Salvatore Gentile1, 2
(1)
Department of Mental Health, ASL Salerno, Mental Health Center n. 63, Piazza Galdi, 84013 Cava de’ Tirreni, Salerno, Italy
(2)
Department of Neurosciences, Medical School “Federico II”, University of Naples, Naples, Italy
Salvatore Gentile
Email: salvatore_gentile@alice.it
7.1 Anxiety Disorders and Motherhood
7.1.1 Epidemiology of Antenatal Anxiety Disorders
7.1.2 Hormonal Changes in Pregnancy and Their Relationship with the Onset of Anxiety Disorders
7.1.3 Anxiety Disorders in Pregnancy: Antenatal and Postnatal Effects
7.2 Benzodiazepines and Pregnancy
7.2.1 Structural Teratogenicity
7.2.2 Gestational Teratogenicity
7.2.3 Perinatal Teratogenicity
7.2.4 Neurobehavioral Teratogenicity
7.3 Pregabalin and Pregnancy
7.3.1 Structural, Gestational, Perinatal, and Behavioral Teratogenicity
7.4 Insomnia and Pregnancy
7.5 Hypnotic Agents and Pregnancy
7.5.1 Structural Teratogenicity
7.5.2 Gestational Teratogenicity
7.5.3 Perinatal and Neurobehavioral Teratogenicity
7.6 Management of Anxiety Disorders in Pregnancy
7.6.1 Pharmacological Treatments
7.6.2 Antidepressants
7.6.3 Non-pharmacological Interventions
References
Abstract
Antenatal anxiety may adversely impact on several aspects of fetal maturation, pregnancy, the puerperium, and child development, thus demonstrating an intrinsic teratogenic structural, gestational, and neurobehavioral liability. Moreover, insomnia during the first trimester of pregnancy is quite common and is usually a result of associated hormonal changes. Insomnia is also common during the third trimester of pregnancy. There are a number of reasons for this, but by far the most common is the discomfort as the mother gets bigger and her baby begins to place more pressure on her internal organs, making it more difficult to find a comfortable position to sleep in. However, when possible, benzodiazepines should be avoided in both the first trimester and third trimester of pregnancy because of possible structural teratogenicity (especially, anal atresia and other gastrointestinal tract anomalies, and oral cleft), ascertained gestational teratogenity (spontaneous abortion) when taken in overdose, and ascertained perinatal teratogenicity (neonatal withdrawal syndromes). As regards hypnotic agents, preliminary data, although apparently encouraging, are too limited to confirm or exclude a potential structural teratogenic liability. Above all, concordant safety signals seem to discourage the use of hypnotic agents during pregnancy because of an increase in the risk of gestational teratogenicity (preterm birth, low birth weight, and babies small for gestational age). Given these considerations, interventions alternative to pharmacological treatments should be considered first-line options for managing anxiety and sleep disorders in pregnancy.
Keywords
BenzodiazepinesPregnancyTeratogenicityPregabalinZaleplonZolpidemZopiclone
7.1 Anxiety Disorders and Motherhood
7.1.1 Epidemiology of Antenatal Anxiety Disorders
Antenatal clinics can expect at least one in five pregnant women to experience mental health problems, especially depression and anxiety (Qiao et al. 2012). In fact, pregnancy is a period highly vulnerable to the onset of anxiety symptoms.
“Health anxiety” is particularly elevated in pregnancy, especially in women who have experienced earlier obstetric complications (Collingwood 2012). Miscarriage, fetal death, and preterm birth indeed reduce women’s quality of life scores and significantly raise their anxiety scores during subsequent pregnancies.
The prevalence of specific anxiety disorders in pregnancy is highly variable. Panic disorder (PD) has a reported prevalence of 1.3–2.0 %. Although an increased risk of relapse and new-onset PD has been reported in the postpartum period, the risk in pregnancy per se is not known (Vythilingum 2008).
Few studies have examined the prevalence of obsessive–compulsive disorder (OCD) in pregnant women, with reported prevalences varying between 0.2 and 3.5 % (Ross and McLean 2006; Uguz et al. 2007). There is no data on the course of preexisting posttraumatic stress disorder (PTSD) during pregnancy (Vythilingum 2008). Perinatal PTSD (i.e., PTSD related to medical procedures, childbirth, or other obstetric events) has been reported (Beck 2004). One study found that 20 % of women reported traumatic pregnancy-related procedures. Of these, 6 % met criteria for PTSD (Menage 1993).
To diagnose generalized anxiety disorder (GAD) symptoms must be present for at least 6 months (APA 1994). Thus, it is unlikely that criteria for new-onset GAD will be met in pregnancy (Vythilingum 2008). Indeed, limited data exist on the epidemiology of GAD in pregnancy. Only one study investigated the prevalence of GAD in pregnancy. It found a rate of 8.5 % in the third trimester (Shear and Oommen 1995). No information is available on the course of preexisting GAD in pregnancy.
7.1.2 Hormonal Changes in Pregnancy and Their Relationship with the Onset of Anxiety Disorders
Hormonal changes in pregnancy may facilitate the onset of anxiety disorders (Miller 2011). Progesterone, metabolized into pregnanolone and allopregnanolone in the brain, is neuroactive gamma-aminobutyric acid (GABA) agonist. As levels of these hormones increase during pregnancy, GABA receptors are downregulated, and this phenomenon may confer the increased vulnerability of the expectant mothers (Smith et al. 2007; Parízek et al. 2005; Altemus et al. 2004; Hill et al. 2001; Maes et al. 2001).
Moreover, abrupt estrogen reduction can reduce serotonergic functioning. Tryptophan is an amino acid that is a “building block” of serotonin (Miller 2011). In pregnancy, serum tryptophan is reduced, especially relative to other amino acids that compete to cross into the brain (Miller 2011). The fall in serum tryptophan levels may also contribute to the onset of anxiety disorders (Smith et al. 2007; Parízek et al. 2005; Maes et al. 2001; Altemus et al. 2004; Hill et al. 2001).
7.1.3 Anxiety Disorders in Pregnancy: Antenatal and Postnatal Effects
Antenatal anxiety may adversely impact on several aspects of fetal maturation, pregnancy, the puerperium, and child development, thus demonstrating an intrinsic “teratogenic structural, gestational, and neurobehavioral liability” (Gentile 2012).
As noted by Glover and O’Connor (2002) in an interesting editorial, studies of the effects of antenatal stress and anxiety in humans found that women who experience severe life events in the first trimester of pregnancy have a 50 % increase in the rate of congenital abnormalities, especially cleft palate (Hansen et al. 2000).
Reports from the pre-ultrasound era had suggested that prenatal maternal stress, anxiety, and emotions might affect fetal functioning, as evidenced by increased fetal heart rate and mobility (Van den Bergh 1992). A review describing results obtained during the post-ultrasound era confirms that good evidence exists for a direct link between antenatal anxiety/stress and abnormal fetal behavior (Van den Bergh et al. 2005).
Moreover, interesting research indicates that severe maternal anxiety in late (but not early) pregnancy might be associated with impaired blood flow or raised resistance index to the fetus through the maternal uterine arteries (Teixeira et al. 1999). High resistance is associated with adverse obstetric outcomes, particularly intrauterine growth restriction and pre-eclampsia, and could therefore help to explain why anxious mothers are likely to have babies small for gestational age (Glover and O’Connor 2002). In fact, preterm labor and low birth weight are the outcomes linked most consistently with antenatal stress or anxiety in humans (Hedegaard et al. 1993; Lou et al. 1992). These findings are relatively robust across different measures of stress/anxiety (Glover and O’Connor 2002).
In addition, well-designed studies have shown a relationship between antenatal stress or anxiety and behavioral/emotional disturbance in the child. The Avon Longitudinal Study of Parents and Children (ALSPAC) suggests a strong link between maternal anxiety in the third trimester and behavioral/emotional problems in 4-year-old children (O’Connor et al. 2002). Analyses from the ALSPAC cohort also found evidence of an impact of antenatal anxiety on neurological development. High levels of maternal anxiety at 18 weeks gestation may indeed predict atypical laterality (i.e., mixed handedness) in the child, independently of maternal and paternal handedness and obstetric and other antenatal risks.
Furthermore, a recent study demonstrated that neurocognitive functioning at 5 years of age is impaired in those children whose mothers had suffered from anxiety symptoms during the gestational period (Loomans et al. 2012). At the same age, such children show behavior and hyperactivity/inattention problems, emotional symptoms, peer relationship impairment, and conduct disturbances (Loomans et al. 2011). Of note, in boys exposure to antenatal anxiety is associated with a stronger increase in overall problem behavior compared to girls. Moreover, high levels of maternal state anxiety during pregnancy enhances the offspring’s susceptibility for developing childhood disorders, such as attention-deficit hyperactivity disorder (ADHD) symptoms, externalizing problems, and anxiety at 8–9 years of age (Van den Bergh and Marcoen 2004). Impaired patterns of decision-making processes may persist up to 17 years of age (Mennes et al. 2009).
Several plausible mechanisms linking antenatal stress/anxiety and disturbances in offspring have been suggested. Preterm birth is the single largest perinatal risk factor for later morbidity, including ADHD and schizophrenia, and being small for gestational age is associated with similar adverse mental and behavioral problems (Hultman et al. 1999). Research supporting a mechanism involving the maternal hypothalamic–pituitary–adrenal (HPA) axis is also increasing. Gitau et al. (2001) suggested that high levels of maternal cortisol levels (due to chronic anxiety) can cross the placenta to significantly alter fetal exposure.
It should also be highlighted that, after accounting for the presence of other antenatal anxiety disorders, antenatal depression, maternal age at child’s birth, socioeconomic status, and ethnicity in the models, antenatal GAD independently predicts depression at all time points after delivery (Coelho et al. 2011).
Therefore, anxiety disorders at onset or worsening during pregnancy may require pharmacological treatment to obtain a prompt remission of maternal mental impairment and, thus, to prevent potential serious complications to the mother–infant pair (Gentile 2011).
7.2 Benzodiazepines and Pregnancy
Benzodiazepines (BDZs) are the class of medication most frequently prescribed in pregnant women to treat anxiety symptoms (Daw 2012). They have been on the market for more than 40 years and it is estimated that at least 3–15 % of any adult population in the world is using prescribed BDZs (Bendtsen et al. 1999). Pharmacoepidemiological data suggest that not only are women are more likely to be prescribed such medications compared to men (Taylor et al. 1998), but women are also more likely to be prescribed BDZs for longer periods of time (Jorm et al. 2000). Women are also more likely than men to be prescribed BDZs and sleeping pills for nonmedical reasons such as coping with grief or stress (Currie 2004). They are also prescribed these drugs when adjusting to natural processes such as childbirth (Morales-Suárez-Varela et al. 1997).
Worldwide, an estimated 85 % of all psychotropic medicines prescribed to pregnant women are for BDZs (Marchetti et al. 1993). The incidence of BDZ use during pregnancy is unclear (Bncc.org.uk 2012), and figures varying from 1–3 % to 40 % have been suggested (Ormond and Guttmacher 1995; McElhatton 1994). These figures do not include women who misuse BDZs, 90 % of whom are of childbearing age (Institute for the Study of Drug Addiction 2012).
However, the safety of their use during pregnancy remains controversial because there have been conflicting results regarding their teratogenicity. Thus, the risk/benefit ratio of using such medications is still unclear.
7.2.1 Structural Teratogenicity
7.2.1.1 Studies Suggesting an Increase in the Risk of Birth Defects
A significantly higher risk of cardiovascular malformations (OR 2.5) was observed in 201 newborns whose mother was exposed to chlordiazepoxide during pregnancy (Czeizel et al. 2004). However, it should be noted that more than 90 % of cases were exposed concomitantly to other drugs (promethazine, prevalently). In an analysis by Milkovich and Van den Berg (1974) of 19,044 live births, severe congenital anomalies (including spastic diplegia, microcephaly, duodenal atresia, and mental deficiency) occurred more often among infants of mothers who took chlordiazepoxide during the first 42 days of pregnancy than among infants of mothers who took other drugs or no drugs (11.4 % compared with 4.6 % and 2.6 %, respectively).
In a sample of 262 newborns with a congenital birth defect, those antenatally exposed to either lorazepam or bromazepam were at a statistically significant increased risk of anal atresia and digestive tract anomalies (OR 6.19 and 6.15, respectively) compared to newborns exposed to other BDZs (Bonnot et al. 2001). Godet et al. (1995) described a study in which 187 malformed infants were observed among 100,000 births that involved exposure to BDZs, including lorazepam, during the first trimester of pregnancy. A significant association was found between lorazepam and anal atresia (five cases, p < 0.001).
Two studies investigating the reproductive safety of diazepam analyzed the rate of birth defects recorded in the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA). The first of these studies found a statistically significant increase in the risk of limb malformations, rectal–anal stenosis/atresia, cardiovascular malformations, and multiple congenital abnormalities (Czeizel et al. 2003). In the second study, Kjaer et al. (2007) examined data from the HCCSCA according to a case-time-control design. The results confirmed that antenatal diazepam exposure may significantly increase the risk of birth defects (OR 1.2).
Other studies had already suggested that the use of diazepam during the first trimester of pregnancy was significantly greater among mothers of children born with oral cleft. Aarskog (1975) found that 6.3 % of 30 infants born with cleft palate in the USA between 1967 and 1971 had been exposed to diazepam in the first trimester, compared with 1.1 % of control infants. Such results were confirmed by the contemporaneous study by Saxen (1975a). Safra and Oakley (1975) also reported that mothers of infants with cleft lip, cleft palate, or both had used diazepam four times more frequently than mothers of control infants.
A review of 599 oral clefts by Saxen and Saxen (1975) showed a significant association (p < 0.05) between ingestion of anxiolytics, mostly diazepam, during the first trimester of pregnancy. Many other epidemiological studies have shown an association between the use of diazepam in the first trimester and oral clefts (Rosenberg et al. 1983; Entman and Vaughn 1984; Czeizel 1976; Saxen 1975b). In prospective studies of the effect on the infant of maternal use of psychoactive drugs during pregnancy, an embryofetopathy that resembles the fetal alcohol syndrome (Olegård et al. 1979) has been associated with antenatal maternal use of BDZs (Laegreid et al. 1987). The authors reported a specific BDZ syndrome among 7 infants with dysmorphism in a prospective study in which 36 mothers of 37 infants regularly took such medications during pregnancy. Five of these mothers had taken diazepam.
An association with BDZ exposure following suicidal attempts by overdose and increased rates of birth defects was confirmed for nitrazepam (Gidai et al. 2010).
7.2.1.2 Studies Suggesting No Increase in the Risk of Birth Defects
Short-term exposure to 10 mg b.i.d. of diazepam during the first trimester of pregnancy for hyperemesis gravidarum was not associated with higher risks of birth defects (Tasci et al. 2009).
Two studies considered exposure to clonazepam monotherapy during pregnancy. In the study by Lin et al. (2004), 73 newborns had been exposed antenatally to clonazepam at doses up to 2 mg/day during the first trimester. No increased rates of birth defects were recorded. In the second study no significant variations in birth weight-adjusted head circumference were observed in 71 newborns after intrauterine clonazepam exposure (Almgren et al. 2008). However, the specific risk of microcephaly was not investigated.
In several studies, the frequency of congenital anomalies was not greater than expected amongst infants of women who took chlordiazepoxide during the first trimester of pregnancy (Czeizel 1988; Bracken and Holford 1981; Kullander and Källén 1976; Crombie et al. 1975; Hartz et al. 1975).
In a prospective study conducted between 1982 and 1992, St Clair and Schirmer (1992) evaluated the pregnancy outcomes of 542 women who were exposed to alprazolam during the first trimester of pregnancy. They noted neither a pattern of defects, nor excess of congenital anomalies in 411 infants who were exposed to alprazolam during the first trimester. Another study prospectively identified 236 women who were exposed to therapeutic dosages of alprazolam during the first trimester and found only five cases of congenital malformations (Schick-Boschetto and Zuber 1992). These data do not support an association between antenatal alprazolam exposure and congenital defects.
7.2.2 Gestational Teratogenicity
7.2.2.1 Studies Suggesting an Increase in the Risk of Miscarriage
Some studies investigated the reproductive safety of BDZs in women who took high doses of such medications as suicide attempts.
A small sample of women who were exposed to high doses of alprazolam (mean 29.8 mg; range 7.5–100 mg) showed an increase in the rate of spontaneous abortion (7 out of 30 pregnancies: 23.3 %), but no increased risk of birth defects was observed (Gidai et al. 2008a).
High rates of spontaneous abortions, as well as low birth weight, were also found in women who ingested chlordiazepoxide or diazepam as overdoses (Gidai et al. 2008b, c). Exposure to both medazepam and nitrazepam confirmed that BDZ overdose is strongly associated with an increased risk of miscarriage (Gidai et al. 2008d, 2010).
7.2.3 Perinatal Teratogenicity
7.2.3.1 Studies Suggesting an Increase in the Risk of Perinatal Teratogenicity
If used during pregnancy, all BDZs have been associated with an increased risk of inducing neonatal withdrawal symptoms (Iqbal et al. 2002). Symptoms of neonatal withdrawal, which may also include signs resembling the “floppy infant syndrome”, are summarized in Table 7.1. This neonatal withdrawal can appear within a few days to 21 weeks (depending on the half-life of the specific BDZ used) after birth and can last up to several months. This syndrome is best minimized by gradually tapering the BDZ dose before delivery and usually infants who develop BDZ withdrawal symptoms will recover without any long-lasting sequelae (Iqbal et al. 2002).
Table 7.1
The benzodiazepine neonatal withdrawal syndrome
|
Hypo/hypertonia |
Hyperreflexia |
Tremors |
Sleep disturbances |
|
Cyanosis |
Bradycardia |
Apnea |
Feed aspiration |
|
Vomiting |
Diarrhea |
Suckling difficulties |
Growth retardation |
7.2.4 Neurobehavioral Teratogenicity
7.2.4.1 Studies Suggesting an Increase in the Risk of Neurobehavioral Teratogenicity
A small and so far unreplicated study (which did not explore the role of potential confounders and the effects of specific medications) found a combination of delayed mental development and neuropsychological symptoms in 18-month-old children prenatally exposed to various BDZs (Viggedal et al. 1993).
7.2.4.2 Studies Suggesting No Increase in the Risk of Neurobehavioral Teratogenicity
In contrast, reassuring results emerged from a study performed on a large number of children exposed prenatally to chlordiazepoxide (Hartz et al. 1975). In fact, such children showed normal motor, mental, and IQ scores at 3 years of age.
Preschool children exposed to diazepam during the last stages of their intrauterine life showed no neurodevelopmental problems (Gidai et al. 2008c).
Even if taken in overdose (for maternal suicidal attempts), BDZs (specifically, alprazolam) were devoid of effects on the principal neurodevelopmental milestones (Gidai et al. 2008a).
7.3 Pregabalin and Pregnancy
Pregabalin (PGB) is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for GAD and is (as of 2007) approved for this use in the European Union.
7.3.1 Structural, Gestational, Perinatal, and Behavioral Teratogenicity
No published information is available on PGB use during pregnancy. A single case report found that passage of the drug into breast milk is extensive, but low concentrations were measured in the infant (Ohman et al. 2011).
7.4 Insomnia and Pregnancy
Pregnancy is a time of great change in a woman’s life. Likewise, sleep is altered and may not return to pre-pregnancy quality for several years after the birth of the child (Sharma and Franco 2004). Some sleep disturbances are a harbinger of sleep disorders (Sharma and Franco 2004). If they are not recognized and treated, there can be negative effects for the patient and her unborn child (Sharma and Franco 2004).
Insomnia during the first trimester of pregnancy is quite common and is usually a result of the hormonal changes (Pregnancy Calendar 2012). One of the main causes of insomnia is a result of the progesterone that is released. Progesterone is a natural sedative, which leads to women feel tired and often fall asleep at hours which are not in their normal sleeping cycle, which leaves them wide awake when they are supposed to be sleeping (Pregnancy Calendar 2012). This also explains why fatigue is a common symptom of pregnancy (Pregnancy Calendar 2012). Furthermore, progesterone has been shown to increase non-REM sleep (Friess et al. 1997). Indeed, studies on the sleep architecture of pregnant women demonstrate increased light sleep (stage 1 sleep) and suppression of dream sleep (REM sleep), as well as more awakenings (Driver and Shapiro 2002).
Insomnia is also common during the third trimester of pregnancy. There are a number of reasons for this, but by far the most common is obviously discomfort as the mother gets bigger and her baby begins to place more pressure on her internal organs, making it more difficult to find a comfortable sleeping position (Pregnancy Calendar 2012). Add to that the constant pressure on the bladder from the baby; the expectant mother will need to urinate more frequently throughout the night (Pregnancy Calendar 2012). Also, many pregnant women report that it is hard to sleep due to leg cramps (BabyCenter Medical Advisory Board 2012).
With so many physical and emotional changes happening, it is no surprise that 8 out of 10 women have insomnia and other sleep problems during pregnancy (BabyCenter Medical Advisory Board 2012).
7.5 Hypnotic Agents and Pregnancy
Hypnotic BDZ receptor agonists (HBRAs: zolpidem, zopiclone, and zaleplon) are widely used in the treatment of insomnia.
7.5.1 Structural Teratogenicity
7.5.1.1 Studies Suggesting an Increased Risk of Birth Defects
To date, no reports are available suggesting that hypnotic agent exposure during pregnancy may increase the rate of fetal malformations.
7.5.1.2 Studies Suggesting No Increase in the Risk of Birth Defects
Data from the Swedish Medical Birth Registry from July 1, 1995, up to 2007 were used to identify 1,318 women who reported the use of HBRAs in early pregnancy (Wikner and Källén 2011). Such drugs were not associated with an increased risk of congenital malformations.
Zolpidem crosses the human placenta and rapidly clears the fetal circulation. The ratio of umbilical cord to maternal plasma zolpidem concentrations ranges from 0.48 to 2.75 (Juric et al. 2009). Although the use of zolpidem has not been associated with teratogenic effects in usual clinical doses, a case of fetal neural tube defect has been reported following high dose exposure in the first trimester of pregnancy (Sharma et al. 2011).
7.5.2 Gestational Teratogenicity
7.5.2.1 Studies Suggesting an Increase in the Risk of Gestational Teratogenicity
To examine the extent and clinical sequelae of fetal exposure to zolpidem, pregnant women with psychiatric illness participated in a study of psychotropic pharmacokinetics (Juric et al. 2009). Outcomes were compared between the zolpidem-exposed group and a 1:1-matched comparator group. Forty-five women taking zolpidem during pregnancy were studied. Rates of preterm delivery and low birth weight were 26.7 % and 15.6 %, respectively, in the zolpidem-exposed group versus 13.3 % and 4.4 % in the matched comparator group, but no significant differences were found. However, pregnant women with psychiatric illness treated with zolpidem may have less optimal obstetrical outcome, though it is unclear if this was related to the medication (Juric et al. 2009).
A nationwide population-based study was carried out in Taiwan with the aim of comparing the risk of adverse pregnancy outcomes in women who received zolpidem treatment for insomnia during pregnancy with women who did not (Wang et al. 2010). The adverse outcomes identified and assessed were delivery of low-birth-weight (LBW) infants, preterm deliveries, delivery of small for gestational age (SGA) infants, delivery of infants with congenital anomalies, and cesarean delivery. The incidences of these were compared between the groups after adjusting for other characteristics of the mothers and infants. The study used the Taiwan National Health Insurance Research Dataset (NHIRD) and Birth-Certificate Registry. In total, the data from 2,497 mothers who received zolpidem treatment during pregnancy and those from 12,485 randomly selected mothers who did not receive the drug were included in the analysis. The results show that the adjusted odds ratios (ORs) for adverse pregnancy outcomes (LBW infants, preterm deliveries, SGA infants, and cesarean delivery) were all higher in mothers who received zolpidem treatment during pregnancy, relative to the randomly selected controls (1.39 (95 % confidence interval (CI) = 1.17–1.64), 1.49 (95 % CI = 1.28–1.74), 1.34 (95 % CI = 1.20–1.49), and 1.74 (95 % CI = 1.59–1.90), respectively).
7.5.3 Perinatal and Neurobehavioral Teratogenicity
To date, there have been no reports of perinatal complications and neurobehavioral impairment associated with in utero exposure to HBRAs.
7.6 Management of Anxiety Disorders in Pregnancy
Women with antenatal anxiety disorders require timely and efficient management that aims to reduce all such symptoms that may adversely impact on baby’s health.
7.6.1 Pharmacological Treatments
7.6.1.1 Benzodiazepines
When possible, BDZs should be avoided in both the first trimester and third trimester of pregnancy due to:
1)
2)
3)
7.6.1.2 Pregabalin
Since no information is available about the outcomes of pregnancies exposed to PGB, the drug should be avoided during pregnancy.
7.6.1.3 Hypnotic BDZ receptor agonists
Preliminary data, although apparently encouraging, are too limited to confirm or exclude a potential structural teratogenic liability. Above all, however, concordant safety signals seem to discourage the use of hypnotic agents during pregnancy because of an increase in the risk of gestational teratogenicity (preterm birth, low birth weight, and babies small for gestational age).
7.6.2 Antidepressants
Antidepressants have been shown to be an effective treatment for a range of Anxiety Disorders including OCD (Insel and Murphy 1981) and GAD (Ballenger et al. 2001). Details regarding the risks of antidepressant treatment in pregnancy are outlined in Chap. 6: Depression, Pharmacology and Pregnancy.
7.6.3 Non-pharmacological Interventions
Given these considerations, alternative interventions to pharmacological treatments should be considered first-line options.
Mild to moderate symptoms of anxiety are highly treatable using Cognitive Behavioral Therapy (CBT), an evidence-based, short-term, and focused treatment, in which patients learn to identify their distorted thinking, increase awareness of triggers, and modify maladaptive behaviors (Butler et al. 2006). Guidelines issued by the National Institute for health and Clinical Excellence recommend CBT as a first-line intervention especially for managing antenatal GAD and PD, whereas pharmacological treatment should be preferred for severe OCD (NICE 2007). Trauma-focused psychological therapy, for example, eye movement desensitization and reprocessing therapy, should be offered to those patients diagnosed with antenatal PTSD (NICE 2007). In contrast, insufficient evidence exists to determine if interpersonal psychotherapy is truly effective (Dennis et al. 2007).
Stress reduction techniques such as meditation, modified deep breathing for pregnant women (Wiegartz and Gyoerkoe 2009), and exercising (when medical conditions allow) may complement other forms of treatment (Avni-Barron 2001).
Similarly, treatments such as acupuncture and biofeedback (where patients learn to use their own bodily responses to monitor and control their anxiety) show promise, but their effectiveness is not conclusive (Avni-Barron 2001).
Another treatment evaluated by Chinese researchers is music therapy, a safe and inexpensive method to reduce antenatal anxiety. They explored whether this approach could relieve anxiety in pregnant women confined to bed. They recruited 120 women and gave them music therapy for 30 min on 3 consecutive days. Anxiety levels fell significantly in this group, compared to another group given usual health care (Yang et al. 2009).
Preliminary information seems to suggest that both aromatherapy and massage may be successful in producing clinically significant reductions in anxiety (Bastard and Tiran 2006).
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