Depression is a psychiatric pathology with a prevalence of 10% in the general population(1,2) and over 20% in women(3), with the highest frequency being found in the fertile period(4). Thus, cases of pregnant women with depression become a public health problem and have strong legal and moral implications that should be known in detail by each medical professional in order to be able to inform the pregnant woman of all aspects of the therapeutic management, regardless of the chosen one.
According to the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), the diagnosis of a major depressive episode is based on five or more symptoms present in a period of at least two weeks(5). More than five of the next symptoms are present almost every day, in a two-week period, as revealed by the patient or related by housemate: low mood, loss of energy, fatigue, feelings of insignificance, or inappropriate culpable, agitation, poor concentration, indecisiveness, suicidal ideation or attempt, anhedonia, change in appetite associated with more than 5% body weight loss in a short period of time.
The more severe the depressive episodes are in the past, the greater the risk of developing another episode in the future. In general, about half of the people who have had a major depressive episode will develop another, while the risk after two episodes increases to 80%(6).
Depression is based on two theories regarding etiopathogenesis: dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis), and monoamine theory.
When it comes to HPA axis theory, it is well known that overactivating stress response systems or activating them for long periods leads to an increased secretion of CRH (corticotropin releasing hormone), ACTH (adrenocorticotropic hormone), and cortisol(7-9). Normally, there is a feedback mechanism that regulates this axis. However, during pregnancy, the placenta independently produces several hormones (CRH, ACTH and cortisol) which alters the physiological systems of self-regulation, by down-regulating the autoreceptors in the hypothalamus and anterior pituitary(10). Physiologically, there is an adaptive status in pregnancy through which cortisol receptors are downregulated to protect the conception product from the potential adverse effects of excessive cortisol(8), but in the cases of maternal depression, these systems are overwhelmed.
Serotonin, norepinephrine and dopamine, monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) are monoamines that ensure the physiological functioning of the nervous system. The fine balance between their concentrations gives rise to the mechanisms of emotion regulation(7). Thus, a disorder at their level leads to various imbalances that are encountered in psychiatric pathology. The activity of the serotonin transporter in the postpartum period is higher in women with depression than in those without depression(11). By using positron emission tomography, studies have shown that early postpartum MAO-A levels correlate with decreased estrogen levels, thus laying the groundwork for postnatal depression(12).
Estrogen and progesterone, through their varying levels in pregnancy versus outside it, can also induce mental imbalances, having a recognized impact on the regulation of neurotransmitters(8). It is generally believed that high levels of sex hormones protect women against depression during pregnancy and that their sudden decrease in postpartum is the trigger for depression(13). To verify this hypothesis, a study was conducted where women were supplemented with estrogen for a period of time after giving birth to achieve a gradual decrease and obtain easily adaptive estrogen levels. The women treated like that no longer showed depressive symptoms and, thus, the relationship between hormonal balance and the mental status was demonstrated once again(14,15).
Another problem is the addressability to the doctor. Only 25.5% of nonpregnant women with a mood disorder received mental services in the prior year, whereas only 14.3% of pregnant women did(16). Due to this, unfortunately, the number of pregnant women with depression that is properly diagnosed is low and, subsequently, the number of the ones who are treated is extremely small. This problem is caused by the fact that there is still stigmatization of people with psychiatric pathologies and the addressability to the doctor is still far below the optimal limit of the entire population. Moreover, when it comes to pregnancy, there are still women who choose not to have any control during pregnancy.
Regarding the timing of depressive episodes, variability is the keyword. There are studies that have shown that this pathology is most frequently diagnosed in the second trimester, followed by the postpartum period. Contrary to old expectations and theories, the prevalence of depression is higher in pregnancy than in the postpartum period in terms of major depressive episodes(17). Major depressive disorders are estimated in 12.7% of cases during pregnancy, with manifestation in the postpartum period in 19.2% of cases.
In the cases of women stopping antidepressants before pregnancy, they have a 68% risk of decompensating the disease, 50% during the first trimester, and 90% in the second trimester(18).
Einarson et al. showed that 70.3% of women who stopped the treatment had side effects like tremors or even suicidal episodes(19). Roca et al. showed that 57% of women who stopped antidepressants were forced to resume the treatment, 48% of them during the first trimester(20).
It has been shown that about half of women with postnatal depression already had depressive episodes during and even before pregnancy(21).
To support the treatment of depression, another study shows that 20% of postpartum deaths are due to suicide, with this being the second leading cause of death in the postpartum period(22).
The effects of depression during pregnancy
Depression during pregnancy has adverse effects on both women and the fetus. Stopping the antidepressant medication leads to the accentuation of the depressive episodes as intensity and to the diminution of the interval between them, with the possible afferent complications. Depression during pregnancy has been shown to be associated with premature birth(23,24), low birth weight(25), fetal growth restriction(26,27) and multiple postnatal complications(8,24,28).
The postnatal complications may include malformations across multiple organ systems, such as eye, ear, respiratory, digestive, skin, musculoskeletal and genitourinary(29). Cases of orofacial defects (cleft palate and lip) and cardiac defects such as tetralogy of Fallot have also been reported in the literature(30).
The concentration of cortisol in girls exposed to maternal depression is higher than normal(31,32). This hormonal change frequently extends, at least during adolescence, thus increasing the risk of developing mental pathologies(33).
In the mild forms, there is a delay in the neuropsychomotor development until the age of 18 months old(34) which can later be outlined by internalizing and externalizing behaviors, fearful temperament and anxiety(35-37). In late childhood and adolescence, children who have been exposed in the intrauterine life to biochemical-humoral disorders caused by maternal depression may develop altered stress response, attention deficit hyperactivity disorder, anxiety and depression(38-40).
Depression and anxiety can activate the glucocorticoid cascade during pregnancy and the inflammatory response, which affects fetal growth and the nervous system development. Thus, changes in brain structures that are important in regulating emotions, such as the fetal amygdala, may also occur(41).
Moreover, it has also been shown that the exposure of conception products to maternal depression during intrauterine life causes epigenetic changes that are detectable at birth (DNA methylation changes) and which persist in the adult brain(42).
From a genetic point of view, an inversely proportional relationship between telomere length and intrauterine stress exposure has been demonstrated(43). This change predisposes to a higher risk of developing various pathologies during life, due to their essential role in chromosomal integrity.
Treatment of depression in pregnancy
There is no general recommendation regarding the treatment of perinatal depression, and an individualized approach for each case is necessary(44,45).
Depending on the severity of the depressive episodes, there are several treatment methods: behavioral treatments, antidepressant medication, alternative somatic treatment, and other forms of treatment such as bright light therapy and exercise.
Behavioral treatments, also named psychosocial and psychological treatments for depression, may be recommended for women with mild or mild-moderate depression. This treatment option can be applied alone or together with drug therapy. These treatment variants consist of: group psychoeducation(46-49), antenatal and/or postnatal classes(50,51), nondirective counseling(52,53), interpersonal psychotherapy(54-58), cognitive behavioral therapy(59-64) and postpartum debriefing before leaving the hospital or clinic(65-67).
Additionally, selective serotonin reuptake inhibitors (SSRI) antidepressants are the most common class of drugs prescribed to pregnant women(68).
The dose of antidepressants should be chosen such as it is the smallest dose to which the patient responds and to which the possible negative effects on pregnancy are minimal. When choosing this dose, it should be taken into account the fact that, during pregnancy, changes in pharmacokinetics such as cytochrome P (CYP) 450 isoenzymes that metabolize SSRIs are altered(69), CYP3A4, CYP2D6, CYP2C9 and CYP2A6 activity is increased, and thus the metabolism of the drug becomes faster. Therefore, in order to achieve optimal plasma concentrations, the dose should be increased. On the other hand, the activity of CYP1A2 and CYP2C19 is low during pregnancy, which leads to a slower metabolism of the active substances predominantly metabolized by these enzymes(70-74).
Alternative somatic treatment options
Electroconvulsive therapy is rarely used to treat major depressive episodes that do not respond to other therapeutic options. It requires general anesthesia which has its own unfavorable effects on the product of conception(75).
Thus, in pregnancy, this method of treatment is rarely used, except for severe cases, with suicidal tendencies, with psychotic manifestations, which primarily endanger the mother’s life.
Other alternative treatments include psychotherapy, exercise(76), massage therapy(77,78) and bright light therapy(79,80). These alternative treatment options can only be applied in cases of mild depression.
Estrogens have also been considered in the postpartum treatment regimen(14,15), but there are insufficient data to prove their benefit in the treatment of depression when considering the numerous thrombotic effects in the immediate postpartum period.
To quantify the effectiveness of any treatment against depression, the severity of symptoms is measured by the 10-item Edinburgh Postnatal Depression Scale for which the recommended cutoff is 15 for MDD Evans 2001. Alternatively, the Edinburgh Postnatal Depression Scale is used to monitor the effectiveness of Spinelli psychotherapy 2003 and Ververs pharmacotherapy 2009.
Adverse effects of antidepressant treatment
Antidepressant use during pregnancy has been associated with various adverse effects on the fetus, including malformations(24), neonatal problems(81) and autism(82). In the studies describing these side effects in intrauterine and neonatal development, it is necessary to distinguish between the side effects of the treatment and the ones caused by the influence of maternal depression on the fetus. This aspect must be considered as much as possible in each research study to be able to draw the appropriate conclusions, as close as possible the statistically important truth(82,83). Neonatal “adaptation” problems, however, seem to be caused by treatment(81). On the other hand, malformations like septal heart defects are still disputed and do not appear to be a cause of the medication itself(24).
A study by Kjaersgaard et al. (2013), on a population of women without a diagnosis of depression, showed that the use of antidepressants during pregnancy was associated with an increased risk of miscarriage. However, compared to cases where women did not take antidepressant treatment, the risk no longer existed, and thus the abortion could no longer be considered an adverse effect of medication(84).
Vasilakis-Scaramozza et al. compared a group of women who had been exposed to tricyclics or selective serotonin reuptake inhibitors (SSRIs) during first-trimester pregnancy with another group of pregnant women with no exposure. The article shows that the risk of developing malformations fetal growth does not increase with tricyclic or SSRI(85). The same conclusion emerges from the meta-analysis performed by Grigoriadis et al.(24)
Numerous studies have shown a link between antidepressant treatment during pregnancy, especially paroxetine, and possible fetal heart defects. In contrast, Einarson et al. argue that precisely this concern associated with the paroxetine treatment would lead to more frequent checkups of newborns from mothers treated with this SSRI than of other newborns. There is no protocol for routine examinations to rule out heart malformations, therefore their frequency in the general population sometimes remains uncertain(86). Cases of neonatal adaptation syndrome have also been described in the literature, and these are defined as a combination of signs and symptoms such as increased muscle tone, tremulousness, feeding and sleep problems, jitteriness and respiratory difficulties. There is a significant similarity between this and the newborn’s withdrawal syndrome, although there are authors who have considered it to be due to drug toxicity. This syndrome was found in pregnant women who received antidepressant medication in the third trimester(87,88). However, it is important to keep in mind that this syndrome is mild, self-limiting and reversible in 3-5 days without remote effects(89). Autism is also a controversial side effect. Rai et al. conducted a study to show that there is a link between antidepressant treatment and an increased incidence of autism without intellectual disability (“high functioning autism” and Asperger’s syndrome)(90). However, in these cases, it is also unclear whether autism had developed due to maternal depression, in which case it was not the drug itself that would have generated the pathology, but its insufficient dose.
Nulman et al. prospectively followed‑up children born to depressed mothers who did not receive treatment and to mothers who received venlafaxine or SSRI. The authors aimed to determine the long-term effects of these treatments. Children in this series were tested at 3 years, 6 years, and at 11 months of mothers with untreated maternal depression. Those whose mothers took SSRIs or venlafaxine had intellectual quotients scores, (IQs) between 105 and 108. The severity of a mother's depression during pregnancy was the greatest predictor of behavioral problems. Antidepressant dose and duration during pregnancy did not predict any cognitive or behavioral outcomes. The mother's IQ was the best predictor of the child's IQ(91).
Many of the side effects of antidepressants described so far in the literature are in fact also influenced by the effects of maternal depressive status on the development of the newborn. Thus, it is not advisable to perpetuate the idea that maternal depression should not be treated to avoid the possible adverse effects on the fetus. Moreover, most studies on this topic are retrospective and there is no certainty that pregnant women have actually received the recommended treatment.
Depression is one of the most common pathologies found in the current population, and it is the most common one in women during the fertile period. Thus, women should be encouraged to consult specialists for regular checkups and whenever they consider that an improvement in their mental state can be made. In this case, it is necessary that they are explained in detail each variant of treatment.
It is also the duty of both obstetricians and psychiatrists to know the treatment possibilities and risks of each one to be able to present them to patients and, together with them, to choose the most appropriate scheme for each one of them. It is well known that the patient often chooses the doctor’s recommendation when put in the situation of choosing between several treatment options and, because of this, the physician’s recommendation must be relevant and supported by the latest publications in the literature.
Disclaimer: The authors declare no conflicts of interest.