Разрешенные гипотензивные препараты во время 1 триместра беременности.

Так и не пришла к единому заключению какие гипотензивные лекарственные препараты можно принимать в 1 триместре беременности при повышенном артериальном давлении.
Один доктор говорит, что Папаверин и Дибазол только можно принимать.Другой врач говорит, что эффекта от них нет и надо принимать только те препараты, которые помогают.Общее мнение среди мной опрошенных врачей - нельзя принимать ингибиторы АПФ.

Пытаюсь найти ответ на этот вопрос,но информации очень мало.

Подскажите пожалуйста или ссылки , или выскажите свое мнение.

[Gilarov]

Правда ваша-нельзя, они влияют на развитие почек плода. Можно метилдофу, нифедипин (коринфар) и, по-моему, бета-блокаторы.

[Straus]

Нельзя: ИППФ, диазоксид (гиперстат), резерпин, спиронолактон, тиазидные диуретики. резерпин (т.е. адельфан и аналоги). А также варфарин и ряд НПВС (индометацин).
Можно: аспирин (до начала родов), бетта-блоки, верапамил, гадралазин (апрессин), метилдофа (клофеллин), нифедипин, фуросемид. А также гепарины и дигоксин.

[Alexei]

Для простоты использования лекаственные препараты целесообразно разделять на следующие категории в отношении использования при беременности:

Категория А: контролируемые исследования не выявили риска для плода в первом триместре (и нет доказательств риска в последние триместры) и возможность вредного воздействия на плод маловероятна (the possibility of fetal harm appears remote);
Категория В: исследования на животных не выявили риска для плода, но отсутствуют контролируемые исследования на беременных женщинах, или исследования на животных выявили побочные эффекты (иные чем снижение фертильности), которые не были подтверждены в контролируемых исследованиях на женщинах в первом триместре (и нет доказательств риска в последних триметрах);
Категория С: исследования на животных показывают неблагоприятное влияние на плод (тератогенное или эмбриоцидное или другое), но отсутствуют контролируемые исследования на женщинах или исследования на женщинах и животных недоступны. Препараты должны назначаться только если потенциальная польза превышает потенциальный риск для плода;
Категория Д: имеются данные о вредном влиянии препарата на плод, но польза от использования допускает применение препарата у беременных несмотря на риск (напр., жизнеугрожающие ситуации или серьезные заболевания, при которых более безопасные лекарства не могут быть использованы или неэффективны);
Категория Х: исследования на животных или людях демонстрируют вредное воздействие на плод или доказательства вредного воздействия основаны на опыте или и то, и другое, и риск использования у беременных женщин явно превышает любую возможную пользу. Препараты противопоказаны для использования у беременных или у тех кто собирается беременнеть.

Так вот, к категории А относятся: доксиламин, ниацин, растворы электролитов, левотироксин, тироглобулин, многие витамины и вроде б все. Из гипотензивных к категории В относятся (по алф.) ацебутолол, целипролол, эпопростенол, фенолдопам, гуанадрель, гуанфацин, метилдопа, пиндолол, соталол. Нитроглицерин относится к категории В/C. Все антагонисты кальция относятся к категории С. Атенолол к категории Д. Все иАПФ к С/Д. Надо заметить, что я не нашел ни одного "сердечно-сосудистого" препарата из категории Х.

Приведу далее краткие обзоры литературы по часто используемым препаратам. Прошу извинить за английский, но а. на русского такой инфы нет; б. у меня нет времени переводить; в. кто хочет тот сам прочтет. Прошу иметь в виду, что информация не предназначена для самостоятельного использования и высталена лишь для обсуждения, и я за те или иные обстоятельства, связанные с прочтением данного топика ответственности не несу.

Вот по препаратам уважаемого Евгения - все они относятся к категории С, за исключением фуросемида (Risk Factor D if used in pregnancy-induced hypertension). Его можно использовать только при отеке легких, тяжелой гипертензии и застойной сердечной недостаточности. Для лечения хронической гипертонии у беременных его использовать нецелесообразно.

[Alexei]

Name: NIFEDIPINE
Class: Calcium Channel Blocker
Risk Factor: Cm

Fetal Risk Summary
The use of nifedipine, a calcium channel-blocking agent, during pregnancy is controversial. Studies in pregnant sheep with IV infusions of the drug indicate that a progressive decrease in mean maternal arterial blood pressure occurs without a significant alteration of uterine vascular resistance (1). The hypotensive effect of nifedipine resulted in a decrease in uterine blood flow and fetal arterial oxygen content. Other investigators have reported similar results in animals with other calcium channel blockers (2). Although these studies indicated the potential problems with nifedipine, the investigators cautioned that their findings were preliminary and needed to be confirmed in humans (1,3).
Reproduction studies with nifedipine have been conducted in mice, rats, and rabbits (4). The drug was teratogenic (digital anomalies similar to those reported with phenytoin) in rats and rabbits, an effect that might have resulted from compromised uterine blood flow. Other toxicities were noted in the embryos and fetuses of mice, rats, and rabbits at doses 3.5 to 42 times the maximum recommended human dose (MRHD) on a weight basis, or doses higher or lower than the MRHD on a mg/m2 basis (4). These toxicities included stunted fetuses (mice, rats, rabbits), rib deformities (mice), cleft palate (mice), embryo and fetal deaths (mice, rats, rabbits), and prolonged pregnancy and decreased neonatal survival (rats; not evaluated in other species) (4). Small placentas and underdeveloped chorionic villi were observed in monkeys at doses equivalent to or less than the MRHD on a mg/m2 basis (4).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 37 newborns had been exposed to nifedipine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Two (5.4%) major birth defects were observed (two expected), one of which was a cardiovascular defect (0.5 expected). No anomalies were observed in five other categories of defects (oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.
A human study was reported in 1988 in which nine hypertensive pregnant women in the 3rd trimester were treated with 5 mg of nifedipine sublingually and compared with nine hypertensive women treated with placebo (5). The women were randomly assigned to the two groups but treatment was not blinded. Both maternal arterial blood pressure and uterine artery perfusion pressure were significantly lowered by nifedipine, but no apparent reduction in uteroplacental blood flow was detected. The investigators interpreted their findings as suggestive of a relative uterine vasodilation and a relative decrease in uterine vascular resistance that was proportional to the decrease in blood pressure.
Nifedipine has been used during the 2nd and 3rd trimesters for the treatment of severe hypertension (6). No fetal heart rate changes were observed after reduction of maternal blood pressure, nor were other adverse effects noted in the fetus or newborn. In a 1987 study, 23 women with severe hypertension of various causes (4 gestational, 17 essential, 1 renal, and 1 systemic lupus erythematosus) who either failed to respond to first-line therapy (atenolol, methyldopa, or hydralazine) had slow-release nifedipine, 40–120 mg/day, added to their regimens (N=22) or nifedipine, 40 mg/day, was used as initial therapy (N=1) (7). Good blood pressure control was obtained in 20 women. The mean duration of therapy was 8.75 weeks (range 1–24 weeks). There were three perinatal deaths (rate 130/1000), but none could be attributed to drug therapy. The mean gestational age at delivery was 35 weeks (range 29–39 weeks), and 15 (71%) of the 21 liveborn infants were delivered by cesarean section. A high percentage of the 22 infants with accessible data were growth retarded, 9 (41%) had birth weights at or below the 3rd percentile, and 20 (91%) were at or below the 10th percentile for body weight. The investigators could not determine whether this outcome was caused by the severe maternal disease, drug therapy, or a combination of both (7).
Nifedipine has been used as a tocolytic agent. An in vitro study using pregnant human myometrium found that nifedipine caused a dose-related decrease in contraction strength and lengthened the period of contraction in a non–dose-related manner (8). In three studies totaling 31 women, nifedipine was used for this purpose (9,10 and 11) . In one patient, nifedipine, 20 mg 3 times daily combined with terbutaline, was given for a total of 55 days (10). A study involving 60 women in presumed early labor was reported in 1986 (11). Women were included in this open trial if they had a singleton pregnancy and intact membranes, were between 20 and 35 weeks' gestation, and were contracting at least once every 10 minutes, and if their cervix was less than 4 cm dilated. Included among the various exclusions were a history of midtrimester abortion or previous preterm delivery. The women were equally divided into three groups: nifedipine, ritodrine, and no treatment. Nifedipine dosage was 30 mg orally followed by 20 mg every 8 hours for 3 days. Ritodrine was initially administered as a standard IV infusion followed by 48 hours of oral therapy. The days from presentation to delivery in the nifedipine, ritodrine, and no treatment groups were 36.3, 25.1, and 19.3 days (p<0.001 nifedipine compared with the other two groups), respectively (11). No complications of the therapy were found in any of the infants from the three studies. Two of the studies (9,10) conducted follow-up examinations of the infants at 5–12 months of age and all were alive and well.
Two apparently clinically significant drug interactions when nifedipine and magnesium were used concurrently have been reported (12,13). A woman, at 32 weeks' gestation in premature labor, was treated with 60 mg of nifedipine orally for 3 hours followed by 20 mg every 8 hours. Uterine contractions returned 12 hours later and IV magnesium sulfate was started followed by the onset of pronounced muscle weakness after 500 mg had been administered. Her symptoms consisted of jerky movements of the extremities, difficulty in swallowing, paradoxical respirations, and an inability to raise her head from the pillow (12). The muscle weakness resolved 25 minutes after the magnesium was stopped. The effects were attributed to nifedipine potentiation of the neuromuscular blocking action of magnesium. In a second report, two women were hospitalized for hypertension at 30 and 32 weeks' gestation (13). In both cases, oral methyldopa 2 g and IV magnesium sulfate 20 g daily were ineffective in lowering the mother's blood pressure. Oral nifedipine 10 mg was given, and a marked hypotensive response occurred 45 minutes later. The blood pressures before nifedipine were 150/110 and 140/105 mm Hg, respectively, then decreased to 80/50 and 90/60 mm Hg, respectively, after administration of the calcium channel blocker. The blood pressures returned to the previous levels 25–30 minutes later. Both infants were delivered following the hypotensive episodes, but only one survived.
The pharmacokinetics of nifedipine in pregnant women have been studied (14).
A prospective, multicenter cohort study of 78 women (81 outcomes; 3 sets of twins) who had 1st-trimester exposure to calcium channel blockers, including 44% to nifedipine, was reported in 1996 (15). Compared with controls, no increase in the risk of major congenital malformations was found.
In summary, the experience with nifedipine in human pregnancy is limited, although the agent has been used for tocolysis and as an antihypertensive agent in pregnant women. The agent does not appear to be a major human teratogen based on the results of one study. Severe adverse reactions, however, have occurred when the drug was combined with IV magnesium sulfate. Moreover, IV nifedipine in pregnant rhesus monkeys has been associated with fetal hypoxemia and acidosis (16). As a consequence of this and other animal studies, nifedipine should probably be reserved for women with severe hypertension who are unresponsive to standard therapy or in controlled trials until this toxicity has been studied more carefully.
Breast Feeding Summary
Nifedipine is excreted into human breast milk (17). A woman with persistent hypertension after premature delivery at 26 weeks' gestation was treated with nifedipine 30 mg every 8 hours for 48 hours, then 20 mg every 8 hours for 48 hours, then 10 mg every 8 hours for 36 hours. Concentrations of the drug in milk were related to dosage and the time interval between the dose and milk collection. Peak concentrations and time of occurrence were 53.35 ng/mL 30 minutes after 30 mg, 16.35 ng/mL 1 hour after 20 mg, and 12.89 ng/mL 30 minutes after 10 mg. The estimated milk half-lives after the three doses were 2.4 hours (30 mg), 3.1 hours (20 mg), and 1.4 hours (10 mg). In comparison with controls, nifedipine had no effect on milk composition. The authors concluded that these amounts, representing less than 5% of a therapeutic dose, posed little risk to a nursing infant. If desired, delaying breast feeding by 3–4 hours after a dose would significantly decrease the amount of drug ingested by the infant (17). The American Academy of Pediatrics considers nifedipine to be compatible with breast feeding (18).

Refers restr. in forum vers.

[Alexei]

Name: ATENOLOL
Class: Sympatholytic (Antihypertensive)
Risk Factor: Dm

Fetal Risk Summary
Atenolol is a cardioselective b-adrenergic blocking agent used for the treatment of hypertension. The drug did not cause structural anomalies in pregnant rats and rabbits, but a dose-related increase in embryo and fetal resorptions in rats was observed at doses up to and greater than 25 times the maximum recommended human dose (MRHD) (1). This effect was not seen in rabbits at doses up to 12.5 times the MRHD.
Atenolol readily crosses the placenta to the fetus, producing steady state fetal levels that are approximately equal to those in the maternal serum (2,3,4,5,6,7,8 and 9). Atenolol transfer was one third to one fourth the transfer of the more lipid-soluble b-blockers propranolol, timolol, and labetalol in an in vitro experiment using perfused human placentas (10). In 11 pregnant patients treated with 100 mg/day, the serum half-life (8.1 hours) and the 24-hour urinary excretion (52 mg) were similar to those in nonpregnant women (7).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 105 newborns had been exposed to atenolol during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 12 (11.4%) major birth defects were observed (4 expected). Specific data were available for six defect categories, including (observed/expected) 3/1 cardiovascular defects, 1/0 oral clefts, 0/0 spina bifida, 0/0 polydactyly, 1/0 limb reduction defects, and 4/0 hypospadias. Only with the latter defect is there a suggestion of a possible association, but other factors, including the mother's disease, concurrent drug use, and chance, may be involved.
A 1997 abstract (11) and later full report (12) described a case of retroperitoneal fibromatosis in a fetus exposed in utero to atenolol from the 2nd month of gestation through delivery at 37 weeks. The obese (134 kg at term), 25-year-old mother, in her third pregnancy, was treated for hypertension with 100 mg atenolol daily until giving birth to the 3790-g male infant. Other drug therapy included magnesium supplements and occasional metoclopramide. The mother had no familial history of cancer and both of her other children were normal. Treatment of the tumor with chemotherapy during the first 3 months of life was successful, but a severe scoliosis was present in the child at 4 years of age. The authors attributed the rare tumor to the drug because, among other reasons, the location of the mass was similar to fibroses reported in adults exposed to atenolol (11,12).
Use of atenolol for the treatment of hypertension in pregnant women has been described by several investigators (6,9,13,14,15,16,17,18, 19,20,21 and 22). No fetal malformations attributable to atenolol were reported in these trials, but treatment with atenolol in most cases did not occur during the 1st trimester. Intrauterine growth retardation and persistent b-blockade in the newborn have been observed after atenolol exposure. In one study in which therapy for mild essential hypertension was begun at a mean gestational age of 15.9 weeks, the newborns in the treated group (N=15) had a significantly lower birth weight (2620 g vs. 3530 g) than untreated controls (N=14) (20). Moreover, in the treated group, 5 of the newborns had weights below the 5th percentile and 10 were below the 10th percentile, compared with 1 newborn below the 25th percentile in controls.
A 1992 report described the outcomes of 29 women with pregnancy-induced hypertension in the 3rd trimester (23). The women were randomized to receive either the cardioselective b-blocker, atenolol (N=13), or the nonselective b-blocker, pindolol (N=16). The decrease in mean maternal arterial blood pressure in the two groups did not differ statistically, 9 and 7.8 mm Hg. In comparing before and after therapy, several significant changes were measured in fetal hemodynamics with atenolol but, except for fetal heart rate, no significant changes were measured with pindolol. The atenolol-induced changes included a decrease in fetal heart rate, increases in the pulsatility indexes (and thus, the peripheral vascular resistance) of the fetal thoracic descending aorta, the abdominal aorta, and the umbilical artery, and a decrease in the umbilical venous blood flow (23). Although no difference was observed in the birth weights in the two groups, the placental weight in atenolol-treated pregnancies was significantly less, 529 g vs. 653 g, respectively.
Interestingly, a 1987 study had used Doppler ultrasound to evaluate maternal and fetal circulation during atenolol therapy in 14 women with pregnancy-induced hypertension at a mean gestational age of 35 weeks (range 33–38 weeks) (24). The results suggested that peripheral vascular resistance was increased on both the maternal and fetal sides of the placenta. However, the study design and techniques used have been criticized based on concerns for reproducibility, including day-to-day variability in Doppler measurements, the lack of controls in the study, and the uncertainty of the clinical significance of velocity waveform measurements (25).
A 1997 report described an open, prospective survey on the use of antihypertensives in 398 consecutive pregnant women who attended an antenatal hypertension clinic between 1980 and 1995 (26). Atenolol was used by 76 of the women and compared to those using calcium channel blockers (N=22), diuretics (N=26), methyldopa (N=17), other b-blockers (N=12), or no drug therapy (N=235). The newborns exposed in utero to atenolol had the lowest mean birth weight (p<0.001), and, along with those who received calcium channel blockers, the lowest mean ponderal index and mean placental weight.
In a group of pregnant women with symptomatic mitral valve stenosis, 11 were treated with atenolol and 14 with propranolol (27). The mean birth weight of the 25 infants was 2.8 kg (range 2.1–3.5 kg). Atenolol, 25 mg twice daily, was administered from 18 weeks' gestation to term in a normotensive woman who had suffered a myocardial infarction (28). She delivered a 2720-g infant with normal Apgar scores and blood gases.
In a nonrandomized study comparing atenolol with two other b-blockers for the treatment of hypertension during pregnancy, the mean birth weight of atenolol-exposed babies was markedly lower than infants exposed in utero to either acebutolol or pindolol (2745 g vs. 3160 g vs. 3375 g) (18,29). A similar study comparing atenolol with labetalol found a significant difference in the birth weights of the two groups, 2750 g vs. 3280 g (p<0.001) (5). No difference was found in the birth weights of atenolol- vs. placebo-exposed infants (2961 g vs. 3017 g) in a randomized, double blind investigation of 120 pregnant women with mild to moderate hypertension (16). Additionally, in a prospective randomized study comparing 24 atenolol-treated women with 27 pindolol-treated women, no differences between the groups were found in gestational length, birth weight, Apgar scores, rates of cesarean section, or umbilical cord blood glucose levels (30). Treatment in both groups started at about 33 weeksi gestation. Intrauterine fetal deaths have been observed in women with severe hypertension treated with atenolol, but this has also occurred with other b-blockers and in hypertensive women not treated with drugs (5,16,31).
In eight mothers treated with atenolol or pindolol, a decrease in the basal fetal heart rate was noted only in atenolol-exposed fetuses (32). Before and during treatment, fetal heart rates in the atenolol patients were 136 and 120 beats/minute, respectively, whereas the rates for the pindolol group were 128 and 132 beats/minute, respectively. In 60 patients treated with atenolol for pregnancy-induced hypertension, no effect was observed on fetal heart rate pattern in response to uterine contractions (33). Accelerations, variables, and late decelerations were all easily distinguishable.
Persistent b-blockade was observed in a newborn whose mother was treated with atenolol, 100 mg/day, for hypertension (3). At 15 hours of age, the otherwise normal infant developed bradycardia at rest and when crying, and hypotension. Serum atenolol was 0.24 µg/ml. Urinary excretion of the drug during the first 7 days ranged from 0.085–0.196 µg/mL. In another study, 39% (18 of 46) of the newborns exposed to atenolol developed bradycardia compared to only 10% (4 of 39) of placebo-exposed newborns (p<0.01) (16). None of the infants required treatment for the lowered heart rate.
In summary, exposure to atenolol in utero may result in intrauterine growth retardation. The reduced fetal growth appears to be related to increased vascular resistance in both the mother and the fetus and is a function of the length of drug exposure. Treatment starting early in pregnancy, such as in the 2nd trimester, is associated with the greatest decrease in fetal and placental weights. In comparison, when therapy is initiated in the 3rd trimester, only placental weight appears to be significantly affected. Although growth retardation is a serious concern, the benefits of maternal therapy with b-blockers may, in some cases, outweigh the risks to the fetus and must be judged on a case-by-case basis. Infant behavior is apparently not affected by atenolol exposure as no differences were noted in the development at 1 year of age of offspring from mothers treated during the 3rd trimester for mild to moderate pregnancy-induced hypertension with either bed rest alone or rest combined with atenolol (34). The mean duration of therapy in the atenolol-treated patients was 5 weeks. Because only one case has been reported, an association between atenolol and fetal retroperitoneal fibromatosis requires confirmation.

[Alexei]

Newborns exposed to atenolol near delivery should be closely observed during the first 24–48 hours for signs and symptoms of b-blockade. Although the results of the study cited above are reassuring, the long-term effects of prolonged in utero exposure to this class of drugs have not been studied but warrant evaluation.
Breast Feeding Summary
Atenolol is excreted into breast milk (4,7,9,35,36,37,38 and 39). The drug is a weak base, and accumulation in the milk occurs with concentrations significantly greater than corresponding plasma levels (4,35,36,37 and 38). Peak milk concentrations after single (50 mg) and continuous dosing (25–100 mg/day) regimens were 3.6 and 2.9 times greater than simultaneous plasma levels (37). Atenolol has been found in the serum and urine of breast-fed infants in some studies (4,7,35). Other studies have been unable to detect the drug in the infant serum (test limit 10 ng/mL) (36,37).
Symptoms consistent with b-adrenergic blockade were observed in a breast-fed, 5-day-old, full-term female infant, including cyanosis, hypothermia (35.5°C rectal), and bradycardia (80 beats/minute) (39). Blood pressure was 80/40 mm Hg. Except for these findings, physical examination was normal and bacterial cultures from various sites were negative. The mother had been treated orally with atenolol, 50 mg every 12 hours, for postpartum hypertension. Breast feeding was stopped 3 days after onset of the symptoms and 6 hours later the infantis symptoms had resolved. A milk sample, collected 10 days postpartum and 1.5 hours after a 50 mg dose, contained 469 ng/ml of atenolol. Concentrations in the infant's serum, 48 and 72 hours after breast feeding, were 2010 ng/mL and 140 ng/mL, respectively. The calculated serum half-life in the infant was 6.4 hours. By extrapolation, the minimum daily dose absorbed by the infant was estimated to be 8.97 mg, approximately 9% of the motheris daily dose (39). (These calculations have been questioned and defended [40,41].)
In a 1994 reference, the American Academy of Pediatrics classified atenolol as compatible with breast feeding, although the above adverse reaction report was not cited (42). This was called to their attention in two 1995 letters to the editor (43,44), and elicited a response that atenolol would be reclassified in a later revision (45).
Except for the single case cited above, adverse reactions in other infants have not been reported. However, because milk accumulation occurs with atenolol, nursing infants must be closely monitored for bradycardia and other signs and symptoms of b-blockade. Moreover, one author has recommended that water-soluble, low-protein-bound, renally excreted b-blockers, such as atenolol, should not be used during lactation (44). Because of the availability of safer alternatives (e.g., propranolol), this seems to be good advice. Long-term effects on infants exposed to b-blockers from breast milk have not been studied but warrant evaluation.

refers rest