Links between serotonin reuptake inhibition during pregnancy and neurodevelopmental delay/spectrum disorders: A systematic review of epidemiological and physiological evidence

1.1 Biological plausibility

As regards a linkage between antidepressant use and neurodevelopmental issues, serotonin is notably the most primitive of neurotransmitters; it has a role in early reproduction, and as a result it has long been recognized that acting on serotonin during the gestational period has the potential to cause significant problems [8, 9].

In 1960, linked to studies of the effects of antidepressants on serotonin, Ashcroft suggested that there might be a lowering of serotonin in depression [10]. By 1970, Ashcroft and others had discounted this link [11].

In contrast in 1961, a first report was published of elevated serotonin levels in autism [12]. This finding has been consistently replicated since [13–15].

In the early 1960s, a first linkage was made between serotonin and birth defects in animal studies [16–18]. In the early 1970s the first reports linking serotonin reuptake inhibiting antidepressants to birth defects appeared [19]. In 1990, the first independent study linking SSRI intake to teratogenic potential in animal studies was published [20].

As of the 1980s,following descriptions of Fetal Anticonvulsant Syndrome (FACS) and Fetal Valproate Syndrome (FVS), characterized by prominent deficits in social communication and other ASD features [21, 22], a consensus emerged that psychotropic drugs could produce behavioral teratological effects even if they did not show clear anatomical abnormalities such as cardiac or neural tube abnormalities after use during pregnancy [23].

These developments led companies producing novel centrally acting drugs in the 1980s, including SSRIs, to undertake animal studies. In the case of the SSRIs, the animal studies looked at embryo-lethality and gross malformations, but an associated objective was to investigate the behavior of neonatal pups. Many of these company studies show a dose related fetal death and other features consistent with a teratogenic capability. The existence of these studies designed to look for evidence of behavioral consequences of SSRI intake during pregnancy for the most part remains unknown with the studies unpublished and the data inaccessible.

There is however a growing set of independent animal studies demonstrating birth defects linked to SSRI use with a range of mechanisms that may underpin these effects [24].

Consistent with these studies and mechanisms, a series of epidemiological studies from 1998 onwards have demonstrated that SSRIs come with a teratogenic potential [25–52]. These findings are summarized in Healy et al. [53] and Berard et al. [24].

Finally published animal studies consistently show that pups born to animals administered antidepressants during pregnancy show a range of behavioral changes indicative of reduced social confidence and communication deficits consistent with a diagnosis of neurodevelopmental spectrum disorders in humans [54–61].

1.2 Objectives

Question: Is there evidence to suggest a link between maternal ingestion of SSRI antidepressants during pregnancy and later effects on measures of cognitive function that may lead to diagnoses of behavioral deficits in children exposed in utero, primarily a diagnosis of ASD?

Question: If a link exists, is there evidence from animal intervention studies of a biological mechanisms that might underpin the effect?

2.1 Design

We carried out a systematic search for all epidemiological studies linking the use of serotonin reuptake inhibiting antidepressants during pregnancy to ASD, and related constructs such as developmental delay or pervasive developmental disorder in offspring. In addition we searched for publications relevant to the range of possible mechanisms through which antidepressant usage might give rise to a diagnosis of ASD in offspring. We followed the MOOSE Guidelines for meta-analyses and systematic reviews of observational studies [62].

2.2 Search strategy

We searched Embase, OVID and the Cochrane Library to identify English-language abstracts published up to December 2015. Search terms and strategy were determined by the investigators with advice from a librarian. We applied the following search terms in various combinations which was adapted for each database: Search terms: antidepressants, selective serotonin reuptake inhibitors, SSRIs, pregnancy, autistic spectrum disorder, developmental delay, autism, ADHD, birth defects.

We also hand-searched reference lists of included and excluded articles for articles of potential relevance.

2.3 Data management

Abstracts were retrieved and screened and articles determined to be of potential relevance were retained. These articles were screened in detail and articles meeting inclusion criteria were included. Each abstract screened and each potentially relevant article retrieved was reviewed independently by two authors (JLN and DM). Discordances were resolved by discussion among the three authors. Review articles were excluded, though references were hand searched for other relevant original data-containing studies.

Abstracts were included for analysis (human) if they satisfied the following inclusion criteria:

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Provided exposure data on gestational SSRI use

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Provided quantitative measures of cognitive behavioral or developmental function in the children exposed in utero

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Controlled for exposure to other potentially teratogenic medications

Abstract were included for analysis (animal) if they •

Provided data on gestational antidepressant use

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Provided quantitative measures relevant to cognitive behavioral or developmental outcomes

We did not restrict by study design but quantitative results had to be available. We excluded articles where we could not obtain an English translation, review articles, and studies where we had abstracts.

Data from included articles were extracted using a standardized form describing the following study characteristics: year, target population, location, sample size, study design, outcome measure, knowledge gaps, key conclusions and study setting. We assessed for duplicate citations and tools.

Where the data on outcomes was available within the published study, we abstracted it from each of these studies. Where the data was not available, we wrote to the authors to request it.

2.4 Statistical analyses

All analyses were conducted using Review Manager 5.2 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012).

We performed two main analyses, one assessing the association between maternal SSRI use in pregnancy and ASD and the other assessing the association between maternal SSRI use in pregnancy and other neurodevelopmental abnormalities related to autism.

There are methodological issues in plotting these data. In studies looking at children, some less than a year old, it is only possible to look at developmental delay rather than at outcomes that by consensus point to specific failures of social communication rather than cognitive impairment in general. Some studies present outcomes across a range of soft neurological indicators (up to 10 in one study). In order to plot the data, it is necessary therefore to take a representative measure from each study to include in the forest plot. This has been outlined in the appended tables. All data are available from the authors which will permit others to enter different data sets into the plot, as indicated.

3.1 Potential mechanisms

In terms of the effects of antidepressants on neurodevelopment, we have abstracted a range of mechanisms through which gestational SSRIs might impact on cognitive function that recent literature supports.

First, as noted above serotonin has a role in embryogenesis and there is convincing evidence that disturbing this function leads to defects in many systems from cardiac through to neurological [24]. In addition to evidence for gross birth defects, there has been evidence from animal studies for over a decade that SSRIs can lead to abnormalities in cerebral architecture [85–87]. We have not found any studies demonstrating normal brain architecture. These changes appear linked to reduced exploratory behavior and reduced reactivity [88].

Second, SSRIs have profound effects on sexual behavior and this can be expected to have longer term consequences in the social domain [55, 56, 89].

Third, SSRIs can induce compulsive alcohol intake [84] and this might be expected to make some contribution to the epidemiological picture. The study by Malm et al. [43] suggests it does.

Fourth, a noted feature of SSRIs is that they produce the experience of blunted emotion [90]. Linked to this it would appear, they lead to decrements in our abilities to read emotion [91]. These behavioral effects are consonant with changes that will register on instruments currently used to detect communication difficulties and are likely to lead to an ASD diagnosis.

This point has become of greater interested in the light of evidence linking acetaminophen (paracetamol) to ASD [92]. While the link here might arise indirectly, if acetaminophen is used to treat a fever, this medicine also appears to have comparable effects to SSRIs on sociability in animals [93] and on the ability of people to read emotions [94]. Acetaminophen also has effects on S-1 receptors so there is a considerable overlap in its mechanism of actions with SSRIs.

Both acetaminophen and SSRIs may therefore mediate their effects through end-stage behavioral changes. These behavioral changes can endure for months after treatment stops in adults. If administered in utero, one possibility is that such changes may be even more likely to endure and produce an ASD clinical picture.

Fifth, given that current diagnoses of ASD may include children with general cognitive problems rather than specific disturbances of a discrete communication function, a range of treatment related factors from SSRI withdrawal to postnatal operative interventions to correct birth defects may contribute to the potential of these drugs to give rise to ASD clinical pictures.

Finally when considering these mechanisms it would be a mistake to focus solely on a supposed ASD. It is important to establish the full range of effects these drugs have and there is emerging but as yet unpublished literature that rates of ADHD for instance may be increased in children born to mothers on SSRIs. Any mechanisms proposed need to be able to account for such changes also.

4.1 SSRIs in pregnancy

For SSRI usage to have played a part in increasing rates of ASD, we would expect there to be evidence that there has likely been an increase in the use of these drugs in women of child-bearing years and a more relaxed medical and public attitude about the use of these drugs duringpregnancy.

Unlike earlier antidepressants where the market was largely in older age groups, it was clear that a large part of the market for SSRIs would be to women of child-bearing years.

In the early 1990s when the SSRIs were marketed first, the prevailing wisdom was that giving psychotropic drugs in pregnancy was to be avoided; regulators supported avoidance [119], professional bodies supported avoidance [120], and leading psychiatrists warned of the teratogenic potential of psychotropic drugs [121–123].

There was not thought to be any increase in the incidence of mood disorder during pregnancy [124]. There was not thought to be any risk from mood disorders to the fetus; the risk from mood disorders lay in the risk posed to the mother such as suicide [125].

In contrast today it is common to hear claims that depression directly or indirectly causes birth defects; to see a conflation of depressive symptoms with depressive illnesses, so that rates of 15–20% for depressive disorders are cited when this should only apply to depressive symptoms [53]; and it is not widely noted that the majority of states treated with these drugs left untreated clear up spontaneously within weeks.

In 2015, in the absence of any intervening data that depression causes birth defects or that SSRIs are effective in antenatal depression, it is possible to find the same authors who advocated caution about the use of antidepressants in the early 1990s, supporting claims that:

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Depression can cause birth defects [126]

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Antidepressants do not cause birth defects or cognitive problems [127]

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That coming off antidepressants is inadvisable [128]

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Professional bodies endorse the use of antidepressants [129]

If SSRIs work, as claimed by marketing, namely by correcting a serotonergic abnormality it might be thought they would reduce the risk of things going wrong. But there is no such abnormality and treatment with an SSRI on balance will leave serotonin systems more abnormal that they were to begin with [130].

If working means that SSRIs reduce risky behaviors including alcohol and drug intake, the evidence is somewhat to the contrary; SSRIs may increase alcohol and drug use [84, 131].

4.2 Alternative explanations

Concerns about a link between SSRIs and birth defects have met the following counter arguments that are as readily applicable here.

First, rates of ASD from these studies, as is the case with rates of birth defects on SSRIs, fall within the background rate of the population at large and on this basis it is claimed that even where the rates in the treated group exceed those in the control group, these rates can be discounted [see 128, 132]. This argument is not valid for birth defect studies where the background rate is determined by the study design. The argument is misplaced for a condition like ASD or neurodevelopmental spectrum disorders where the background rate appears to be changing by the year.

Second, studies of SSRI use during pregnancy show a consistent rate of problems and that when all studies are meta-analyzed the risks disappear. We have not been able to analyze all studies as some groups, such as the Motherisk group, refuse to share their data.

Third, it is claimed that depression causes both birth defects and ASD and is endemic in pregnant women at rates of 15–20%. We believe there is no good evidence for these propositions.

Fourth, it is proposed that there are no adequate and well-conducted studies in this area. This statement means that there are no RCTs and assumes the reader will accept the proposition that only RCTs can demonstrate if an antidepressant causes birth defects or ASD or not. In our opinion this position is incorrect. RCTs can get the answer as badly wrong as any other epidemiological study [see 133]. To establish what is happening will need judgements that take both the epidemiological and biological data into account. It is only when there is a good understanding of what is happening that an appropriate RCT can be designed.

Finally, it is claimed that the results cited from a majority of studies show no statistically significant difference between women treated and those not treated. For some if an increase in risk is not significant, they take a view that there is in fact no increase in risk. This is not the most widely accepted view in the field [134]. The visual plots of the meta-analyses demonstrate this point clearly.