The present article will briefly discuss pharmacokinetic changes during pregnancy. Furthermore, a short presentation focused on treatment of pregnant women with antidepressants, sleeping remedies, anxiolytics and second generations antipsychotics.
Pharmacokinetic changes
The adaption of the human body to pregnancy is fascinating. Apart from psychological changes, a multitude of physiological, anatomical, and biochemical alterations occurs, and it starts immediately post conception and continues throughout the pregnancy. The physiological changes affect the pharmacokinetics of all drugs i.e., their absorption, distribution, metabolism, and their clearance. In healthy women, the pregnancy-induced absorption and distribution changes are more of theoretical interest. They probably play a minor role with regard to the pharmacokinetics of antidepressant drugs (AD), second generation antipsychotics (SGA) and benzodiazepines. Of greater importance is the changes in the activity of the drug metabolizing enzymes. The cytochrome P-450 enzymes (CYP) are vital for the metabolism of a substantial number of drugs. During pregnancy the CYP isozymes CYP2C9, CYP2D6, and CYP3A4 all are induced. An induction of the metabolizing enzyme can result in decreased plasma drug concentration - risking treatment failure. An important example is CYP2D6. The enzyme expression is increased by almost 200% during the course of pregnancy, probably mostly during the third trimester. It is responsible for the metabolism of over 250 drugs including many antidepressants, antipsychotics, analgesics, antiarrhythmics and β-adrenoreceptor antagonists. All of them are commonly used by pregnant women. Data suggests that doses of CYP2D6 substrate drugs may have to be increased during the third trimester to prevent loss of effect. The opposite is seen with other isoenzymes which are inhibited during pregnancy, foremost CYP1A2 and CYP2C19.
One of the most important pregnancy-caused changes is the impact on the glomerular filtration rate (GFR). Renal extraction of drugs depends on GFR, and already during the first trimester GFR increases by 50% compared to the woman’s pre-gravidae status, and up to 80% during the second trimester. Some studies indicate a normalization of GFR during the last 3 weeks of the pregnancy. The consequence of GFR changes is that doses of renally excreted drugs might, sometimes, have to be increased during pregnancy. In psychiatry, foremost lithium and lamotrigine serum concentration levels have to be observed closely both before, several times during the pregnancy, and postpartum. Consecutively taken serum concentrations during the pregnancy can sometimes be of guidance also for antidepressants and antipsychotics. A rule of thumb when it comes to psychotropic drugs is that if the drug dose has been raised during pregnancy it should quickly be changed back postpartum to the pre-gravidae dose. The pregnancy-induced pharmacokinetic changes normalize relatively fast postpartum and, consequently, the drug serum concentrations can increase and cause adverse effects or even toxicity to the woman or the nursed newborn.
All the above described changes are important to bear in mind. However, when treating a pregnant woman, the dosage should be adjusted according to the clinical outcome in the same way as in a non-pregnant women!
When prescribing a drug to a pregnant woman a risk–benefit analysis must be performed. Weigh the risk the mother takes if she is not prescribed her drug against the risk of harming the fetus with the drug and the possibility of the mother’s illness injuring the fetus.
Further, always consider the gestational week the mother is in when you plan to prescribe a drug. For example, a drug with an increased risk for congenital malformation of the heart can be prescribed in the second or third trimester without problems while only with great caution in the first trimester.
Depression and anxiety disorders during pregnancy are very common. In a recent study, the pooled prevalence of 173 studies on “Any antenatal depression” was 20.7% and of 72 studies on “Major antenatal depression” the pooled prevalence was 15.0%. This is the reality we have to face.
SSRI and SNRI
In the western world, between 4-13 % of pregnant women take an antidepressant, primarily SSRIs but also SNRIs. A majority of the antidepressants gain access to the fetoplacental unit and serotonin has a significant role in the development of the brain and other organs. Manipulating synaptic serotonin by antidepressant drugs might alter this development. However, recent studies suggest that antidepressant use in pregnancy itself does not increase the risk of neurodevelopmental disorders in children. Moreover, most studies on prenatal exposure to serotonergic drugs have not found significant embryonic or fetal damage. One exception is a slight increase in cardiac malformations by paroxetine and possibly by fluoxetine. SSRIs and SNRIs are also associated with a small increase in risk of pre-eclampsia, postpartum hemorrhage, preterm delivery, persistent pulmonary hypertension of the newborn, the latter probably only by SSRIs taken during the last trimester, and a cause-and-effect relationship is far from clear! Further, a small increased risk of admission to a neonatal intensive care unit due to withdrawal symptoms from the antidepressant is seen. Nota bene, the absolute risk of these outcomes is low.
When considering a risk-benefit analysis if prescribing an antidepressant or not, be careful and “don’t shoot the messenger”. We know from several studies that women taking an antidepressant are significantly older, smoke more frequently, have significantly higher BMI and take significantly more OTHER drugs in addition to the antidepressant than women not taking antidepressants. Remember that high age, smoking, high BMI and comedication all are factors that, each independently, increase the risk for congenital malformations. So, what are we looking at and are the different cohorts of women even comparable? It has been shown that increased neonatal morbidity is significantly more common among women taking a TCA than an SSRI or SNRI. Is this a drug effect or is it caused by confounding factors including different severity of the depressive illness?
When reading statistics on risks with drugs during pregnancy it is important to interpret it correctly. How could you otherwise advise the pregnant woman in front of you? What does a risk increase mean and which background data is increased? When it comes to congenital malformations, 3-5% of all newborns have a malformation, of which less than 3% is serious. For a majority the cause is unknown. A giant in the field of drugs, risks and pregnancy, the late professor Bengt Källén, once wrote: “A risk ratio of 1.7 means that after exposure, the outcome is 70% more common than without exposure. One should not mix this up with the absolute risk – the risk that a woman who has taken a drug in early pregnancy has to get a malformed baby. If we say that the general risk to have a baby with a major malformation is 3%, a 70% risk increase means that the risk increases to 5.1%.
In conclusion, consensus today, is that antidepressant drugs are considered safe during pregnancy when a complete risk-benefit analysis is performed. That is, never ever forget the impact psychiatric illness has on the fetus and the ability of the expecting woman to bond with her baby post-partum. An untreated depression during pregnancy is associated with an increased risk of premature birth and the baby being born small for gestational age, a decreased quality of life for the mother, and difficulties for her to bond with the baby.
Sleeping problems and anxiety during the pregnancy
A good sleep is always important, but essential during pregnancy. Not the least in women suffering from a psychiatric illness. If nothing else is working, there are several pharmacological ways to help out.
Promethazine is a first-generation antihistamine and antiemetic used to treat allergies, insomnia, and nausea. It’s been widely used in pregnant women for decades and is considered safe to use in early pregnancy, i.e., the malformation risk is not increased. But some caution has to be taken during the latter part of the pregnancy. There might be a small increased risk for neonatal withdrawal symptoms affecting breathing. However, the data is conflicting.
Propiomazine is also considered safe in early pregnancy. But, as for promethazine, keep the dose as low as possible during the latter part of pregnancy.
When considering zopiclone or zolpidem, only occasional use is recommended. Conclusive studies are missing but an increased malformation risk is not expected. None of the drugs are, however, recommended during the latter part of the pregnancy due to risk of negative effects of the infant like withdrawal syndrome, hypotonia, hypoglycemia and respiratory difficulties.
Finally, melatonin where there is a paucity of studies. It is an endogenous hormone and the malformation risk is supposedly low. But experience with treating pregnant women is limited and, hence, melatonin cannot be recommended for more than occasional use until we have more data.
If benzodiazepines are necessary in treating anxiety during pregnancy, caution has to be taken especially in the last trimester. Occasional use is sometimes necessary and low doses do not seem to cause malformations. But there are conflicting data (many times due to study designs) and high doses should be avoided. If a benzodiazepine has to be used it is recommended to use oxazepam which has the shortest elimination half-time. Babies born to continuously benzodiazepine-using mothers are at great risk of preterm birth, low birth weight, floppy infant syndrome, withdrawal syndromes, hypotonia, and hypothermia.
In acute anxiety disorder, when suicide can be the worst outcome – use as much benzodiazepines as necessary!
Hydroxyzine is sometimes used for anxiety, and it can be prescribed to pregnant women as well. Studies do not indicate an increased malformation risk when used in early pregnancy. During the latter part the dose, also for this drug, should be kept as low as possible to prevent negative effects of the newborn.
Second generation antipsychotics
Treating pregnant women with psychotic disorders is a challenge for the woman, her family, and her doctor. The benefit of pharmacological treatment has to outweigh the possible risks in a short and a long perspective for both the woman and the fetus/infant, and no single optimal treatment option is available. The major indications for antipsychotics are schizophrenia and as a mood stabilizer in bipolar disorder, the latter in lieu of, or in combination with, lithium or anticonvulsants. The first or second generation antipsychotics (SGA) and lithium all pass the blood-placenta barrier, although with significant differences between individual compounds. Nevertheless, they are by clinical necessity frequently used by reproductive age women worldwide.
As a group, SGA does not seem to significantly increase the risk for congenital malformation with one exception. A recent study (Huybrechts el a JAMA psychiatry 2016) found a small, but significant, malformation risk when taking risperidone in the first trimester. Later data disagree with those findings, but more studies are required.
When studying prenatal antipsychotic exposure, considerations have to be taken whether there is an increased risk of a neurodevelopmental disorder (NDD). A recent, large, and reliable study (Straub et al JAMA intern med 2022) concluded: “The findings of this birth cohort study suggest that the increased risk of NDD seen in children born to women who took antipsychotic drugs late in pregnancy seems to be explained by maternal characteristics and is not causally related with prenatal antipsychotic exposure. This finding highlights the importance of closely monitoring the neurodevelopment of the offspring of women with mental illness to ensure early intervention and support.” There was one exception, aripiprazole, which showed a small increased risk of NDD but the authors conclude that this “…. potential signal for aripiprazole requires replication in other data before causality can be assumed.”
The use of SGA during pregnancy is associated with an increased risk of gestation diabetes, foremost with olanzapine and quetiapine, but possibly also for clozapine. Cesarean section due to the child being large for gestational age and preterm birth are also risks associated with SGA treatment of the mother.
I conclude this section with a reminder of the risk–benefit analyses that have to be performed. Never ever overlook the impact the psychiatric illness itself may have to the fetus/child and the relatively small risks an SGA treatment implies! □