A gigantic uncontrolled experiment

Part II: Please don’t forget about me“: Antidepressants and birth defects

Since the beginning of the modern psychopharmaceutical era, the proportion of the population diagnosed with depression has skyrocketed. A condition that once affected fewer than one person out of a thousand now afflicts more than one out of twenty. Today major depression is the leading cause of disability for adults between the ages of 15 and 43.

During that same period, consumption of antidepressants also has skyrocketed.

Currently one in six American women between the ages of 20 and 44 (an age bracket corresponding to the prime childbearing years) is taking some kind of antidepressant medication. Since more than half of pregnancies are unplanned, and many women continue taking antidepressants after learning they are pregnant, untold numbers of babies have been exposed to these drugs in the womb. These drugs readily cross the placenta and become part of the environment bathing the developing fetus, and not one of them was tested for safety and effectiveness in pregnant women before being released. This is a gigantic uncontrolled experiment.

Part I: “Please don’t forget about me”: Antidepressants and birth defects

A mountain of evidence has accumulated linking antidepressants to spontaneous abortions, preterm birth, and low birth weight

An early indication that something might be amiss appeared in 1996, when a NEJM study compared pregnancy outcomes in 228 women taking Prozac with 254 matched controls. The researchers found that the rate of major structural abnormalities in the offspring of the Prozac-exposed women was higher than those of unexposed women, although not significantly so (5.5% versus 4.0%). In addition, the percentage of offspring with three or more minor structural abnormalities was significantly higher in the Prozac-exposed group (15.5% versus 6.5%), as was the rate of premature birth and a condition identified as “poor neonatal adaptation,” characterized by tremors, rapid shallow breathing, hypoglycemia, hypothermia, poor tone, weak or absent cry, respiratory problems, and oxygen desaturation on feeding.

Perhaps most disturbingly, 2.7% of the Prozac-exposed newborns suffered from primary pulmonary hypertension of the newborn, or PPHN, the same condition that afflicted Christiane and Amery’s sons Jacob and Matthew. None of the controls had this condition, and the prevalence in the general population is estimated to be on the order of one in a thousand or less.

Since then, a mountain of evidence has accumulated linking antidepressants to spontaneous abortions, preterm birth, and low birth weight. The latter two are themselves risk factors for a whole host of physical and mental problems, including depression.

In addition, as many as 30% of newborns exposed to antidepressants during late pregnancy suffer from “neonatal abstinence syndrome” (the condition identified by in the aforementioned NEJM study as “poor neonatal adaptation”), sometimes requiring prolonged hospitalization in the neonatal intensive care unit, along with sedation, ventilation, oxygen, tube feeding, antibiotics, and intravenous fluids. This latter condition is often dismissed in the medical literature as a minor and transient problem, with one expert opining “Although there is now a significant literature demonstrating that exposure to SSRI’s during pregnancy may be associated with adverse neonatal effects, these are predominantly mild and short-lived, and there have not been any reported deaths.” No consideration ever seems to be given to the possibility that having one’s newborn baby confined to an incubator, subjected to a whole slate of high-tech medical interventions, might itself be a depressing experience for a new mother.

Possibility that some of these drugs could cause major birth defects

Even more disturbing is the possibility that some of these drugs could cause major birth defects. One of the best-established associations is between paroxetine and cardiac malformations. Paroxetine (known as Paxil in America and Seroxat in the UK) was first introduced by SmithKline Beecham at the end of 1992. (In 2001, SmithKline Beecham merged with Glaxo Burroughs Wellcome to form industry behemoth GlaxoSmithKline). Paroxetine belongs to a class of drugs known as selective serotonin reuptake inhibitors, or SSRI’s. In 2005 GlaxoSmithKline researchers examined data from one of their own studies designed to assess whether bupropion exposure during pregnancy was associated with major congenital malformations. The researchers found no such effect, but they did find that paroxetine caused a two-fold rise in heart defects. The FDA and Health Canada, in agreement with GSK, issued an advisory stating “there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience in humans, but potential benefits might warrant the use of the drug in pregnant women despite potential risks. Paroxetine should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.”

The following year, two Swedish researchers examined data from the Register of Congenital Malformations and found that paroxetine nearly doubled the incidence of heart defects, from 1.1% to 2.1%. That same year, Anick Bérard and her colleagues at the University of Montreal examined registry data from Quebec and found a dose-dependent relationship between paroxetine and congenital heart defects: women taking more than 25 mg/day of this drug during the first trimester of pregnancy have a three-fold increase in the rate of major cardiac malformations. Since then, the link between paroxetine and congenital heart defects has been confirmed by a long series of empirical studies and meta-analyses, including a 2009 meta-analysis published in Birth Defects Research by Keele Wurst and his colleagues. In an accompanying commentary, the aforementioned Dr. Bérard reviewed the evidence for the link between paroxetine during pregnancy and congenital heart malformations, using the criteria put forth more than fifty years previously by Sir Austin Bradford Hill, Professor of Statistics at the University of London and the discoverer of the link between cigarette smoking and cancer:

Danish researchers confirmed the link between SSRI antidepressants and congenital heart defects

1. Strength of association: The meta-analysis by Wurst et al. showed that paroxetine increases the risk of cardiac malformations by at least 50%.

2. Temporality: Exposure always preceded events in all of the studies reviewed by Wurst et al.

3. Consistency: Major studies consistently show that paroxetine increases the risk of cardiac malformations.

4. Theoretical plausibility: Paroxetine blocks the uptake of serotonin, a signaling molecule that stimulates cell division and plays an essential role in the development of the heart (and probably every other organ in the body).

5. Coherence: the association between paroxetine and heart defects is coherent, meaning it does not conflict with other knowledge, and there are no competing or rival theories to explain the association.

6. Specificity: This one is admittedly is hard to come by, as there are multiple known causes of birth defects.

7. Dose-response relationship: As mentioned above, Dr. Bérard and her colleagues have demonstrated a dose-response relationship between paroxetine in early pregnancy and major congenital heart defects.

8. Experimental evidence: The quality of experiment evidence is good, with most of the experimental studies being adjusted for potential confounders.

9. Analogy: We know that environmental exposures during early pregnancy (including medication exposure) have a direct effect on the risk of major congenital malformations, including cardiac malformations.

A 2012 study by Danish researchers confirmed the link between SSRI antidepressants and congenital heart defects, finding that SSRI’s during the first trimester of pregnancy doubled the risk of cardiac malformations. The researchers also found that the risk was almost identical for women who stopped taking antidepressants 3-12 months before pregnancy—lending support to Amery Schultz’s suspicion that their son Daniel’s heart problems could have been caused by Effexor, even though his wife Christiane stopped taking the drug before getting pregnant. (Effexor is classified as a serotonin-norepinephrine reuptake inhibitor, not an SSRI, but like SSRI’s it does inhibit the uptake of serotonin.)

Unfortunately all these revelations came too late for the Schultzes—or for Michelle David, a young woman living in southeastern Pennsylvania who was trying to begin a new family around the same time.

Part I: “Please don’t forget about me”: Antidepressants and birth defects

Next: Part 3: “I was absolutely distraught

Written by Patrick D. Hahn and published by Canada Free Press ~ June 6, 2017.

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