The placenta serves two interrelated functions, and at first sight, this organ that comes to line the inside of a mother’s womb might seem like a paradox. Placentas help developing fetuses receive the nutrients they need, by connecting them to a mother’s blood supply. At the same time, placentas divide fetal blood from maternal blood, maintaining an important separation that keeps developing children safe from some, but not all, of the chemicals that might be floating around in a mother’s blood.
The placenta’s role, however, goes far beyond that. The organ produces hormones, including estrogen and progesterone, essential to healthy fetal development. Chemicals made by the placenta help a mother’s body prepare for lactation and, before delivery, relax the pelvis to ease childbirth.
How Does The Placenta Develop?
The placenta starts developing right when an embryo does, at the moment that a small bundle of cells, or blastocyst, which will grow into a fetus first implants in the uterus. Overtime, these cells begin to differentiate, taking on different forms and functions. The outer layer of cells, which is called the trophoblast, comes to form the placenta’s outer layer.
Cells from the trophoblast attach to the wall of the uterus, and then start going deeper, branching out in many little fingers, or villi, which poke into open spaces in the uterus. When those spaces fill up with maternal blood, the villi soak some up and deliver the nutrient-rich fluid to an embryo’s umbilical cord.
The umbilical cord develops during the fifth week of gestation, attaching to the embryo’s abdomen on one end and to the placenta on the other. This cord serves as the main conduit between a mother and her growing child.
Inside the placenta, babies are surrounded by the amniotic sac. This thin, strong sac is filled with fluid, and its outer layer, the chorion, is part of the placenta.
What Is The Placental Barrier?
“Placental barrier” is a term that refers to one of the placenta’s primary functions, which we mentioned earlier, to keep fetal blood separate from maternal blood. As a fetus develops, the actual structures that make up this “barrier” change, but throughout pregnancy, the cells involved make sure that a developing baby’s blood never mingles directly with the blood of its mother.
What Can Cross The Fetal Placental Barrier?
Lots of good things can cross the barrier. Essential nutrients, like minerals, and oxygen pass from mother to child through the placenta. Waste products created by the fetus, like carbon dioxide, go the other way, passing through the umbilical cord to a mother’s blood stream.
The placenta actively filters maternal blood of some, but by no means all, of the molecules that can potentially harm a fetus. Most infectious agents are removed from the blood before it reaches the fetus, but there are notable exceptions, including:
- Human Cytomegalovirus
Beyond these viruses, most toxic pollutants are able to cross the placental barrier, entering fetal tissues. Even mothers who stick to organic foods, and don’t consume any drugs, have harmful chemicals floating through their blood streams. In today’s world, it’s all but impossible to avoid pollutants. Unfortunately, many of these harmful chemicals are passed directly to developing babies, and there’s not much we can do about it.
In 2013, Canadian environmental group Environmental Defence tested the umbilical cord blood of three newborns. Each of the babies, according to the group’s report, was born with between 55 and 121 “toxic compounds and possible cancer-causing chemicals in their bodies.”
A staggering 137 different, and potentially harmful, chemicals were identified in the newborns’ cord blood:
- 132 of those chemicals have been linked to cancer
- 110 are currently believed to be toxic, affecting the brain and nervous system
- 133 have been been found to cause developmental problems in mammals
A similar study, performed using the cord blood from 10 American newborns, found almost identical results. “Numerous environmental contaminants can cross the fetal placental barrier”, according to the National Cancer Institute, “to a disturbing extent, babies are born ‘pre-polluted.’ ”
Can Drugs Pass Through The Placenta?
Absolutely. Like lead and mercury, both of which can cross the placental barrier and affect fetal development, prescription and illegal drugs are fundamentally chemicals, and the placenta is hard-strapped to filter them out.
But being potentially harmful, and actual harming a fetus, are two different things. In reality, every chemical, natural or man-made, poses a potential risk. What really matters is how much of a chemical is able to pass through the placenta.
What Should I Know About Zofran?
In over 200 recent lawsuits, US families have claimed that GlaxoSmithKline’s anti-nausea drug Zofran increases the risk of birth defects.
In fact, these plaintiffs say the drug’s manufacturer has been aware of Zofran’s “unreasonable risk of harm to unborn babies” since at least the 1980s. Despite this alleged knowledge, plaintiffs claim that GlaxoSmithKline, one of the world’s most profitable drug companies, continuously promoted Zofran as a “safe and effective” treatment for morning sickness, a use never approved by the FDA.
GlaxoSmithKline Never Studied Zofran In Pregnant Women
In 1991, Zofran was approved for the treatment of severe nausea and vomiting in cancer patients undergoing chemotherapy and radiotherapy. But according to recent complaints, GlaxoSmithKline also began marketing the drug as a safe treatment during pregnancy at around the same time.
It is a matter of public record that GlaxoSmithKline has never studied Zofran’s effects during pregnancy. In the most recent Zofran birth defect lawsuits, plaintiffs have said that the company intentionally avoided performing these studies “because it had knowledge of the drug’s toxicity and the studies would have impeded the drug’s marketability and profits.”
In support of these allegations, plaintiffs have unearthed a wealth of early study data, trials conducted by GlaxoSmithKline to determine the safety and efficacy of Zofran’s active ingredient (ondansetron) prior to FDA approval. They say that several of these studies provided GlaxoSmithKline with evidence that Zofran could affect fetal development, evidence they claim GlaxoSmithKline intentionally withheld from the public.
Can Ondansetron Enter Fetal Tissue In Humans?
In a 2006 study conducted by researchers at the Chinese University of Hong Kong, ondansetron’s ability to pass the fetal placental barrier was confirmed in human subjects.
The study used an experimental group of 41 women who had scheduled surgical terminations of pregnancy before the end of their first trimester.
Each patient was given three 8 milligram doses of ondansetron prior to surgery. According to Zofran’s most recent labeling instructions, this is the recommended dosage for adult patients prior to highly “emetogenic” chemotherapy treatments, ones likely to cause severe nausea and vomiting.
Researchers then analyzed the concentration of ondansetron in post-operative samples of:
- maternal blood – theoretically, this blood would serve as the transport medium for any ondansetron that entered fetal tissue
- coelomic fluid – the coelom is the main body cavity in most animals, a large chamber that surrounds the digestive tract. During early fetal development, the coelom actually surrounds the embryo itself. Researchers now believe that nutrients delivered by maternal blood are filtered and stored in coelomic fluid.
- amniotic fluid – this gel-like fluid surrounds a developing embryo inside the amniotic sac. Made from a mother’s blood plasma, amniotic fluid is absorbed directly by a fetus’ skin.
- fetal tissue – the researchers also took cell samples from the embryo
The article noted that “ondansetron was found in all samples[,]” including fetal tissue. In fact, the concentration of ondansetron in the average sample of fetal tissue amounted to 41% of its concentration in a mother’s blood. The drug’s concentration was “significantly higher” in fetal tissue than it was in amniotic fluid. Coelomic fluid contained about the same concentration as fetal tissue.
Since ondansetron was found to pass the placental barrier at high concentrations, the researchers advocated for further investigation of the drug’s effects on fetal development.
Did GlaxoSmithKline Know?
As we’ve already mentioned, GlaxoSmithKline never studied Zofran’s activity in pregnant patients before submitting the drug for FDA approval. Since the company sought approval only for the drug’s use in cancer patients, they were not required to conduct clinical trials involving pregnancy.
But ondansetron’s ability to cross the placental barrier was demonstrated in animal studies that GlaxoSmithKline conducted during the 1980s. In a series of recent lawsuits, plaintiffs have said that those study results suggest ondansetron is able to cross the placental barrier “at concentrations high enough to cause congenital malformations.” And despite the study authors’ call for further research, plaintiffs claim that GlaxoSmithKline “simply chose not to study Zofran in pregnant women.”
Plaintiffs argue that this early knowledge obligated GlaxoSmithKline to strengthen Zofran’s labeling instructions and discourage the drug’s use during pregnancy. Needless to say, Zofran’s warning label makes no mention of placental transfer.
Do Doctors Care If A Drug Can Cross The Placental Barrier?
An editorial published in 1962 by the Journal of the American Medical Association (JAMA) laid out guidelines to help doctors make prescribing decisions during pregnancy. Here’s what the editors of JAMA wrote, and remember that this was well understood a full 53 years ago:
“If a drug is to be prescribed for the pregnant woman, three basic points should be considered:
- first, the known toxic effects;
- second, the possibility that the drug might pass the placental barrier to a significant degree; and
- third, the stage of development of the fetus.”
We’ll walk through each of the editorial’s three recommendations in turn, and provide pertinent examples that relate to Zofran.
1. Does Zofran Have Any Known Toxic Effects?
In their lawsuits, plaintiffs have claimed that GlaxoSmithKline’s early clinical studies, which tested Zofran’s effects in pregnant rats and rabbits, “revealed evidence of toxicity.” According to Cornell University, signs of toxicity include all “adverse effects produced by poisons,” and can “range from slight symptoms like headaches or nausea, to severe symptoms like coma and convulsions and death.”
- In Study No. R10937, 160 pregnant rats were administered Zofran intravenously. Complaint 5:15-34 claims that “clinical signs of toxicity were observed in the pregnant rats includ[ing] ‘low posture, ataxia, subdued behavior and rearing, as well as nodding and bulging eyes.’”
- In Study No. R10873, four separate groups of pregnant rabbits were injected with varying amounts of Zofran. Complaint 5:15-34 says that “there was a reported increase in the number of intra-uterine deaths in [the group that received the highest dose] versus lower-dose groups.” Rabbits exposed to Zofran evidenced maternal weight loss in comparison to unexposed rabbits, and signs of developmental retardation were noted in both offspring and fetuses.
- In Study No. R10590, 120 pregnant rats were administered Zofran orally at varying dosages. Among rats exposed to the highest doses, “subdued behavior, labored breathing, […] and dilated pupils were observed.” The study’s authors noted a “slight retardation in skeletal ossification” among the rats’ offspring.
- In Study No. L10649, between 56 and 64 pregnant rabbits were given oral Zofran at varying dosages. Complaint 5:15-34 claims that “the study reported lower weight gain in all of the exposed groups, as well as premature delivery and ‘total litter loss,’ referring to fetal deaths during pregnancy” in rabbits receiving the highest dose of Zofran. As in the previous study, retardation of skeletal development was observed in the fetuses.
In reporting these results to the FDA, GlaxoSmithKline stated that none of the studies revealed evidence of harm to fetuses. Plaintiffs dispute that claim, saying that the study results provided sufficient evidence of Zofran’s ability to affect fetal development in pregnant animals.
But even if GlaxoSmithKline had accurately described the study results in its report to the FDA, trials involving animals are never assumed to predict similar effects in human subjects. As a result, Zofran’s disputed safety during animal pregnancy would not have been sufficient to support claims of its safety during human pregnancy. Plaintiffs allege that GlaxoSmithKline has continuously made unsubstantiated statements to that effect since as early as 1991.
2. Does Zofran Pass The Placental Barrier To A Significant Degree?
We’ve already covered how Zofran is able to cross the fetal placental barrier, and was found in both human and animal fetal tissue at high concentrations. But this is information that GlaxoSmithKline has not publicized, both after its early studies in pregnant animals and in 2006, after the researchers from Hong Kong confirmed placental transfer in pregnant humans.
3. When Is Zofran Most Likely To Be Prescribed?
The editorial’s third point stresses “the stage of development of the fetus.” We could rephrase this to emphasize the fact that fetuses can be affected differently by the same drug at different stages of development, and doctors should consider these fetal stages in making prescribing decisions during pregnancy.
This point is still accepted as fact within the medical community. Organogenesis, the process in which an embryo’s cells differentiate to form separate organs, occurs almost entirely in the first trimester of pregnancy. Major birth defects caused by harmful drugs are most likely to develop at this time, before an embryo’s bodily structures have formed completely. This is also the period during which morning sickness is most likely to occur.
More often than not, Zofran is prescribed to alleviate the symptoms of nausea and vomiting of pregnancy during the period in which fetuses are most susceptible to a drug’s harmful effects.
Should GlaxoSmithKline Have Warned Us?
JAMA’s 1962 prescribing recommendations are still the industry standard. For example, an article published in 2010, “Prescribing in pregnant women: guide to general principles,” advises that general practitioners consider every drug’s known toxic effects and ability to cross the placental barrier before prescribing it to a pregnant woman. They also recommend that physicians consider the stage of fetal development before making any prescribing decisions.
If we adopt those guidelines, GlaxoSmithKline’s failure to notify the public of Zofran’s significant placental transfer would make it extremely difficult for physicians to make fully-informed prescribing decisions.
It is an accepted fact that drugs able to cross the placental barrier are more likely to cause fetal harm than drugs that can not. As a result, plaintiffs claim that evidence of Zofran’s ability to enter fetal tissue is essential information, data that every doctor who considers prescribing Zofran to a pregnant woman should have access to.
How Do We Learn That Drugs Are Unsafe During Pregnancy?
Plaintiffs claim that pregnant women and their physicians have a right to know what effects a drug can cause in pregnancy. I think most of us would agree with that statement. But the vast majority of drugs are never studied in pregnant women, at least not in rigorously controlled clinical trials. And for that reason, it is rare that the medical community has an accurate picture of a drug’s effects during pregnancy before it is approved for sale. That’s why very few drugs are explicitly approved for use during pregnancy.
With that being said, most new drugs are administered to pregnant animals in clinical trials. Based on the results of those studies, pharmaceutical manufacturers can elect to categorize the drug in one of several Pregnancy Categories. For example, Pregnancy Category C indicates that “animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans.” Seeing a statement like that may give a doctor pause. While the effects of a drug in animals are never assumed to be the same as those it will cause in humans, many chemicals have similar effects in humans and other mammals.
Zofran is listed in Pregnancy Category B, and its labeling states that: “reproduction studies have been performed in pregnant rats and rabbits […] and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate and well-controlled studies in pregnant women.”
As we’ve seen, plaintiffs in recent birth defect lawsuits consider that a misrepresentation of GlaxoSmithKline’s early animal studies. Further, they reference four recent epidemiological studies, all of which have found an increased association between Zofran and birth defects in human pregnancies. Plaintiffs claim that GlaxoSmithKline had a duty to report the results of these studies, as well, but failed to do so.
To find more information on the regulation of drugs used “off-label” during pregnancy, click here.
How Much Information Are Patients Entitled To?
One point we can probably all agree on is that patients should be provided with whatever pertinent information does exist.
At the time of Zofran’s initial approval, there was no study data that could indicate Zofran’s specific effects on fetal development. Now, several large studies have found an increased incidence of birth defects among babies exposed to ondansetron prenatally. But back in 1991, those studies hadn’t been conducted and there was only one fact GlaxoSmithKline knew unconditionally about Zofran and pregnancy: that Zofran is able to cross the placental barrier. Regardless of whether or not Zofran actually causes birth defects, this evidence indicated that the drug presents a greater risk of harm than drugs that do not cross the placental barrier.
According to the recent Zofran lawsuits, this information was withheld by GlaxoSmithKline from doctors and the public. Despite the accepted fact that drugs able to cross the placental barrier are more likely to cause fetal harm, GlaxoSmithKline never made attempts to discourage doctors from prescribing it to pregnant women. In fact, according to both recent lawsuits and civil charges filed by the federal government, GlaxoSmithKline encouraged Zofran’s use as a morning sickness treatment.