is well-absorbed orally, and has a half-life of about 2 hours. The mechanism of action in the CNS is not known. It is activated by decarboxylation to (\-methyl-noradrenaline, a false transmitter with a much weaker action than noradrenaline. Methyldopa is well suited for long-term use because it does not normally alter cardiac function. Cardiac minute output particularly, and blood How to the kidney or uterus, is not changed, but peripheral total resistance is lowered. According to one study, tvmethyldopa had no influence on the vascular resistance of the umbilical artery (Houlihan 2004). Giincng (2002) analyzed the effect of a-methyldopa in 24 pregnant women with pre-eclampsia using Doppler sonography: The vascular resistance in the uterine artery was reduced, but not in the umbilical artery or in the fetal middle cerebral artery.

Methyldopa is well-absorbed both by the intravenous (i.v.) and oral routes. The onset of action is delayed for 1-2 hours after i.v. administration and 4-6 hours after oral administration. It is effective for 6-12 hours. Methyldopa crosscs the placenta, producing fetal serum concentrations similar to those in the mother (Jones 1978).

Toxicology

In a group of 242 children exposed in the first trimester, neither the frequency nor the type of birth defect was remarkable (Rosa, cited in Briggs 2005).

Concerns have been raised regarding the effect of methyldopa on brain development due to its effects on cerebral monoamine metabolism. Results of a 7.5-year follow-up study of children born to hypertensive women who had participated in a trial of methyldopa treatment during pregnancy produced inconclusive results (Ounsted 1980, ¡Vloar 1978, Redman 1976). The sons of mothers who had started treatment at 16-20 weeks' gestation were found to have smaller (about 1.3 cm) head circumferences than those born to untreated hypertensive mothers. This statistically significant difference was no longer seen at 6 and 12 months of age. There were no other differences, including in mean intelligence quotients, between the two groups at 4.5 and 7.5 years of age. A reduction in skull growth has not been confirmed by other workers, and no consistent adverse effect has been observed among children born to women treated with methyldopa late in pregnancy (Montan 1996, Pearson 1993, Fidler 1983). One recently published case report describes maternal hepatitis during pregnancy probably caused by methyldopa (Phadnis 2006). Another publication discusses the causal relationship between intrauterine long term methyldopa exposure and neonatal suppurative parotitis (Todoroki 2006), which has been seen in adults previously.

Transient tremor, irritability, and mildly decreased systolic blood pressure (4-5 mmf lg lower in the first 48 hours of life) have been reported in neonates whose mothers were treated with methyldopa cither chronically or late in pregnancy (Suiyok 1991. Bodis 1982, Whitelaw 1981). No clinically significant long-term problems have been associated with these findings. In individual cases, hepato-toxic effects were observed following the use of methyldopa during pregnancy (Smith 1995).

Recommendation, a-methyldopa is one of the preferred first-line drugs of choice for the treatment of hypertension in pregnancy.

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