Birth Defects

 The FDA approved Ortho-McNeil’s anticonvulsant drug Topamax in 1996 for treating epilepsy in children and adults. Topamax is also FDA approved for treating migraines, which remains the most popular reason for prescribing the drug. In addition, alternative, off-label uses have been proposed, such as treating obsessive-compulsive disorder, addiction, and bi-polar disorder. Patent protection for Topamax expired in 2006, and currently the generic version is marketed by Mylan Pharmaceuticals.

The Controvery

In 2010, Ortho-McNeil was criminally fined $81.5 million after entering a guilty plea for promoting Topamax to treat off-label psychiatric disorders without following FDA requirements. However, larger concerns have materialized. Specifically, reports have begun to surface suggesting Topamax use during pregnancy may result in birth defects.

In 2008, researchers at the UK Epilepsy and Pregnancy Registry evaluated the risk of birth defects following maternal use of Topamax during pregnancy. Of 178 live births, 9% had some type of major congenital malformation. Three incidents occurred in mothers receiving only Topamax, while the remaining mothers were on some sort of polytherapy regimen which included Topamax. The primary malformation observed was the development of oral clefts, an affliction where a small notch or groove runs from the top of the mouth to the nose, and may lead to problems eating, talking, and resisting ear infections. Male newborns also displayed an increased incidence of hypospadias, an affliction where the urethra fails to develop properly.

In late 2010, the North American Antiepileptic Drug Pregnancy Registry confirmed the aforementioned results following an analysis of 6,456 pregnant women, some of whom were taking antiepileptic drugs. The prevalence of oral clefts occurred in 1.4% of newborns maternally exposed to Topamax, compared to .38-.55% in infants exposed to alternative anti-epileptic drugs. The rate for these malformations in the general population was only .07%.

In response to the concerns raised by these reports, the FDA recently changed the drug classification from Pregnancy Category C, wherein there is some evidence for the potential development of birth defects in animal studies, to Pregnancy Category D. Pregnancy Category D denotes positive evidence of birth defects in human clinical studies, but the beneficial effects of the drug may outweigh the potential risks, at least in some specific situations. The FDA further advised doctors to carefully weigh the prescribing options in women of childbearing age. If alternative treatment is unavailable, then doctors are advised to recommend the use of birth control, primarily due to evidence suggesting oral clefts occur following Topamax exposure during the first trimester of pregnancy.

Symptoms

• Cleft Lip
• Cleft Pallet
• Hypospadia

If you or a loved one took Topamax during pregnancy and your child was born with a birth defect, please contact Daniel P. Kondos today

 Synthesis of valproate first occurred in the late 1800s, and was subsequently used as a ‘metabolically inert’ vehicle for drug delivery. Nearly 80 years later, French scientist Pierre Eymard serendipitously discovered the anticonvulsant potential of the drug during a routine screening of potential antiepileptic drugs (AEDs) using Valproate as a vehicle. Shortly thereafter, Abbot Labs received FDA approval in 1978 to market the drug for the treatment of epilepsy under the trade name Depakene.

Epilepsy can very generally be described as a chronic disorder of brain dysfunction due to excessive neuronal discharge. Put another way, brain cells communicate with neighboring neurons in part by generating electrical currents called action potentials. When an action potential is emitted, the neuron fires an electrical charge which ultimately causes the release of neurotransmitters which then travel to neighboring neurons. These neurotransmitters comprise the means by which neurons communicate and influence the activity and behavior of neighboring neurons. In epileptics, this method of cellular communication becomes dysfunctional, and neurons begin firing uncontrollably and with greater frequency, resulting in impaired motor function and consciousness. Valproate products prevent the initiation of such dysfunctional communications between neurons primarily through two mechanisms. First, valproate inhibits certain neuronal channels (called voltage gated calcium and sodium channels) necessary for the neuron to generate an action potential, in turn reducing the ability of the cell to fire. In addition, the drug blocks the degradation of the neurotransmitter GABA, an inhibitory chemical messenger found in the brain which also decreases the ability of the neuron to initiate action potentials. For reference, GABA is the main target of many anti-anxiety drugs and sleep medications as they dampen neuronal activity. Together, these mechanisms of action make it more difficult for neurons to fire, resulting in the reduced capacity to initiate and sustain an epileptic episode.

Today, valproate and its related analogues are marketed as Depakene, Depacon, Divalproex sodium (known also as Depakote, Depakote CP, and Depakote ER), and Stavzor. It remains one of the most prescribed AEDs on the market, and has received FDA approval for the treatment of epilepsy, manic episodes associated with bipolar disorder, and as a prophylactic treatment for migraines. Off-label uses, or uses that have not received FDA approval, include borderline personality disorder, Alzheimer’s related disorders, post-traumatic stress disorder, and others. Currently, the Department of Justice is investigating Abbot Labs for alleged illegal marketing and promotion of Depakote for off-label uses.

The Controversy

The teratogenic potential of valproate has been documented since 1980. In 1982, researchers found a 20-fold risk of spina bifida in children exposed to valproate in utero, and in 1984, the medical community recognized a constellation of minor and major malformations called Fetal Valproate Syndrome. Despite these advances in understanding, only recently has the extraordinary range and danger of the drug become documented and appreciated.

The risk of birth defects following in utero exposure to valproate is extraordinarily high and produces a wide-range of birth defects. For example, in a 2005 study published in Neurology, researchers analyzed outcomes in 1,956 women taking AEDs during the first trimester of pregnancy. Compared to the average incidence of birth defects in the general unexposed population (a rate of 1.62%), valproate produced a 7-fold greater risk for major malformations. The authors concluded that, in addition to previously reported birth defects, valproate produced an unacceptable risk of developing additional, previously unknown defects including pulmonary atresia, craniosynostosis, and metopic synostosis. The authors also reported that the risk of neural tube defects (e.g. spina bifida) following first trimester valproate exposure is 1 in 20, whereas in the general population the risk remains at 1 in 1500.

Similar results were observed in a 2006 study in which researchers published one of the more important studies in the field looking at the incidence of malformations in the US and UK following first trimester exposure to antiepileptic drugs. Their results exhibited an extraordinary rate of malformations following exposure to valproate, finding that 20.29% of births resulted in serious adverse outcomes. Furthermore, the risk presented by valproate was twice that of the second most dangerous AED studied, phenytoin, which produced a risk percentage of 10.71%. The effects were dose related, with valproate doses above the median increasing the risk of adverse outcomes to 24.2%.

In response to these studies and others, in 2009 the FDA issued a statement for patients and healthcare professionals warning that valproate products increase the risk of neural tube defects, craniofacial defects such as cleft palate and cleft lip, and cardiovascular malformations. This warning concluded with an assertion by the FDA that they were actively involved in working with manufacturers to update labeling information.

Fetal exposure to valproate also impairs the cognitive development of children, resulting in decreased IQ. This conclusion was reached in a 2009 study published in the New England Journal of Medicine. In the study, researchers in both the US and UK pooled results from mothers and their children exposed to AEDs during pregnancy, and determined the average child’s IQ by drug. Results exhibited that on average, children exposed to valproate had a significantly lower average IQ than children exposed to alternative AEDs such as lamotrigine, carbamazepine, and phenytoin. The study confirmed results seen in a number of previous studies from throughout the world, in both children and in animals. In response to these data and others, the FDA issued a bulletin in June of 2011 warning patients and healthcare professionals that first trimester exposure to valproate products may impair cognitive development. Importantly, the FDA also warned that the long-term effects of the drug on cognitive development remain unknown.

As it currently stands, the list of potential defects following valproate exposure is immense. Some of the more predominant defects include:

• Premature birth
• Low birth weight
• Newborn withdrawal
• Disrupted cognitive development
• Craniofacial defects such as cleft lip and cleft palate
• Neural tube defects such as spina bifida.
• Congenital heart defects such as ventral septal defects
• Genital abnormalities such as hypospadias
• Limb defects such as extra or missing digits
• Malformed limbs and skeletal defects such as radial ray defects and phalangeal hypoplasia (both involve defects in finger bones)
• Craniosynostosis (abnormal formation of the skull)
• Fetal Valproate Syndrome, which is associated with
  • Musculoskeletal abnormalities
  • Minor skin defects
  • Cardiovascular abnormalities
  • Neural tube defects
  • Anomalies of the eye, brain, kidney, and hearing.
  • Growth retardation
  • Infant death
  • Mental retardation

Others, which are not as well characterized but nonetheless have been reported in the literature include:

• Inguinal and umbilical hernias
• Supernumerary nipple (an accessory nipple)
• Postaxial polydactyly (fifth digit duplication in the hands or feet)
• Bifid ribs
• Congenital heart disease
• Septal defects and valvular problems
  • Aortic valve stenosis
  • Interrupted aortic arch
  • Secundum atrial septal defects
  • Pulmonary atresia without ventral septal defects
  • Perimembranous ventral septal defects
  • Hypoplastic left heart syndrome
  • Coarctation of the aorta
  • Atrial septal defects
• Brachycephaly (flat head syndrome)
• Hydronephrosis (obstruction of the free flow of urine from the kidney)
• Undescended testes
• Dysplastic ribs (abnormal growth/development of the ribs)
• Pulmonary stenosis (obstructed blood outflow from the heart)
• Pulmonary atresia (obstructed blood flow from the heart to the lungs)
• Metopic synostosis (abnormal head shape and impaired brain growth)
• Tetralogy of fallot (heart defects which result in low oxygenation of the blood)
• Microcephaly (abnormally small head)
• Failure to thrive in newborn infants
• Hypotonia (decreased muscle tone and weakness)
• Bilateral multicystic dysplastic kidneys
• Lamboid suture synostosis (deformity of the skull .

If you or a loved one have taken Depakote, Depakene, Depakon, or Stayzor and suffered from any side effects please contact 

Daniel P. Kondos today.  

 Belonging to the class of anti-depressants known as selective serotonin reuptake inhibitors (SSRIs), Celexa operates by increasing the amount of available serotonin in the brain. This mechanism of action presumably allows the drug to correct low levels of serotonin associated with depressed patients. Consequently, its primary usage since FDA approval in 1989 has been for treatment of major depression. Off-label uses (uses not approved by the FDA) include treatment of ADHD, premenstrual dysphoric disorder, obsessive compulsive disorder, as well as anxiety and panic disorders.

The Controversy

In 2006, researchers at the University of San Diego published data in the New England Journal of Medicine supporting an association between late-pregnancy maternal use of SSRIs, including Celexa, and the development of persistent pulmonary hypertension of the newborn (PPHN). In these infants, the normal physiological response required for infants to breath outside the womb is impeded, resulting in difficulty oxygenating blood. This affliction is often fatal, and even if treated, may lead to neurological impairment. In response to this report, the FDA issued a public safety advisory the same year, warning that the use of SSRIs during pregnancy may cause PPHN.

In addition to the risk of PPHN, other studies suggest that SSRIs impair cardiac development of the infant during pregnancy. In one study involving almost 500,000 births out of Denmark, the authors concluded that mothers who were prescribed SSRIs during pregnancy had an increased chance of bearing an infant with septal heart defects, particularly with Celexa. These results were later supported by a similar study concluding that maternal use of SSRIs early in pregnancy was associated with a 1.7 fold increase in the risk of congenital heart defects, with septal heart defects being the most predominant.

Research also suggests that the use of SSRIs during pregnancy may result in cognitive, behavioral, and physiological defects at birth. For example, the use of SSRIs, including Celexa, resulted in lower birth weights, longer hospital stays, increased admissions to neonatal intensive care wards, and an increase in preterm births. Physiologically, other reports suggest maternal SSRI use may result in a child born with craniosynostosis, anencephaly, omphalocele, and respiratory distress. Finally, still other research indicates that even healthy, full-birth-weight infants exposed to SSRIs during pregnancy exhibit clinical features associated with neonatal withdrawal syndrome. These same features, when exhibited by adults, are symptomatic of serotonin toxicity. Sadly, these children were described by the authors as “tremulous, motorically erratic, underaroused and in an unchanging REM state.”

The following symptoms and afflictions have been associated with SSRI use during pregnancy and may require surgery and/or treatment both at birth, and later in life.

Symptoms

• Peripheral arterial disease
• Congenital heart defects
• Persistent pulmonary hypertension of the newborn
• Serious withdrawal symptoms
• Difficulty breathing requiring a ventilator
• Anencephaly: absence of the brain and/or skull
• Craniosynostosis: closing of the infants head before the appropriate time, leading to malformation of the skull
• Omphalocele: a birth defect in which the infant’s intestine or other abdominal organ protrude out of the belly button

If you or a loved one took Celexa during pregnancy and your child was born with a birth defect, please contact Daniel P. Kondos today

 Paxil, Paxil CR or Pexeva (generic: paroxetine hydrochloride) is manufactured by GlaxoSmithKline. On December 8, 2005, the FDA determined that exposure to paroxetine in the first trimester of pregnancy may increase risk for congenital malformations, particularly cardiac malformations. At the FDA’s request, the manufacturer has changed paroxetine’s pregnancy category from C to D and added new data and recommendations to the warnings section of paroxetine’s prescribing information. Paroxetine is available as Paxil, Paxil CR, Pexeva, and generic paroxetine hydrochloride.

Paxil May Cause Neonatal Persistent Pulmonary Hypertension

On July, 2007, the FDA issued additional black box warnings for the increased risk of Neonatal Persistent Pulmonary Hypertension. Babies born with PPHN have abnormal blood flow through the heart and lungs and do not get enough oxygen to their bodies. Babies with PPHN can be very sick and may die.

Contact Us

If your baby was born with PPHN or another malformation and you were taking Paxil during pregnancy, you may have a legal claim. Please contact Daniel P. Kondos today.

 Approved by the FDA in 1987, Prozac remains one of the most successful selective serotonin reuptake inhibitors (SSRIs) ever released on the market. As a class, SSRIs work by increasing the amount and availability of serotonin in the brain by blocking its reuptake. This increase is thought to have a corrective effect in patients with depressive symptoms, as research has shown depressed patients have significantly decreased levels of serotonin in the brain. In addition to treating major depression, Prozac has also been used to treat premenstrual dysphoric disorder, bulimia nervosa, panic and anxiety disorders, as well as obsessive compulsive disorder. In 2007, Prozac represented the third most popular antidepressant, with 22.2 million prescriptions filled.

The Controversy

Over the past two decades, a growing body of research has implicated SSRIs, including Prozac, as harmful to the development of infants during pregnancy. These concerns were first raised in 1996 by researchers at UCSD who found a link between third trimester exposure to Prozac, and perinatal complications. Specifically, these children exhibited an increased risk for persistent pulmonary hyptertension of the newborn (PPHN), as well as developing three or more minor abnormalities. These results were confirmed a decade later, when researchers found that mothers who took SSRIs in the second half of pregnancies were six times more likely to give birth to babies with PPHN. Because Prozac is easily passed from the mother to the child, either through blood or breast-feeding, the FDA has issued warnings that SSRIs should be used with caution during pregnancy. These concerns are further underscored by the estimated 80,000 women per year who take SSRI’s during pregnancy.

Some researchers have theorized that perhaps depression, rather than exposure to SSRIs, was responsible for the associated birth defects. This question was put to test by researchers in Canada, who compared birth outcomes between depressed mothers, and depressed mothers treated with SSRIs. Even when maternal illness was accounted for, exposure to SSRIs increased the risk of both low birth weight, and respiratory distress.

Other research suggests additional deleterious effects in children born of mothers taking SSRIs. Research out of Denmark suggests a causal link between SSRIs and cardiac malformations such as septal defects. In Israel, a study of thousands of mothers yielded data indicating that Prozac, taken during the first trimester, increased the risk of cardiovascular defects by one and a half, while doubling the risk of major abnormalities. Consequently, it would appear that regardless of the trimester in which the child is exposed, maternal consumption of Prozac during pregnancy can produce birth defects.

Finally, other studies have shown exposure to SSRIs during pregnancy doubles the risk of preterm delivery, increases the risk and time spent in a neonatal ICU, and produces symptoms of jaundice, seizures, respiratory problems, and withdrawal in infants. In addition, neurobehavioral and developmental deficiencies, such as motor defects, heart rate variability, and variances in sleep states have also been shown as disturbed by SSRI exposure.

The following symptoms and afflictions have been associated with SSRI use during pregnancy and may require surgery and/or treatment both at birth, and later in life.

• Peripheral arterial disease
• Congenital heart defects
• Persistent pulmonary hypertension of the newborn
• Serious withdrawal symptoms
• Difficulty breathing requiring a ventilator
• Anencephaly: absence of the brain and/or skull
• Craniosynostosis: closing of the infants head before the appropriate time, leading to malformation of the skull
• Omphalocele: a birth defect in which the infant’s intestine or other abdominal organ protrude out of the belly button

 Symptoms 

The following symptoms and afflictions have been associated with SSRI use during pregnancy and may require surgery both at birth, and later in life.

• Peripheral arterial disease
• Congenital heart defects
• Persistent pulmonary hypertension of the newborn
• Serious withdrawal symptoms
• Difficulty breathing requiring a ventilator

If you or a loved one took Prozac during pregnancy and your child was born with a birth defect, please contact

 Daniel P. Kondos today.

 Like Prozac and Paxil, Zoloft is classified as an antidepressant SSRI, or selective serotonin reuptake inhibitor. These drugs exhibit their effects by increasing the amount of available serotonin in the brain, thus alleviating depressive symptoms. As a result, Zoloft is primarily used for treating major depression, as well as panic disorders, social anxiety, and obsessive compulsive disorder. Since its approval in 1991, Zoloft has exhibited extraordinary success in the market, and in 2007 was the most prescribed antidepressant on the market with over 29.6 million prescriptions filled.

The Controversy

Studies have shown that Zoloft can pass to neonates and newborns when taken by pregnant women, or via breastfeeding. These exposure levels can reach 1/3 of the maternal exposure in utero. Consequently, it is not too surprising that a drug with such bioavailability in an unborn developing child might produce birth defects.

Birth defects associated with Zoloft exposure are wide-ranging and diverse. For example, research published in the New England Journal of Medicine has shown exposure to Zoloft during pregnancy can produce a six-fold increase in omphalocele (inability to properly form an abdominal wall), a four-fold increase in limb reduction defects, and craniosynostosis (malformed skull).

While some disagreement does exist regarding the incidents of the aformentioned defects, there is greater agreement in the literature suggesting that Zoloft impedes the development of the heart, resulting in septal and atrial heart defects. Furthermore, persistent pulmonary hypertension of the newborn (PPHN), wherein the newborns circulation system doesn’t adapt to breathing outside the womb, is also associated with in utero exposure to Zoloft. As a result, the FDA issued a warning in 2006 that SSRIs should be used with caution during pregnancy.

Finally, data exists supporting the assertion that Zoloft increases the chances of premature birth by 8% to 17% (as compared to those taking no drugs during pregnancy), decreases birth weight, and may produce abnormal neurobehavioral outcomes, even in otherwise healthy, full-birth-weight infants.

Symptoms

The following symptoms and afflictions have been associated with SSRI use during pregnancy and may require surgery both at birth, and later in life.

• Craniosynostosis: closing of the infants head before the appropriate time, leading to malformation of the skull.
• Omphalocele: a birth defect in which the infant’s intestine or other abdominal organ protrude out of the belly button.
• Anencephaly: absence of the brain and/or skull.
• Neonatal abstinence syndrome: withdrawal.
• Anal atresia: malformation of the anus.
• Limb reduction.
• Septal and atrial heart defects: holes in the heart.
• Persistent pulmonary hypertension of the newborn after birth (PPHN).
• Seizures, respiratory difficulties, oxygen depletion in the blood, difficulty eating, irritability, inconsolable crying, tremors.

Contact Us

If you or a loved one took Zoloft during pregnancy and your child was born with a birth defect, please contact Daniel P. Kondos today