Antiepileptic drugs during pregnancy: pharmacokinetics and transplacental transfer

Epilepsy represents the most common maternal neurological disorder requiring continuous treatment during pregnancy. Maintaining optimum seizure control is an important objective in pregnancy, and the majority of women with epilepsy will need to continue antiepileptic drugs (AEDs). AEDs are frequently used to treat several other conditions, such as headaches and mood disorders. They have been associated with an increased risk of congenital malformations, minor anomalies, congenital syndrome and development disorders. This risk seems to be higher among women using polypharmacy and valproic acid. Neural tube defects are associated with valproic acid and carbamazepine exposure. New AEDs seem to have a less teratogenic effect, but human experience is still limited. The purpose of this review is to provide an update on AED exposure in pregnancy, focusing on pharmacokinetics and transplacental transport.     

Antidepressant drugs during pregnancy and lactation

As depression is common in women during their childbearing years, many women will experience depression during pregnancy or postpartum. This paper reviews the latest scientific knowledge on the effects of antidepressant drugs during pregnancy and lactation. Information is presented on physical and behavioural teratogenic risks, impaired intrauterine growth, and neonatal toxicity, withdrawal, and death. Risk : benefit considerations, such as the effects of antidepressant drugs on the mother and foetus compared with the effects of untreated severe depression, are discussed to facilitate clinical decision-making. Recent studies of the safety of antidepressant drugs during pregnancy and lactation are predominantly reassuring, and should guide and improve the care of depressed childbearing women and their infants.     

Safety of non-steroidal anti-inflammatory drugs during pregnancy and lactation

As inhibitors of cyclooxygenase NSAIDs given during pregnancy have the potential to cause adverse maternal and fetal effects. Maternal effects include prolongation of pregnancy and labour, whereas constriction of the ductus arteriosus, renal dysfunction and haemostatic abnormalities can occur in the fetus and neonate. As weak acids, NSAIDs are excreted in small amounts into human breast milk with little risk for adverse effects in the suckling infant.     

Migraine therapy during pregnancy and lactation

Importance of the field: Migraine affects about 25% of women during childbearing years but few data are available about the risks connected with most antimigraine drugs during pregnancy.

Areas covered in this review: In this report, we review the available data, mainly obtained from published studies, toxicology databases and clinical guidelines, on migraine treatment during pregnancy and lactation.

What the reader will gain: The following drugs should be preferred for the treatment of acute migraine attacks in pregnant women: paracetamol, NSAIDs and sumatriptan. Migraine prophylaxis should be undertaken when patients experience at least three prolonged severe attacks a month that are particularly incapacitating or unresponsive to symptomatic therapy and likely to result in complications. Non-pharmacologic approaches should be preferred, but if they are not effective, preventive treatment should include low doses of β-blockers and amitriptyline.

Take home message: Migraine treatment is often necessary because maternal and fetal risks related to acute attacks may be more harmful than the therapy itself, especially if they are frequent, severe and associated with nausea, anorexia, vomiting, hypotension or dehydration. If non-pharmacologic treatments do not alleviate migraine symptoms, only few drugs can be used during pregnancy and lactation.     

非甾体抗炎药在妊娠期与哺乳期应用的安全性评价

为妊娠妇女及乳母处方非甾体抗炎药时,应谨慎权衡利弊.非甾体抗炎药作为前列腺素合成抑制剂可致凝血功能异常、子宫动脉导管收缩并延长产程.水杨酸盐对动物可致畸,但沿缺乏使人致畸的依据.孕妇使用阿司匹林可致分娩时及产前、产后出血,并致新生儿患出血性疾病.一般认为吲哚美辛对胎儿的循环有影响并能致畸,但也尚有争议.而蔡普生对胎儿的循环、凝血以及肾脏功能均有影响.布洛芬、保泰松也可引起先天性缺损.因此,该类药物一般应避免使用于妊娠妇女.从物理、化学性质,药动学方面看,虽然大部分非甾体抗炎药在乳汁中的排泌率低,对乳儿的影响不大,但吲哚美辛由于半衰期长、代谢物仍有活性,乳母阿司匹林用量的21%又可通过乳汁被乳儿摄入,水杨酸盐应为乳母的禁忌药物.     

The effects of lithium, valproic acid, and carbamazepine during pregnancy and lactation

The chronic, complex, and episodic course of bipolar mood disorder presents a particularly formidable challenge to the clinician making a treatment plan for the onset or recurrence of the illness during pregnancy and lactation. Women treated with anti-manic drugs who become pregnant are commonly considered to be at high risk for fetal complications during the pregnancy or during lactation. The risks of antimanic drug use during pregnancy include teratogenic effects, direct neonatal toxicity, and the potential for longer-term neurobehavioral sequela. The use of medications during pregnancy and lactation requires critical attention to the timing of exposure, dosage, duration of use, and fetal susceptibility. The postnatal period is a time of increased onset and relapse of mental illness. No antimanic drug can be proven completely safe. Prescribing antimanic medications with a long safety record, avoiding exposure in the first trimester; avoiding multidrug regimens, and prescribing the lowest dose for the shortest duration will minimize the fetal risk. This review considers treatment with lithium, valproic acid, and carbamazepine. It assesses the risk to the fetus, the perinatal risks for the infant, the risks associated with treatment during the puerperium and breast-feeding, and the risks to the later development of the child.     

Reproductive effects of deltamethrin on male offspring of rats exposed during pregnancy and lactation

The effects of low doses of deltamethrin administered to female rats on the reproductive system of male offspring were examined. The dams (n=10-12/group) were treated daily by oral gavage with 0, 1.0, 2.0, and 4.0 mg deltamethrin/kg from day 1 of pregnancy to day 21 of lactation. Maternal and reproductive outcome data and male sexual development landmarks were assessed. Fertility, sexual behavior, and a large number of reproductive endpoints, such as organ weights, sperm evaluations, testosterone concentration, and testicular histology were examined on adult male offsprings. No signs of maternal toxicity were detected at the dose levels tested. Significantly adverse effects were only seen on testicular and epididymal absolute weights and the diameter of seminiferous tubules in the group treated with the highest dose of deltamethrin (4.0 mg/kg). The results indicate that in utero and lactational exposure to deltamethrin may induce subtle changes in reproductive behavior and physiology of male offspring rats at dose levels that do not cause maternal toxicity.     

Developmental outcome after exposure to cyclooxygenase inhibitors during pregnancy and lactation

The developmental toxicity of non-selective (ibuprofen, piroxicam, tolmetin) and selective cyclooxygenase-2 inhibitors (DFU) was evaluated in rats. Compounds were administered separately from the eighth gestational to the seventh lactational day. After spontaneous delivery, the weight, length and number of fetuses were determined. The digital radiography and double-staining were used to evaluate the skeleton morphology and mineralization in 7-day-old pups. Maternal toxicity was also assessed. Although decrease in pup weight and length was found, no teratogenic effects were revealed. Decrease in the absolute bone optical density was noted in the groups exposed to the middle and highest doses of tolmetin and ibuprofen, respectively. Increase of the absolute bone density was observed in the groups treated with the middle and the lowest doses of piroxicam, as well as in pups born after the expected day. Non-selective cyclooxygenase inhibitors (non-steroidal anti-inflammatory drugs – NSAID) affected pups growth and influenced mineralization of the lumbar vertebrae.     

Bioavailability and pharmacokinetics of phenytoin during pregnancy

Summary Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration — time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in nonpregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.     

Use of antibiotic and analgesic drugs during lactation.

During lactation, multiple situations can arise that require maternal pharmacological treatment. Because of the many health advantages of human milk to infants, breast feeding should be interrupted only when the needed drug might be harmful to the nursing child and exposure via the breast milk will be sufficient to pose a risk. Since the majority of drugs have not been shown to cause adverse effects when used during lactation, and even temporary interruption of breast feeding can be difficult for the nursing dyad, decisions regarding maternal medication use during breast feeding should be based on accurate and up-to-date information. This article reviews available data on the most commonly used antibiotics and analgesics. The use of most antibiotics is considered compatible with breast feeding. Penicillins, aminopenicillins, clavulanic acid, cephalosporins, macrolides and metronidazole at dosages at the low end of the recommended dosage range are considered appropriate for use for lactating women. Fluoroquinolones should not be administered as first-line treatment, but if they are indicated, breast feeding should not be interrupted because the risk of adverse effects is low and the risks are justified. Paracetamol (acetaminophen), low-dose aspirin (acetylsalicylic acid) [up to 100 mg/day] and short-term treatment with NSAIDs, codeine, morphine and propoxyphene are considered compatible with breast feeding. Safer alternatives should be considered instead of dipyrone, aspirin at a dosage >100 mg/day and pethidine (meperidine). In the light of the many safe alternatives for pain control, breast-feeding mothers should not be allowed to experience pain or be made to feel that they must choose between analgesia and breast feeding.     

Reproductive effects of endosulfan on male offspring of rats exposed during pregnancy and lactation.

1. The reproductive effects of endosulfan on the male offspring of rats were examined. Dams were treated orally with 0, 1.5 or 3.0 mg endosulfan/kg from day 15 of pregnancy to postnatal day (PND) 21 of lactation. The male offspring rats were investigated at PND 65 or 140, corresponding to the pubertal and adulthood stage of development. 2. The dose of 3.0 mg endosulfan/kg induced a decrease in maternal body weight during pregnancy, but litter size and mean birth weight were not affected. Similarly, the age at testis descent and preputial separation was not affected on the male offspring. 3. The daily sperm production (x10(6)) was permanently decreased in the highest dose group when investigated at puberty and at adulthood. At the lowest dose, however, the daily sperm production was significantly reduced only at puberty. 4. Histologically, the percentage of seminiferous tubules showing complete spermatogenesis was significantly decreased at puberty. This finding may explain the decrease in daily sperm production observed in the endosulfan-exposed male rats. 5. The results of this study show that low doses of endosulfan have no apparent effect on developmental landmarks or on the weight of reproductive and accessory sex organ. Daily sperm production was the most susceptible endpoint in the male offspring exposed to endosulfan during pregnancy and lactation. To further understand the reproductive effects of endosulfan on male rat offspring, additional reproductive and toxicokinetic studies should be carried out to determine the extent of endosulfan exposure in male rat offspring in utero and during lactation.     

Ethanol and psychotropic drug interaction during pregnancy and lactation

Prolonged maternal ethanol consumption for 8 days during pregnancy or for five days immediately after birth resulted in 30-46 per cent inhibition in the rate of chlorpromazine metabolism by the rat fetal and neonatal livers respectively. A significant increase in hepatic NADH/NAD and UDPG/UDPGA ratios was observed in suckling neonatal and maternal livers from the ethanol-fed group. Acute administration of ethanol with chlorpromazine led to about 60 per cent inhibition of the metabolism of chlorpromazine. This inhibitory effect of ethanol on the metabolism of chlorpromazine was largely abolished by preincubation of liver homogenates with pyrazole (2 mM). Lactate (10 mM) addition to liver homogenates resulted in a significant inhibition of chlorpromazine metabolism. It is suggested that maternal ethanol consumption during preganancy and lactation inhibits the hepatic metabolism of drugs such as chlorpromazine which require glucuronidation for their detoxification. This ethanol-mediated inhibition is largely exerted through the decrease in the NAD-dependent conversion of UDP-glucose (UDPG) to UDP-glucuronic acid, (UDPGA).     

Changes in lamotrigine pharmacokinetics during pregnancy and the puerperium

To assess changes in the pharmacokinetics of the anti-epileptic drug lamotrigine (LTG) during pregnancy, plasma LTG concentrations at steady-state were determined at different intervals during 11 pregnancies in 10 women with epilepsy stabilized on long-term LTG therapy. In the five pregnancies that could be assessed both during gestation and after delivery, plasma LTG concentrations increased on average by 164% (range +75 to +351%) between the last observation during pregnancy and the puerperium (P < 0.05). When all pregnancies monitored during pregnancy were considered, plasma LTG concentrations declined by an average of 20% (range -64% to +13%) between the first and the last assessment before delivery. These findings confirm that plasma LTG concentrations decrease markedly during pregnancy and that, at least in some cases, this effect occurs as early as the first trimester. Because there is a large interindividual variability in the magnitude and time course of the pregnancy-associated pharmacokinetic changes, it is desirable to establish baseline plasma LTG concentrations in all women of childbearing potential and to monitor LTG levels at frequent intervals during pregnancy and the puerperium.     

Safety and pharmacokinetics of antiretroviral therapy during pregnancy

Combined antiretroviral therapy can reduce the transmission of human immunodeficiency virus (HIV) to an unborn child to less than two percent. An HIV-infected woman of childbearing age and her medical provider are in the unique position of making treatment decisions that not only will impact the woman's health but also that of her child. Treatment recommendations for pregnant women infected with HIV state that therapies of known benefit to women should not be withheld during pregnancy, unless there are known adverse effects for the mother and fetus, and these adverse effects outweigh the benefit for the women. However, the recommendations of antiretroviral drugs for the treatment of HIV-infected pregnant women are subject to unique considerations, including potential changes in dosing requirement resulting from physiologic changes associated with pregnancy, and potential adverse effects on the development of the fetus and/or newborn. Currently there is a general lack of pharmacokinetic data in pregnant HIV-infected women. The limited available information suggests that pregnant women may be exposed to subtherapeutic drug levels of certain antiretroviral agents during the later stages of pregnancy, which can lead to the failure of virologic suppression, development of resistance and increased risk of vertical transmission of HIV infection. The available pharmacokinetic data regarding the use of antiretroviral therapy in pregnancy is reviewed.     

Longitudinal effects of pregnancy on the pharmacokinetics of theophylline

Summary The effects of pregnancy on the disposition of theophylline were assessed in 10 patients throughout pregnancy and post-partum. The clearance relative to total theophylline concentrations was only slightly affected during the first two trimesters (2.61±0.63 l/h and 2.85±1.05 l/h), while a statistically significant reduction was evident late in pregnancy (2.05±0.49 l/h). Post-partum clearance values (2.16±2.81 l/h) suggest an ongoing suppression relative to pre-pregnancy levels. A similar pattern was evident with clearance values based on free theophylline plasma concentrations (p=0.12). Absolute volume of distribution increased in concert with gestation, suggesting that theophylline partitions into the enlarged tissue spaces. In addition, theophylline binding to plasma proteins decreased, albeit insignificantly, during the second (fraction bound=29%) and third (32%) trimesters compared to post-partum values (41%). Increases in half-life during the third trimester (13.00±2.31 h vs 9.53±3.53 h post-partum) were highly significant. This change reflects the net effect of reduced clearance and increased distribution. Breast feeding had no effect on the disposition of theophylline, although the transfer of this compound into breast milk was confirmed.