Baum Hedlund Law
February, 2007
Persistent pulmonary hypertension of the newborn is a life-threatening disorder in which the newborn's arteries to the lungs remain constricted after delivery, limiting the amount of blood flow to the lungs and therefore the amount of oxygen into the bloodstream. Newborns who have PPHN are typically full-term or near-term infants who are born without associated congenital abnormalities, yet present after birth with severe respiratory failure. Babies born with this condition often require intubation and mechanical ventilation. Despite this treatment, 10 to 20 percent of affected infants do not survive.
The connection between PPHN and selective serotonin reuptake inhibitors -- a class of antidepressants used in the treatment of depression, anxiety disorders, personality disorders and several other conditions -- was first reported in the scientific literature in 1996. That year, Dr. Christina Chambers and several of her colleagues performed a case-controlled study of women on Prozac and discovered that infants born to women who took Prozac late in their pregnancy had a host of breathing difficulties, including PPHN. See Christina D. Chambers et al., "Birth Outcomes in Pregnant Women Taking Fluoxetine," N. Engl. J. Med. 1996; 335; 14: 1010-1015.
In a follow-up study, Chambers and her colleagues concluded that mothers who took SSRIs in the second half of their pregnancies were six times more likely to give birth to a baby with PPHN. Christina D. Chambers et. al., "Selective Serotonin-Reuptake Inhibitors and Risk of Persistent Pulmonary Hypertension of the Newborn," N. Engl. J. Med. 2006; 354; 6: 579-587. Despite this research, it was not until July 19, 2006, that a public health advisory from the U.S. Food and Drug Administration alerted physicians and patients about the Chambers studies and the risk of PPHN.
http://www.fda.gov/cder/drug/InfoSheets/HCP/fluoxetineHCP.htm
Although researchers admit their studies cannot conclusively establish causality, they have offered an explanation as to why SSRI exposure causes PPHN. It has been discovered and discussed among researching physicians that the lung acts as a reservoir for antidepressant drugs and, in fact, a 1998 study in The Lancet reported substantial accumulation of SSRIs within the lungs. Moreover, serotonin has vasoconstrictive properties that increase pulmonary vascular resistance, and at the same time has mitogenic and comitogenic effects on pulmonary smooth-muscle cells. Therefore, higher levels of serotonin circulating within the growing fetus and the accumulation of serotonin within the fetus's lungs may result in the proliferation of smooth-muscle cells that is characteristic of PPHN. In addition, SSRIs have an inhibitory effect on the synthesis of nitric oxide, a vasodilator that may have a role in the regulation of vascular tone and reactivity both in utero and during postnatal life.
Less severe complications occur in 20 to 30 percent of all newborns with prenatal exposure to SSRIs late in the pregnancy. These complications include mild respiratory distress, transient tachypnea of the newborn (a condition that results when there is extra fluid in the lungs or the fluid in the lungs is absorbed too slowly, making it more difficult for the baby to take in oxygen properly and requiring the baby to breathe faster and harder to compensate), failure to cry, and cyanosis (the bluish coloration of the skin due to the presence of de-oxygenated hemoglobin in blood vessels near the skin surface suggesting a circulatory or ventilatory problem). According to Chambers' research, it is possible that these respiratory problems represent the less severe end of the spectrum in a range of outcomes consistent with PPHN. When considered along with the new information that women who take certain doses of some antidepressants during their pregnancy are three times more likely to have a baby with a congenital heart malformation, why would anyone take an SSRI while pregnant?
Confusing the Issue
Even in the face of this new information of potentially devastating results from SSRI use during pregnancy, a group of physicians has been speaking out about the "harm" that may result to mothers who stops taking the medications during pregnancy -- complicating and confusing the issue at hand.
Prominent physicians are publishing articles warning mothers that they may experience a recurrence of depression or other underlying conditions if they stop taking whatever antidepressant they are presently prescribed. See, e.g., Lee S. Cohen et al., "Relapse of Major Depression During Pregnancy in Women who Maintain or Discontinue Antidepressant Treatment," J. Am. Med. Ass'n, 2006; 295: 499-507.
They caution that there is a high risk of relapse of depression following discontinuation of antidepressant therapy, and suggest women need to consider the risks of depressive relapse during pregnancy and the effects of untreated depression on fetal and maternal well-being. However, the doctors are extremely vague as to what are the "risks of untreated depression on fetal and maternal well-being." It should also be noted that some of these physicians are spokespersons for, and therefore, paid by the drug companies.
In the absence of solid evidence regarding the risks of untreated depression and mounting evidence of harm, it is believed that most mothers would not risk the death of a newborn child from PPHN or other life-threatening birth defects for the sake of their own sense of "well-being." According to the information reviewed, almost without exception, mothers who have been treated with an antidepressant during pregnancy and given birth to children with PPHN or other birth defects say they never would have taken the risk, had they known it existed.
The Risk/Benefit Analysis
Mothers and their treating physicians must do a risk-vs.-benefit assessment in deciding whether to continue taking antidepressants during pregnancy based on the existing data. In order to perform this risk/benefit analysis, physicians and their patients need to know the true risks and benefits.
Unfortunately, drug companies have been loath to divulge negative information about their drugs and the FDA has failed miserably at its job in monitoring drug safety. To complicate matters, details of clinical trials have been concealed due to their negative outcomes, and published studies have been distorted due to drug company influence. See, e.g., ADepressing research,@ The Lancet, April 24, 2004, 363(9418):1335; S. Okie, "What ails the FDA?@, N. Engl. J. Med., March 17, 2005, 352(11):1063-6.
Physicians cannot simply rely on research funded by the pharmaceutical industry to educate them on risks and benefits. It has been found that studies showing a drug works effectively are three times more likely to be published than those showing they do not work or do more harm than good. Studies that do make it to publication often are ghost-written by drug companies, with names of "opinion leaders" who have not seen the raw data inserted as authors. As a result, many doctors have unwittingly relied on flawed or incomplete data provided by the drug industry, through either marketing material or medical literature influenced by the industry.
The pharmaceutical companies have not only downplayed the side effects of their antidepressants, they have also exaggerated the benefits. In an analysis of efficacy data submitted to the FDA for six of the most popular SSRIs between 1987 and 1999, 75 to 80 percent of the response to medication was duplicated in placebo groups. Kirsch and Moore, "The Emperor's New Drugs: An Analysis of Antidepressant Medication Data Submitted to the U.S. Food and Drug Administration,"5 Prevention & Treatment, Article 23, July 15, 2002. The authors of that study wrote that the "small difference between the drug response and the placebo response has been a 'dirty little secret' known to researchers who conduct clinical trials, FDA reviewers, and a small group of critics who analyzed the published data." Kirsch, Moore et al., "Antidepressants and Placebos: Secrets, Revelations, and Unanswered Questions," 5 Prevention & Treatment, Article 33, posted July 15, 2002.
According to an internal FDA memorandum by Dr. Paul Leber, formerly of the FDA: "Approval [of the antidepressant] may Y come under attack by constituencies that do not believe the agency is as demanding as it ought to be in regard to its standards for establishing the efficacy of antidepressant drug products." An article in the British Medical Journal confirmed these concerns, concluding that "selective serotonin reuptake inhibitors have no clinically meaningful advantage over placebo"; "[c]laims that antidepressants are more effective in more severe conditions have little evidence to support them"; and "[m]ethodological artefacts may account for the small degree of superiority shown over placebo." J. Moncrieff, "Efficacy of antidepressants in adults," British Med. J., July 16, 2005 (7509):155-7.
In our opinion, women have a right to be informed of the risks and benefits revealed by the data. For pregnant women, the risk/benefit analysis comes down to this: the baby is at least three times as likely to have a life-threatening congenital heart defect, is at least six times as likely to have PPHN and has a 20 to 30 percent chance of being born with breathing complications -- not to mention SSRI withdrawal syndrome. The benefit is the "mental well-being" that comes from taking a drug that has been shown to have little more effect than a placebo.
It is difficult to fathom the mentality of drug companies that would place profits over the health of newborn children. Physicians need to put on their critical thinking caps and mothers need to be more discerning in accepting the advice of physicians influenced by drug company hype. The lives of their children are at stake.
By Baum Hedlund
Original version of the article first published on Law.com, February, 2007