In a small town outside of Fort Worth, Texas, a two-year-old boy sits by the window of his family room watching his three-year-old brother playing outside with tears rolling down his face.  He is too little to understand that he cannot go outside because his heart is too damaged and weak for him to play in the hot summer air.  He is too young to know that just by running too long or falling down too hard that he could cause his own death.      

He was born with a very rare heart defect called double outlet right ventricle.  That title encompasses several congenital heart defects that have caused him to have three open-heart surgeries and the installation of a pacemaker, all before his second birthday.  If all goes well as he grows, he will need several additional maintenance-type surgeries to replace an artificial valve in his heart, and to replace the aging batteries in his pacemaker.  If there are additional complications, more surgeries and possibly even a heart transplant could become necessary.  His mother alleges that these defects were caused by the Paxil that she took while she was pregnant.

On December 8, 2005, the Food and Drug Administration (FDA) issued an alert to health care professionals and patients advising that study results suggested that taking Paxil during the first three months of pregnancy increases the risk for birth defects, particularly heart defects. 1   The results indicated that women who took Paxil were twice as likely to have a baby with a heart defect as women in the general population. 2

The Latest Risks
In 2003, GSK sponsored a retrospective study that examined major congenital malformations among infants born to women who had taken bupropion (Wellbutrin–an antidepressant drug also manufactured by GSK) during their pregnancy. 3   The secondary analysis of the study focused on the risk of malformations with other antidepressants, including  Paxil.  When the results were compiled, they showed that Paxil was associated with a 2.2-fold increase risk of birth defects. 4   The most prevalent of the birth defects were cardiovascular abnormalities, in particular, atrial and ventricular septal defects or ASD and VSD, respectively.  A child born with ASD or VSD has a hole in his heart between the upper or lower chambers of his heart.  This hole prevents his blood from being properly oxygenated.  If the hole is large enough, the child will need open heart surgery to repair the defect. 5
           
Further reports of cardiovascular abnormalities associated with Paxil were found in an unpublished Swedish national registry study and were posted by the FDA.  The FDA noted that  Paxil exposure early in pregnancy was associated with a twofold increase in cardiac defects as compared to the general population. 6   This data, along with the also unpublished study conducted by GSK, prompted the FDA to request that GSK change the label for Paxil by increasing the warning with respect to pregnancy.  The label was ultimately changed from category C to category D to reflect evidence of fetal risk associated with Paxil. 7

In September 2005, two years after the initial study, GSK sent physicians in the United States a Dear Doctor Letter which stated that GSK was changing the label with respect to Paxil during pregnancy to provide a stronger warning which would indicate, for the first time, that there could be a connection between Paxil and birth defects. 8

In addition to heart defects, studies have also shown that women who took SSRIs during their pregnancy were more likely to have an infant with omphalocele, a congenital defect where the infant is born with variable amounts of its abdominal contents protruding at the base of the umbilical cord, and craniosynostosis, a defect that causes one or more of the sutures of an infant’s head to close prematurely, causing the shape of the head to become severely deformed. 9

Paxil has also been associated with causing a condition called Persistent Pulmonary Hypertension of the Newborn or PPHN.  PPHN is a very serious and potentially deadly condition in which the newborn’s arteries to the lungs remain constricted after birth, thereby limiting the amount of blood flow to the lungs and, consequently, the amount of oxygen in the bloodstream. 10 Newborns with PPHN are typically full term, or near full term, babies who present with symptoms of severe respiratory failure and require intubation and mechanical ventilation shortly after birth. 11   Studies have shown that infants who are exposed to an SSRIs, including Paxil, after the 20th week of gestation are substantially more likely to develop PPHN than infants who were not exposed to an SSRIs during gestation. 

Paxil exposure during pregnancy has also been linked to a host of other complications.  One study found that twenty-two percent of infants exposed to Paxil in the third trimester of the pregnancy experienced complications that required hospitalization including respiratory distress, hypoglycemia, jaundice and even prematurity. 12  

Additional Risks to Infants
Paxil crosses the placenta during pregnancy and reaches the fetus. 13 As early as 1997, there were reports of babies born with neonatal withdrawal syndrome after their mothers took Paxil during the third trimester of pregnancy. 14   These “Paxil Babies” presented with symptoms that one might expect of a baby exposed to an opiate (heroin, methadone, or morphine) such as irritability, constant crying, shivering, increased tonus, eating and sleeping difficulties and convulsions. 15    Paxil was present in all of these infants’ blood tests. 16   In one study, a baby, although well enough to be discharged from the hospital, was still shivering at four weeks of age. 17

The findings in this study were consistent with an earlier study done regarding in utero exposure to Prozac.  In that case, 31.5% of the infants who had been exposed to Prozac during the pregnancy had neonatal withdrawal syndrome—which shows that withdrawal symptoms in infants exposed to SSRIs are not rare. 18   However, one database that analyzed the withdrawal information in 72 different countries found that Paxil was the SSRIs most commonly associated with neonatal withdrawal syndrome. 19  
           
Further Complications
Unfortunately, all SSRIs, including Paxil, have a similar effect in adults, which makes it extremely difficult for an expectant mother to discontinue her use of Paxil when she finds out that she is pregnant.  Studies show that between 34.5% and 86% of all adults that discontinue their use of all SSRIs experience withdrawal. 20   However, Paxil appears to be the most potent of these drugs. 21   The symptoms of Paxil withdrawal syndrome include: dizziness, vertigo, headache, nausea, vomiting, diarrhea, movement disorders, insomnia, irritability visual disturbances, lethargy, anorexia, tremor, electric shock sensations, and lowered mood. 22   Several people have also experienced suicidal ideation and homicidality.  Although physicians now typically recommend that their patients taper off any SSRIs to prevent these symptoms, medication taper does not always prevent their occurrence. 23   In some cases, patients find the withdrawal symptoms so debilitating that they are unable to tolerate the symptoms, and their only solution is to stay on the drug.  This is of particular concern for women who are of childbearing years, as more than half of all pregnancies are unplanned. 24
           
The withdrawal risk is important in understanding the true risk of birth defects.  Heart development occurs very early in the pregnancy.  The most critical period of the development of the heart occurs between three and seven weeks after fertilization, when a simple heart tube becomes a four-chambered heart. 25   The heart actually begins to beat on the 22nd day of the pregnancy—before many women even realize that they are pregnant. 26  

When a woman who is taking Paxil realizes that she is pregnant, she has a choice to either stop taking Paxil, or to remain on Paxil for the rest of the pregnancy.  Her physician will most likely recommend that she taper off the Paxil to prevent withdrawal syndrome, the symptoms of which, as previously discussed can range from dizziness to suicidal ideation.  If she experiences severe symptoms, she may not be able to stop taking Paxil.  Therefore, her unborn fetus will be exposed to Paxil throughout the pregnancy, increasing the chances that the baby will be born with some other type of birth defect—or will develop PPHN shortly after birth.  Additionally, the child will experience a significant risk of going through its own withdrawal syndrome after birth.  If the mother decides to breast feed, the child will continue to be exposed to Paxil, as Paxil is excreted into human breast milk. 27

Clouding the Issue
Even as these new warnings surface, there are articles being published to cloud the issue,  making what would otherwise be a clear choice to stop using Paxil to avoid birth defects into a potentially difficult decision.  One article discussed the high risk of depressive relapse in women who discontinued SSRIs use during their pregnancy. 28   The article indicated that women should be sure to consider the risks of depressive relapse and the effects of untreated depression on fetal and maternal well being, although failed to specify what those risks actually are. 29   It is also noteworthy that all nine of the physician coauthors of that article were paid by GSK either as consultants, speakers or were on GSK advisory boards.  This financial disclosure was left out of the initial publication, but was added as a correction in the July 2006 issue.  Coincidentally, the same issue contained an editorial from a physician concerned about bias associated with the article, and pointed out the very fact that the financial associations were omitted. 30

Conclusion
There are over 25.5 million prescriptions written each year for Paxil. 31   Twenty five percent of those prescriptions in the United States are written to women in the childbearing years. 32   Will GSK continue to try and preserve these numbers by obscuring the true risks associated with Paxil?  With the mounting body of safety issues at present, it has become an even harder argument to make.

By Jennifer R. Liakos and Karen Barth Menzies
Baum Hedlund

Original version of this article first published in Mealey's Litigation Report Antidepressant Drugs, October 2006