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The British Journal of Psychiatry (2013)202, 347–351. doi: 10.1192/bjp.bp.112.115931 Maternal depression, antidepressant usein pregnancy and Apgar scores in infantsHans Mørch Jensen, Randi Grøn, Øjvind Lidegaard, Lars Henning Pedersen,Per Kragh Andersen and Lars Vedel Kessing BackgroundUse of antidepressants during pregnancy has been antidepressants (OR = 0.53, 95% CI 0.19–1.45). Maternal associated with a low Apgar score in infants but a depression before or during pregnancy, without prescription contribution from the underlying depressive disorder might of antidepressants, was not associated with a low Apgar score (OR = 0.44, 95% CI 0.11–1.74). Women who had onlyused antidepressants prior to pregnancy had no increased rate of a low Apgar score in their subsequent pregnancy, To estimate the effects of maternal depression and use of antidepressants during pregnancy on low Apgar scores (<7)5 min after birth.
Use of SSRIs during pregnancy increases the risk of a low Register study on all pregnant women in Denmark from 1996 Apgar score independently of maternal depression.
to 2006 linking nationwide individualised data from theMedical Birth Register, the Psychiatric Central Register and H.M.J has been a consultant for Bristol-Myers Squibb,Eli Lilly, Janssen-Cilag, Astra-Zeneca, Lundbeck, Servier, Merck Sharp & Dohme and Schering-Plough. Ø.L. has Infants exposed to antidepressants during pregnancy had an received honoraria for speeches including fees from Bayer increased rate of a low Apgar score (odds ratio (OR) = 1.72, Pharma Denmark, MSD Denmark and Theramex, Monaco, 95% CI 1.34–2.20). The increased rate was only found among and has been expert witness for a plaintiff in a legal US case infants exposed to selective serotonin reuptake inhibitors in 2011. L.V.K. has been a consultant for Bristol-Myers (SSRIs) (OR = 1.96, 95% CI 1.52–2.54), not among those Squibb, Eli Lilly, Lundbeck, Astra-Zeneca, Pfizer, Wyeth, exposed to newer (OR = 0.83, 95% CI 0.40–1.74) or older A substantial number of pregnant women experience depressive those born with an Apgar score of 7–10.13 Further, an Apgar score symptoms during pregnancy with prevalence rates of depression 57 at 5 min has been associated with neurological disability, in the range 7–13%1,2 and 4–7.6% of pregnant women are including cerebral palsy, epilepsy and cognitive impairment that treated with antidepressants.1,3 Mental disorders and psychotropic drugs may influence the development of the fetus, but theassociations are unclear, and mechanisms are poorly understood.
Antidepressants readily cross the placenta barrier potentially affecting fetal development4 but maternal depressive illness mayalso cause adverse effects on pregnancy outcome. Increased placental secretion of corticotrophin-releasing hormone resulting We linked data on all pregnancies from 1996 to 2006 from the in increased activity within the gestational cortisol system,5 as well Medical Birth Register with data from the Psychiatric Central as unhealthy behaviour related to depression such as smoking and Register, the Medicinal Product Statistics register and Statistics poor attendance for obstetric care, may have adverse effects.2,3,6 The importance of differentiating the effects of exposure to The Medical Birth Register16 includes data on date of birth, maternal depression from the effects of antidepressants has been gestational age, Apgar score 5 min after birth, birth weight, length highlighted in recent reviews6–9 but, so far, studies have not of fetus, maternal smoking status during pregnancy, parity and sufficiently discriminated between the effects of maternal disease maternal age on all deliveries in Denmark. Data from births of and use of drugs in relation to birth outcomes, except from one more than one child from 1996 to 2006 were included whereas study10 that revealed an increased risk of low birth weight and twin births were excluded, implying that the same woman could respiratory distress even when maternal illness severity was accounted for. The hypothesis of the present study was that birth The Medicinal Product Statistics is a nationwide prescription complications, as reflected in a low Apgar score, are explained by database containing individual information on all prescriptions the effect of the maternal disease. We compared the Apgar score in filled at all Danish pharmacies from 1995 and onwards.17 Data eight risk groups, classified according to maternal depression and included and distinguished between ATC codes (Anatomical exposure to antidepressants, in a nationwide register linkage study.
Therapeutical Chemical classification system) for antidepressant, The Apgar score at 5 min after birth is a clear index of antipsychotics, anti-epileptics and ‘other kinds of drugs’. Anti- problems in adult life; recent studies have shown that infants with depressants were classified as selective serotonin reuptake low Apgar scores (57 at 5 min) are at increased risk of a low IQ inhibitors (SSRIs: fluoxetine, citalopram, escitalopram, paroxetine, score at age 18,11 never receiving graduation grades12 or attending sertraline, fluvoxamine: ATC N06AB03–10), newer antidepressants university and are more likely to have no income from work than (nefazodone, mirtazapine, venlafaxine, reboxetine: ATC N06AX06, –11, –16, –18 and –21) or older antidepressants consisting Logistic regression analyses were applied with Apgar score as mainly of tricyclic antidepressants (imipramine, clomipramine, the outcome and risk group as the variable of interest. The trimipramine, lofepramine, amitriptyline, nortriptyline, doxepin, analyses were adjusted for the effect of calendar periods (1996, dosulepin, amoxapine, maprotiline; mianserin, isocarboxazid, 1997, 1998 etc. to 2006), maternal age, parity (first child, second moclobemide: ATC N06AA02–7, N06AA09–12, N06AA16–17, child, child number three or more), employment status N06AA21, N06AX03, N06AF01 and N06AG02).
(employed, unemployed, disability pension and retired, student, The Danish Psychiatric Central Register is a nationwide child and others), smoking status (non-smoker, quit smoking, psychiatric register18 with data from all public mental health services smoking, unknown), gestational age, gender of the child, birth both as in- and out-patients. Data extracted were ICD-819 and weight and use of other medication during pregnancy, including ICD-1020 codes for depression (i.e. ICD-8 codes 29609 and use of lithium (yes/no), anti-epileptics (yes/no), antipsychotics 29629, ICD-10 codes DF32.00-DF33.99). Statistics Denmark (yes/no) and other kinds of medication than antidepressants, provided data on employment status on a yearly basis for the lithium, anti-epileptics or antipsychotics (yes/no). In the analysis, employment status was dichotomised into ‘working and students’v. the remaining groups.
To account for the fact that some women contributed with more than one live birth, robust standard errors were compared Pregnant women were divided into eight risk groups according to with the model-based standard errors. Since the impact of this their exposure to a diagnosis of depression before the end of adjustment was minimal, only model-based standard errors are antidepressant use during pregnancy (see Table 2, Model 1).
Group 1 was the reference group.
Additional analyses were done using three binary variables (+ diagnosis before end of pregnancy; + antidepressants beforepregnancy; + antidepressants during pregnancy; see Table 1 and The data-set included all pregnant women in Denmark from 1996 to 2006. Infants with a gestational age of less than 22 weeks were To avoid assumptions of linearity, Apgar score at 5 min was excluded from the data resulting in a total of 672 601 live births.
divided into two groups: Apgar score from 0 to 6 and 7 to 10 Data on birth weight were available from 668 144 live births in accordance with the dichotomisation in prior studies showing (99.3%) and data on Apgar score at 5 min were available for poorer intellectual, cognitive, social and clinical outcome related 665 399 live births (98.93 % of all live births) resulting in 664 089 live births with full data on Apgar score and other Characteristics of pregnant women and offspring according to antidepressant therapy and depressive diagnosis IQR, interquartile range.
a. Each of the three columns are binary (antidepressant medication before pregnancy (yes/no), antidepressant medication during pregnancy (yes/no), depression diagnosis beforeend of pregnancy: yes/no) and presents data for those patients fulfilling the criteria (yes). The columns are not mutually exclusive.
Antidepressant use in pregnancy and Apgar scores predictive variables included in the analysis. Among the 664 089 Additional analyses using three binary variables confirmed the children, 22 155 (3.34%) had a birth weight below 2500 g, and results as only children of women using antidepressants during 4076 children (0.61%) had an Apgar score after 5 min between 0 pregnancy had an increased risk of a low Apgar score and 6 whereas 660 013 children had an Apgar score from 7 to 10.
(OR = 1.67, 95% CI 1.30–2.14); unadjusted OR = 1.87 (95% CI Table 1 shows the characteristics of the 664 089 births 1.41– 2.47) whereas there was no effect of use of antidepressants according to the mother’s antidepressant therapy and depressive before pregnancy or a diagnosis of depression (see lower part of diagnosis. As can be seen from Table 1, for 3916 live births the Table 2, Model 2). These results did not change, resulting in mother had a diagnosis of depression before the end of pregnancy.
ORs within the same ranges, when Model 2 was repeated with For a total of 8375 live births the mother redeemed a prescription exclusion of preterm births, i.e. gestational age 536 weeks for antidepressants during pregnancy (Table 1). In 2941 of these (antidepressants before pregnancy: OR = 0.95, 95% CI 0.79–1.14; cases only one prescription was redeemed whereas, in 5434 cases, antidepressants during pregnancy: OR = 1.87, 95% CI 1.41–2.47; two or more prescriptions were redeemed; for 7208 live births the diagnosis of depression before end of pregnancy: OR = 0.69, mother redeemed a prescription for an SSRI, 982 for a newer antidepressant and 780 for an older antidepressant. Among the Further analyses of subtypes of antidepressants showed that 664 089 children included, in 7389 (1.11%) cases the mother only use of SSRIs during pregnancy increased the OR of a low redeemed a prescription for an antidepressant during the first Apgar score whereas there was no effect of use of newer anti- trimester, 3780 (0.57%) during the second trimester and 3246 depressants or older antidepressants during pregnancy (Table 3, although a formal test of homogeneity resulted in only a Prior to pregnancy, 33 084 (4.98%) women redeemed borderline significant difference, P = 0.052). Using antidepressants prescriptions for antidepressants (Table 1), 59 (0.01%) lithium, before conception did not significantly increase the OR for a low 2884 (0.43%) anti-epileptics, 1278 (0.19%) antipsychotics and Apgar score regardless of the type of antidepressant.
450 712 (67.87%) women redeemed prescriptions for other drugs.
There was no differential effect of timing of the use of anti- Table 2 shows the adjusted odds for a low Apgar score (0–6 v.
depressants during various trimesters (first trimester: OR = 1.16, 7–10) in the risk groups according to logistic regression analyses 95% CI 0.83– 1.63; second trimester: OR = 1.51, 95% CI 0.90– (Model 1). The only risk group with a significantly increased risk 2.53; third trimester: OR = 1.42, 95% CI 0.85– 2.38), which may for a low Apgar score 5 min after birth compared with the be explained by the limited sample size in these analyses.
reference group was risk group 4, i.e. children born of womenwithout a diagnosis of depression, who had redeemed a prescription for antidepressants before and during pregnancy(OR = 1.72, 95% CI 1.34–2.20). Odds ratios for risk group 3 (no We found that a low Apgar score was attributed to the use of SSRIs diagnosis + antidepressants during pregnancy) and risk group 8 during pregnancy and not to the effect of the disease or associated (a diagnosis of depression + antidepressants before and during lifestyle factors. Non-SSRI antidepressants were not associated pregnancy) were also increased but did not differ significantly with a low Apgar score. No increased rates were found among from the reference group. If the mother had taken medication women who used antidepressants prior to pregnancy (but not during; risk group 2) or who had a diagnosis of depression but antipsychotics, the OR for a low Apgar score was slightly increased used no antidepressants during pregnancy (risk groups 5 and 6).
The Apgar score 5 min after birth is a clear index of problems All analyses were repeated without correcting for gestational in adult life; studies have shown that infants with low Apgar scores age and birth weight. These analyses resulted in the same findings (57 at 5 min) are at increased risk of a low IQ score at age 18 as when correcting for gestational age and birth weight with ORs (OR = 1.35, 95% CI 1.07–1.69),11 never receiving graduation grades (OR = 1.93, 95% CI 1.75–2.14),12 never attending university Adjusted odds rate of a low Apgar score (0–6 v. 7–10) according to depressive diagnosis and antidepressant therapy end of pregnancy before pregnancy during pregnancy Diagnosis of depression before end of pregnancy a. The eight groups in Model 1 are mutually exclusive and sum up to 100%. The three groups in Model 2 are not mutually exclusive.
b. Odds ratio adjusted for: maternal age, social status, smoking status, calendar year, gender of newborn, and use of anti-epileptics, antipsychotics and other types of medication.
of other birth complications such as low birth weight35–37 and Subtypes of antidepressantsa and risk of a low preterm delivery,38,39 but it should be noted that none of these studieshas taken the potential effect of the depressive illness into account.
We found a lower prevalence of depression (i.e. 0.6%) than previously reported as we used data from nationwide databases, which only include information from hospital-based psychiatric facilities and not from general practitioners. Consequently, we had data on a diagnosis of depression only for women with more severe and complicated depressive illnesses. For these women, we found no association between depression and Apgar score and thus believe that the effects of milder forms of depression areunlikely. We have no reason to suspect a reverse dose–response a. According to the Anatomical Therapeutical Chemical (ATC) classification system.
b. Odds ratios adjusted for: maternal age, social status, smoking status, calendar relationship between depression and birth outcome. Further, the year, gender of newborn, and use of anti-epileptics, antipsychotics and other types impact of antidepressants on birth outcome seems to be In the present study, only 1.26% of the pregnant women were (OR = 1.14, 95% CI 1.05–1.23) and are more likely to have no treated with antidepressants. The low percentage is explained by income from work (OR = 1.19, 95% CI 1.07–1.32) than those born the fact that data were gathered from 1996 at which time it was with an Apgar score of 7–10.13 Further, an Apgar score 57 at uncommon to treat pregnant women with antidepressants. The 5 min has been associated with neurological disability, including number of women treated with antidepressants during pregnancy cerebral palsy, epilepsy and cognitive impairment that seems to in the sample increased steadily each year from 232 in 1996 to 1453 in 2005. The increase in prevalence of pregnant women A number of studies have demonstrated low Apgar scores in undergoing treatment is also found in other countries, for children exposed to SSRIs in utero22–26 whereas the effects of newer and older antidepressants have not been investigated.27We found that the risk of a low Apgar score was associated specifically with the use of SSRIs during pregnancy whereas We used information from national registers with longitudinal there was no increased risk in relation to the use of newer data on inhabitants from an entire country. The data in these antidepressants or older antidepressants (mainly tricyclic anti- registries are collected prospectively and therefore recall bias is depressants; Table 3). A recent review28 suggests that antenatal excluded. In contrast, in retrospective studies the recall of exposure to antidepressants is associated with a higher risk of potential treatment with antidepressants during pregnancy may neonatal adaptation difficulties.22,29 A possible explanation could be influenced by the prevalence of birth complications. The study be a direct effect of SSRIs on the development of the fetal brain.
presents data from almost 665 000 births and is able to adjust for a The serotonergic network projects from the raphe nuclei and number of potential confounders including all medication other arborises over large areas to an array of other nuclei30 comprising than antidepressants. We had almost complete data with, for functionally diverse targets; it interacts with other neurotransmitter example, information on the Apgar scores for 98.9% of infants.
systems31 and plays a role in regulation and developmental signalling The number of women who did not use antidepressants during in the organisation of developing neural networks in the central pregnancy but who previously had used antidepressants or had nervous system (CNS).32 Antidepressants readily cross the placental a diagnosis of depression was rather large and consequently the barrier, exposing the fetal CNS, which from even a very early statistical power to detect an association between depressive illness embryonic stage, displays a serotonergic network,4 and effects in per se and a low Apgar score was high, as reflected by the narrow offspring after maternal exposure to antidepressants have been We were able to take into account other possible risk factors for a low Apgar score (i.e. parity, maternal social status, maternal smoking status, calendar year, other medication and gestational Redeeming a prescription does not necessarily mean that the age). In our models, these factors did not explain the higher woman actually took the medication, although having paid for ORs for a low Apgar score for children born of mothers using it at a pharmacy increases the possibility. The potential exposure antidepressants during pregnancy. This finding was independent misclassification tends to underestimate the effect of antidepressant of whether the mother had a diagnosis of depression or not.
drugs or overestimate the effect of depression among women that Confounding by unmeasured factors or residual confounding is, however, still possible but would have to act specifically on the The timing of maternal depression varied in the study and the women with depression and who took medication and not on extent to which women presented with depressive symptoms the non-medicated controls to explain our main result (see before compared with during pregnancy may be unclear. In fact, below). The aim of this study was not to determine whether 3245 women received a diagnosis of depression before pregnancy pregnant women with depression should be treated with anti- (with a median period from the time of diagnosis to pregnancy of depressants or not. The study shows that treating depression does 801 days (quartiles: 346, 1568)) and 918 received a diagnosis have consequences that should be taken into consideration when a during pregnancy. It is likely that the former group may have physician informs a female patient about risk factors enabling her presented with depressive symptoms of differing severity during to make an evidence-based decision. Thus, although the probability pregnancy although only 27% of this group got antidepressants of a low Apgar score was increased more than 70% in children during pregnancy. Nevertheless, we can only conclude from our whose mother had used SSRIs during pregnancy, compared with results that having a depressive disorder at one point in time healthy women, the absolute prevalence of a low Apgar score before the end of pregnancy was not associated with an increased was still low (1.14%, Table 1). Further, treatment with anti- risk of a low Apgar score when the pregnant women did not use depressants during pregnancy has been associated with a number antidepressants during pregnancy (risk groups 5 and 6 in Table 2).
Antidepressant use in pregnancy and Apgar scores We cannot exclude the possibility that the risk of a low Apgar 12 Stuart A, Otterblad OP, Kallen K. Apgar scores at 5 minutes after birth in score would have been increased for these groups if our sample relation to school performance at 16 years of age. Obstet Gynecol 2011; 118:201–8.
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19 World Health Organization. International Statistical Classification of Diseases In conclusion, women who are treated with SSRIs during and Related Health Problems (ICD–8). WHO, 1967.
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be attributable to treatment and not to the disease.
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