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JUST HOW SAFE IS "SAFE"?
How the F.D.A. Determines The "Safety" of Drugs


FEW AMERICANS REALIZE THAT:

Prepared by Doris Haire, Chair
Committee on Maternal and Child Health
National Women's Health Alliance

QUESTION YOUR DOCTOR AND PHARMACIST.

In light of the fact that many health professionals have not been taught how to distinguish an FDA approved use of a drug from an "off label" use, you may wish to ask your doctor (or pharmacist) to give you the package insert of the drug he or she proposes to use in your care. The package insert is the FDA approved information leaflet (label) which comes in the box of drugs shipped by the manufacturer to the pharmacy. If you are hospitalized and your doctor is not available, ask the hospital pharmacist for a copy of the package insert.

The package insert is written by the manufacturer, then edited by the FDA before the drug is approved for marketing.

Although written for the physician, most consumers can understand the important sections of the package insert, i.e., "Indications", "Contraindications", "Warnings", "Precautions", "Adverse Reactions", etc.

Read the "Indications" section of the insert first.

The "Indications" section of the package insert tells you whether or not the drug has been specifically approved by the FDA for the treatment of your condition. If the Indications section does NOT mention your condition (i.e. high blood pressure, diabetes, pregnancy, etc) then the FDA has NOT approved the drug for treatment of your condition. When in doubt, call the Product Safety Officer of the company that makes the drug.

Don't hesitate to question your doctor about the risks vs. the benefits of the drug he or she prescribes or offers to you.  A simple but important question to ask is:

"Has this drug been approved by the FDA as safe and effective for the treatment of my condition? What about alternatives, including non-treatment?"

Your doctor is legally obligated to obtain your informed consent to treatment.

This requires your doctor to inform you of the drug's known adverse effects, the FDA approval status of the drug, the "areas of uncertainty" regarding the drug's delayed, long-term effects, and the non-pharmacologic alternatives to the drug. Since your doctor may not be aware of the information in this document, you may wish to share the following information with him or her.

What does "approved by the FDA" mean?

It means that in the opinion of the FDA the benefits of using the drug outweigh the risks. You need to know what the risks are before you decide whether or not you are willing to accept those risks.

Dictionary and FDA differ on definition of "safe".

When the FDA does use the term "safe" the agency does not use the definition, "free from harm or injury," which is found in every U.S. dictionary. To the FDA the term "safe" is a relative term, based on data on the known risks and what the FDA considers to be the acceptable potential risks and benefits of the particular drug.

FDA does not guarantee the safety of FDA-approved drugs?

FDA approval of a drug does not mean that the drug has been subjected to a properly controlled scientific evaluation and follow-up of individuals exposed to the drug.

Absence of contraindication(s) no guarantee of safety.

The absence of a contraindication to a specific use or condition, such as infancy, childhood, pregnancy, elderly, etc., in the package insert does not mean that the FDA has approved the drug as safe for that intended use.

How does the FDA determine whether or not a drug is relatively safe?

The FDA often relies on manufacturer's honesty regarding drug's safety. The FDA requires the drug sponsor (manufacturer) to carry out animal studies (rats, mice, etc.) and three phases of human testing. However, the manufacturer's data on safety are usually accepted in good faith by the FDA. The FDA does not check all data to make sure the data submitted are accurate unless there is reason for the Agency to believe otherwise.

Adequate comparison not required.

The FDA does NOT require a drug manufacturer to use a research study design that permits a comparison between drug-exposed and drug-free research subjects.

Freedom of Information (FOI) Act facilitates public access to FDA deliberations.

The FDA will comply with an FOI request for a transcript of the FDA's Advisory Board meeting that deliberated the benefits and risks of a specific drug (see INFORMATION SOURCE at end of document). However, a review of the transcript does not give concerned consumer groups or responsible citizens the opportunity to suggest changes in the design of the research study before the drug is approved by the FDA.

FDA accepts unpublished data as evidence of a drug's relative safety.

Although the scientific community questions the validity of research data which have not been subjected to review by specialists with equal or greater knowledge before publication in a recognized medical journal, the FDA accepts unpublished data from the manufacturer as evidence of a drug's safety.

Data may be biased due to economic pressures.

Data accepted by the FDA as evidence of a drug's safety may be prepared by researchers who are in the employ of, or under contract to, the manufacturer of the drug, or by researchers who are members of university departments receiving grants or gifts from the drug's manufacturer.

Combinations of drugs not required to be tested for relative safety.

In general, only single drugs are evaluated for approval. Common combinations of drugs are not usually subjected to a review for adverse reactions by the FDA. Combinations which are known to be ineffective or unsafe, however, may be noted in the package insert.

Many drugs bypass FDA's Advisory Committees.

Many drugs approved by the FDA are allowed to bypass the deliberations of the outside experts who make up the FDA advisory committee responsible for the category of drugs under which the drugs in question fall. While the outside experts tend to have a pro-specialty bias, their participation in FDA deliberations at least broadens the base for decision-making.

"Me too" drugs approved without adequate scientific evaluation.

A drug may be approved for a specific use merely because it is similar to a drug already on the market C even though the old drug was never subjected to a properly controlled scientific investigation or follow-up to determine its safety.

FDA declares research data on safety to be "trade secrets", therefore withheld from public scrutiny.

The FDA does not allow concerned consumer groups or responsible citizens to examine the design of the research study, or to check the accuracy of the manufacturer's data presented to the FDA. Without such examination it is almost impossible for concerned individuals or groups to know whether there was deliberate exclusion of subjects who may have been adversely affected by the drug. Awareness of the criteria for exclusion is essential to evaluating the quality of any scientific investigation.

Makeup of FDA advisory committees suggests professional bias in decision-making regarding risks vs benefits of drugs.

Members of FDA advisory committees, who analyze and deliberate the relative benefits and risks of a drug, are usually chosen from the ranks of the specialty that administers the category of drugs. Seldom do the committees include a balance of experts who must deal with the adverse effects of the drugs under deliberation. For example: the FDA's Anesthetic and Life Support Drug Advisory Committee is made up almost exclusively of anesthesiologists. Neurologists, internists, neonatologists, pediatricians, etc. who deal with some of the very serious adverse effects of surgical and obstetric anesthesia, are not included as members of that advisory committee.

The FDA has no system for periodic review to determine the delayed, long-term adverse effects of a drug once the drug is on the market.

In effect, the FDA uses the public to determine the delayed adverse effects of drugs. The FDA does not require, as part of the approval process, that the manufacturer of the drug carry out a systematic, long-term follow-up of individuals exposed to the drug.

Data on adverse effects gathered under research conditions do not always reflect the actual incidence of such effects when drug is used in general medicine.

Negative or adverse effects of drugs often appear only after widespread use. The lack of follow-up to evaluate the effects on the child of drugs ingested by or administered to the mother during pregnancy, childbirth, and breast-feeding is particularly irresponsible since no drug has been adequately tested for safety in regard to the exposed offspring.

An investigation by the U.S. General Accounting Office (the Federal "watchdog" agency) of the FDA's policies, procedures, and systems found a wide discrepancy between the data collected by the FDA's adverse reaction reporting system and the data which appeared in the published literature. In the case of one fetal effect, that effect appeared 20 times more often in the published literature than the incidence noted by the FDA. FDA explanations for the incomplete data include not putting research literature reports into the computer system and physician reluctance to report adverse drug reactions to the FDA.

FDA relies primarily on manufacturer for information on delayed adverse effects.

Even the FDA acknowledges that this system is flawed because a manufacturer is not obligated to report adverse reactions to its product and is reluctant to do so because of the possibility of loss of sales resulting the disclosure of a drug-induced injury.

The FDA has no legal authority, nor does it want the authority, to require physicians, nurses, or other health professionals to report adverse drug reactions to the FDA, even if the patient dies as a result of the drug's use.

Therefore, there is no way the FDA can determine the exact rate of adverse reactions to an FDA-approved drug when it is used in general medicine under non-research conditions.

Persuading a physician to change an adverse reaction "Report" to an "Inquiry" removes manufacturer's legal obligation to inform FDA.

The FDA requires drug manufacturers to file with the Agency all adverse drug reaction reports received from physicians. However, the manufacturer can avoid filing such a report if the physician can be persuaded to change a "Report" to an "Inquiry". The manufacturer is not required to file an inquiry with the Agency.

FDA makes no real effort to facilitate public inquiry or reporting of adverse reactions.

The FDA Office of Consumer Affairs, Tel: 301) 827-5006, has a form that can be used by the doctor to report an adverse drug reaction (ADR) . Unfortunately, the FDA does not require the manufacturer to note in the drug's package insert the name of the FDA division responsible for evaluating the safety and effectiveness of the drug. Such inclusion would facilitate the reporting of an ADR or a request for information by concerned consumers. The form to used by the consumer can be obtained by calling Medwatch (800) 332-1088 or (301) 827-7240.

FDA must be prodded to follow up on adverse reaction report by consumers.

If the treating physician refuses to provide the FDA with the patient's medical records, the FDA will usually not follow up and investigate the consumer's report. To obtain a copy of your hospital medical records see "What You Can Do," at the end of this document.

Can a physician prescribe a drug for a condition that is not approved by the FDA?

Physicians are free to use drugs in ways not approved as safe by FDA. The FDA cannot prohibit a physician from using a drug for a use not approved by the FDA. However, in the event of drug-induced injury, the use of a drug not approved for such use by the FDA may affect the court's decision should litigation arise.

Can one trust the information in the "package insert"?

In many cases the package insert will provide far more information regarding the inherent risks associated with the drug than is provided by most physicians and pharmacists' medguides. However, package inserts and commercially prepared medguides are often ambiguous regarding the risks of the drugs they describe.

Check the FDA web site, "www.FDA.gov" for drug information, since the information in the insert may not be up to date.

Whether due to FDA inertia or pressure from the pharmaceutical industry, once information is known regarding a drug's adverse effects it may be months or years before that information appears in the package insert.

The FDA continues to rely on adverse reaction reports from physicians and manufacturers as primary sources of information for the package insert, yet acknowledges that there is significant under-reporting of adverse drug reactions by physicians.

The FDA's other source of information is articles published in the medical journals, most of which appear a year or more after the research findings are known. Unfortunately, most of the researchers who write the articles tend to share the bias and concern shown by the medical specialty which sponsors or is served by the journal.

Package insert often vague on date of last FDA review.

The FDA has chosen not to identify the date printed on the package insert as being either the date of the last reprint of the insert or the date of the last FDA review of the research data on the drug. The user of a package insert, therefore, has no way of knowing if the package insert reflects the current state of knowledge regarding the drug.

No FDA system for retrieving drug information according to approved use.

The FDA has no ready means of identifying those drugs which the agency has approved for a specific use (such as for high blood pressure, diabetes, pregnancy, obstetrics, etc.), according to the Office of Consumer Safety. The FDA has chosen to store drug information in its computer according to the drug's generic (chemical) name and by the manufacturer's trade name, but NOT according to approved indication. In other words, the FDA has chosen not to store in the computer that information which could identify whether a drug has or has not been approved by the FDA for a specific use.

FDA does not distinguish between exhaustive scientific investigation and cursory evaluation in the package insert.

The FDA has provided no system to enable the reader of the package insert to distinguish between those uses of the drug which have been subjected to a controlled scientific investigation, evaluation, and FDA review before being approved as safe by the FDA, and those uses of the drug approved as safe after relatively superficial testing and review, or because the drug is similar to a drug already on the market.

FDA quiet regarding consumer access to drug information.

There is no state or federal law which prohibits the pharmacist from giving the consumer the package insert which comes in the carton of prescription drugs. However, the FDA has made no significant effort to inform the public of this fact, or that the same information in the package insert or labeling can be found in the PHYSICIANS' DESK REFERENCE, found in most libraries.

Many potentially hazardous drugs are being withdrawn from the PDR by the manufacturer, since the FDA does not require drug manufacturers to put their labeling in the PDR.

Such withdrawal prevents the public, and often the care giver, from knowing the drug's inherent risks and whether or not the drug has been approved for its intended use. The enactment of state laws requiring the licensed pharmacist to offer the consumer the opportunity to read or copy the FDA approved package insert of the prescribed drug, prior to purchase, would help the consumer to make a more informed decision as to whether to take or forego the drug.

To insure safe use pharmacists are required to supply FDA-approved patient package inserts (PPIs) with contraceptive drugs but not with drugs to be taken by pregnant and childbearing women.

To our knowledge, the FDA has not taken any action against pharmacists who fail to comply with the law. In the event of drug-induced injury, the pharmacist's failure to protect the consumer from harm may affect a court's decision in favor of the consumer if a lawsuit should be brought.

HOW SAFE ARE THE DRUGS ADMINISTERED TO

CHILDBEARING WOMEN?

The physician or midwife caring for a childbearing woman is obligated to tell the woman about the benefits of the drug he or she is prescribing for her care, the inherent risks of the drug to both the woman and her baby, and the FDA status of the drug before asking her to accept or refuse the drug prescribed.

Only a handful of drugs have been approved by FDA for use in pregnant and childbearing women, and none has been proven safe for such use.

None of the drugs taken by or administered to women during pregnancy, birth or lactation has been subjected to a properly controlled scientific investigation and found to be safe for the infant exposed to the drug in utero (in the womb), or in breast milk. Nor has the FDA required that the drugs be tested in primates, whose neurologic system is closest to that of human offspring.

With 4 million American children afflicted with some form of minimal brain dysfunction, i.e. dyslexia, hyperkinesis, perceptual handicap, attention deficit disorders, and a growing rate of autism that has risen 500% in some states in only one decade, it is time to sound the alarm.

Virtually all drugs taken by or administered to pregnant women cross the placenta and enter the blood and brain of the fetus within seconds or minutes. The drugs and their metabolites remain in the infant's brain, altering brain chemistry, for several hours or days after birth.

Two centers of research have shown that a drug approved by the FDA for use in epidural block can adversely affect normal brain function for several weeks following birth, with no evidence that the problem was resolved when the testing period ended. Sublimaze, a drug frequently used in an epidural block, has never been approved for use in obstetrics.

What is the effect of altering the brain chemistry of a newborn at a time when his or her brain and central nervous system are rapidly forming millions of new connections? Scientists have shown that the migration of neurons along the glial fibers within the brain can be altered by changing the normal chemistry of the rapidly developing brain. The public needs to know which of the many drugs used in obstetric care may contribute to misconnections within the fetal and newborn infant's brain that can leave that infant vulnerable to neurologic problems as that child develops and faces new demands on his or her intellect and ability to control behavior.

FDA does not require manufacturer to mention in the package insert if the use of his product is likely to precipitate the need for a more hazardous drug or procedure.

Most expectant parents are not told that if the mother has an epidural she is very likely to need another drug to stimulate the uterus to contract sufficiently to move the baby through the birth canal, and that forceps and/or vacuum extraction may be necessary to avoid a cesarean section.

The list of adverse effects noted in the package inserts of drugs used in epidural blocks and/or to stimulate contractions is long and should be read and considered by any woman considering an epidural for the birth of her child. Only then can she give her informed consent.

FDA's decision to test drugs in childbearing women does not include plans to follow up on the later development of children exposed to the drugs in utero.

The rapid increase in autistic and learning disabled children underscores the need for the FDA to determine which drugs used in the care of childbearing women are safe for both mother and baby, and which may have delayed, long-term adverse effects.

It is especially important that pregnant women read the "Indications" section of the package insert or label first.

Because of the huge marketing potential, there is a far greater likelihood to see "weasel wording" in the package inserts of drug NOT approved for use in obstetric care. Remember, only if a condition such as "pregnancy, labor, birth or lactation", is mentioned in the Indications section (or label) has the FDA approved the drug for treatment of that condition. If those words appear elsewhere in the text but not in the Indications section, the wording is intended to mislead the reader into assuming that the FDA has approved the drug for such use.

The tocolytic drug, ritodrine (Yutopar), administered to the mother to decrease uterine activity, has been approved for that use by the FDA. Yet

obstetricians frequently prescribe the drug terbutaline "off label" for the same purpose because it is less expensive than ritodrine. Under the doctrine of informed consent the mother has a right to know the FDA status of the drug, as well as the inherent risks, before she is exposed to the drug.

No FDA requirement that obstetric drugs be proven safe for the fetus or newborn.

The criteria used by the FDA to determine the relative safety or risk of an obstetric-related drug have not included a requirement that the drug be proven safe for the fetus or newborn. While the Brazelton Assessment Scale has been found superior to all others, none of the methods currently accepted by the FDA to evaluate the affects of drugs on the offspring is sensitive enough to detect subtle, early neurologic damage that may become apparent as the child develops.

FDA plans to "simplify" the text of the package insert. 

It is important that the FDA not yield to pressure from the pharmaceutical industry to simplify drug labeling by eliminating or altering the Indication section in the label. Such an action would not be in the best interests of the public or health care providers, since the doctrine of informed consent requires the provider to inform the patient as to the FDA status of the drug and the conditions for which the drug has been approved.

Be aware of misleading text in the package insert, such as "Safe use in pregnancy, other than during labor, has not been established".

Such a statement implies that the drug has been proven safe when used in labor. Other statements, such as "Do not use during the first three months of pregnancy" are also misleading. The fetal brain and central nervous system are especially vulnerable as labor begins.

Other federal agencies and medical groups are concerned regarding fetal safety of obstetric drugs.

Officers of the Committee on Drugs, American Academy of Pediatrics and the Center for Research for Mothers and Children, NIH, have repeatedly cautioned that there is no drug, whether an over-the-counter remedy or prescription drug, that has been proven to be without risk for the unborn infant when that drug is taken by or administered to a childbearing woman.

None of the methods currently accepted by the FDA to evaluate the effects of drugs on the offspring is sensitive enough to detect subtle neurologic damage at birth.

The Neurologic and Adaptive Capacity Score (NACS), used for years to document the "safety" of obstetric related drugs, has been found unreliable. Even the Brazelton Assessment Scale, considered superior to all other assessment methods, has never been correlated with child development at age of 8, 9 or 10. In a continued effort to downcode obstetric nomenclature in order to avoid malpractice issues, obstetricians are increasingly omitting the 1 minute Apgar score on newborn records. While the 5 minute Apgar denotes resuscitative skills, it is the 1 minute score that is more likely to denote the baby's condition in utero.

Research in animals has shown that normal blood gases at birth are no assurance that the fetal brain has not sustained significant damage.

Neither "old" nor new obstetric drugs (and devices) adequately tested for safety.

Among those few drugs approved by the FDA as relatively safe for use in pregnancy and obstetrics, there is no evidence that the FDA made its decision on the basis of appropriate, properly controlled, scientific investigation in humans. The safety of many "old" drugs used in obstetrics today was determined by studying the effects of the drug on men, postmenopausal women, and one or sometimes two species of animals and extrapolating those effects.

As previously mentioned, the FDA does not require, prior to giving approval of a drug for obstetric use, that a controlled investigation and long-term follow-up be carried out on infants exposed to the drug in utero (hereafter referred to as "the exposed offspring"). Yet such a follow-up is essential in order to determine whether or not a drug may have latent, delayed, long-term, adverse effects on the subsequent physical, neurological, and mental development of the exposed offspring.

FDA rehashes outdated, uncontrolled data

Although there was no control group of healthy, unmedicated mothers included in the Collaborative Perinatal Project (1959-1965) to serve as a baseline against which to measure deviation from normal development in the exposed offspring, the U.S. Department of Health and Human Services and the FDA continue to examine that data rather than utilizing more current scientific methodology.

FDA has no system for accurately determining the benefit/risk ratio of an obstetric drug for the offspring.

The FDA has not required the manufacturers of obstetric drugs to investigate the effects of their drugs on the subsequent physical and neurologic development of the exposed offspring beyond the first minutes of life. Therefore, it is impossible for the FDA to accurately determine the risk/benefit ratio of a drug as it pertains to the exposed offspring. Nor can the FDA know whether a drug's effect observed in the newborn infant is significant unless such an investigation and follow-up is carried out.

A minimum of 8 years would be required for such a follow-up. A drug's more subtle effects on brain function may not become apparent until the child reaches at least the age of eight, when the brain is called upon to carry out more analytic tasks, such as those necessary for mathematical division, etc. (Our experience with DES has taught us that it may take 20 years before we know the effect of a drug, or medical procedure, on the physical development of the offspring.)

Outmoded method for assessing newborn still accepted by FDA.

None of the current methods accepted by the FDA as evidence of safety has been proven effective in determining a drug's more dysmorphogenic properties - the ability of a drug to cause functional or structural abnormality.

The FDA has traditionally considered the offspring to be essentially unaffected by drugs administered to the mother if the infant scores 7 or above, on the APGAR scale of 10, by one minute after birth. (The Apgar Scale rates two points each for normal: a) heart rate, b) respiration, c) muscle tone, d) response and e) skin color). The rating is crude and subject to bias since frequently it is based on the opinion of those responsible for the infant's delivery.

The American Academy of Pediatrics' Committee on Drugs has cautioned that the Apgar Score will identify only the most gross signs of neurologic dysfunction or brain damage. A follow-up by the National Institutes of Health of over 50,000 children revealed that among the children subsequently found to have cerebral palsy, 43% had been diagnosed as normal when they were discharged from the hospitals' newborn nurseries.

FDA ignores its own guidelines for evaluating neurotoxicity in newborns

The FDA's own guidelines* for the evaluation of drugs used in the care of pregnant women and newborns note that drugs circulating in the bloodstream of the newborn infant can penetrate the infant's blood brain barrier. Drugs trapped in the infant's brain at birth can adversely affect the rapidly developing nerve circuitry of the brain and central nervous system by altering the following brain processes:

  1. Neuronal maturation: the rate at which the nerve cells in the brain mature,
  2. Cell differentiation: the process by which the brain cells develop individual characteristics and capacity to carry out specific functions,
  3. Cell migration: the process by which the brain cells are guided into their proper place within the brain and central nervous system,
  4. Dendritic arborization: the interconnecting of the branch-like nerve fibers as the circuitry of the brain is formed and the
  5. Myelinization of nerve fibers: the forming of an insulating sheath of myelin (fat-like substance) around the nerve fibers. This insulation helps to assure that the nerve impulses C the messages to and from the brain C will travel their normal route at the normal rate of speed.

*     "General Considerations for the Clinical Evaluation of Drugs in Infants and Children," HEW (FDA) No. 77-1977, U.S. Govt. Printing Off., Wash., DC 20402

Any alteration in the development of the complex nerve circuitry of the brain has the potential for permanently altering the way the brain processes and responds to information.

The FDA does not require the manufacturer to state in the package insert the fact that the delayed, long-term effects of his product on the subsequent neurologic development of the exposed offspring are unknown.

The implication of these changes in brain circuitry were succinctly stated in the early 80s by Dr. Donald Tower when, as Director of the National Institute of Neurological and Communicative Disorders and Stroke, he cautioned:

"It is the biochemical circuitry C the biochemical messengers and the relevant nerve cells in the brain - that form the basis for mankind's behavior."

"Criteria for exclusion" permitted to bias research conclusions:

The FDA appears to make no effort to evaluate how the "criteria for exclusion" (reasons for excluding an infant from the group to be tested) skew the findings of safety in regard to the infant. For example, many studies of FDA-approved obstetric drugs excluded from testing any infant born to a healthy mother who received an epidural block during labor if that infant showed evidence of severe intrauterine trauma and/or an abnormal physical or neurologic condition at birth or during the postpartum period. These exclusions ignore the fact that the trauma and abnormal conditions observed in the infant could have been caused by the drugs administered to the mother during labor and birth.

Obstetricians and anesthesiologists, not pediatricians, decide the fetal safety of obstetric drugs.

It is well recognized that it is the fetus and newborn infant who are the most vulnerable to the adverse effects of obstetric-related drugs. Yet the FDA relies primarily upon its Reproductive Health Drugs Advisory Committee, comprised primarily of obstetricians, to evaluate the safety of new drugs, and also of drugs currently marketed for use in childbearing women. Rarely does an expert specifically trained to evaluate the effects of obstetric drugs on the subsequent development of the exposed offspring attend the Advisory Committee meetings.

The obstetricians who make up the Advisory Committee seem very aware that if they recommend that the FDA remove its approval of a drug used in obstetrics, they will increase the possibility of malpractice litigation for themselves and their colleagues who have had "trouble" with the drug. Their own self-interest works against their recommending that the FDA remove its approval of a drug for use in obstetrics unless there is blatant evidence of danger. Such self interest results in a considerable effort being made to avoid wording such as "inadvertent" or "accidental" in the package insert since such words suggest malpractice.

FDA has made no effort to establish a perinatal drug committee

The FDA has refused repeated appeals to establish a multi disciplinary perinatal drug advisory committee which would have the expertise to evaluate the effects on the child of drugs administered to the mother during pregnancy, childbirth, and lactation.

How reliable are the package inserts for obstetric drugs?

The FDA permits manufacturers to imply that the major risk to the fetus is limited to the first three months of pregnancy when, in fact, it is the brain and central nervous system that are rapidly developing as labor begins, and therefore vulnerable to drug-induced injury.

Evasive wording permitted in package insert.

Virtually all pain relieving drugs cause a rise in cerebral spinal fluid pressure, yet the implications of this effect are not dealt with in the insert.

Manufacturers are permitted to use wording in the package insert which implies that a serious adverse reaction to the drug will occur in the mother, the fetus, or the newborn infant only if the mother is "hypersensitive" to the drug. However, one out of every four infants whose mothers received only 50 mg. of meperidine during labor (considered by many to be a minimal dose) showed signs of neurologic depression at birth. No later follow up was ever carried out on the exposed offspring to see if there was any correlation between in utero exposure to meperidine and subsequent learning disfunction in the children.

The FDA permits manufacturers to state in the package insert that a drug has "no significant effect on fetal development," or words to that effect, even though the manufacturer has made no effort to carry out, and the FDA has not required, a controlled scientific investigation and long-term follow-up of the exposed offspring to determine whether an observed effect in the newborn is or is not significant to the child's physical and neurologic development. The significance of an adverse effect can only be determined by a follow up as the child develops physically and neurologically.

Manufacturers permitted to bury warnings on serious risks

Far along in the package insert of bupivacaine (Marcaine) the manufacturer acknowledges:

"There are no adequate and well-controlled studies in pregnant women of the effect of bupivacaine on the developing fetus. Bupivacaine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus"....

"Local anesthetics rapidly cross the placenta, and when used for epidural, caudal or pudendal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity...Adverse reactions in the parturient, fetus and neonate involve alteration of the central nervous system, peripheral vascular tone, and cardiac function....."

"Neurologic effects following epidural or caudal anesthesia may include

  1. spinal block of varying magnitude (including high or total spinal block)
  2. hypotension secondary to spinal block
  3. urinary retention
  4. fecal and urinary incontinence
  5. loss of perineal sensation and sexual function
  6. persistent anesthesia
  7. paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control all of which may have slow, incomplete or no recovery
  8. headache, backache
  9. septic meningitis
  10. meningismus
  11. slowing of labor
  12. increased incidence of forceps delivery
  13. cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid."

"Neurologic effects following other procedures or routes of administration may include persistent anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete, or no recovery".

The administration of bupivacaine epidural during labor can significantly decreases uterine contractility, remove the mother's reflex urge to bear down, and interfere with motor function. Such disruption in the normal physiology of birth increases the likelihood that a uterine stimulant will be used, that a postpartum hemorrhage will occur and a hysterectomy performed to stop excess bleeding.

There is no FDA approved indication for the use of fentanyl citrate in labor and delivery, although the drug is frequently administered in conjunction with bupivacaine. The manufacturer of the fentanyl citrate (Sublimaze) cautions:

"There are insufficient data to support the use of Sublimaze in labor and delivery. Therefore such use is not recommended".

Despite the growing concern that regional block anesthesia (epidural, spinal, etc.) may be contributing to the rising rate of cesarean section and subsequent hysterectomy in the U.S., the FDA has made no effort to require an investigation into whether regional block anesthesia without oxytocic drugs increases the need for cesarean section performed because of dysfunctional labor and/or fetal distress.

Significant adverse effects frequently omitted from package insert

The loss of the gag reflex is one of the most dangerous effects of obstetric drugs. If the mother's gag reflex has been blunted by a drug and she retches vomitus or gastric fluid, her gag reflex may fail to prevent the acidic, caustic substance from being inhaled into her lungs. Pneumonia or a life-threatening condition called "aspiration of vomitus" can result. This condition can also occur in the newborn infant whose neurologic system is depressed by its mother's obstetric drugs. Yet these effects are not mentioned in the package insert of those drugs which can cause these hazardous neurologic dysfunctions. (Administering an antacid to the mother during labor will reduce the acidity of her stomach. However, aspiration of the antacid can create problems in itself.) The true incidence of suffocation or chemical pneumonia resulting from aspiration of vomitus is unknown.

Timing of fetal uptake of obstetric drug not required in package insert

With rare exceptions, the drugs administered to the mother during labor and delivery, including pudendal block and local perineal infiltration, rapidly filter through the placental membranes and enter the fetal circulation and brain. The drugs and their metabolites continue to circulate in the fetal blood, brain, and other organs during labor and for several hours or days after birth. The manufacturer is not required to note in the package insert the number of hours or days the drug and its metabolites can still be detected in the blood of the newborn infant. This information is important to pediatricians and others caring for and prescribing for the newborn infant.

Manufacturer of oxytocin cautions obstetrician to be immediately available.

The FDA approved package insert for oxytocin ("pit drip") cautions that all patients receiving oxytocin must be under continuous observation by trained personnel who have a thorough knowledge of the drug, and are qualified to identify complications, and that:

"A PHYSICIAN QUALIFIED TO MANAGE ANY COMPLICATION SHOULD BE IMMEDIATELY AVAILABLE.

Maternal deaths due to hypertensive episodes, subarachnoid hemorrhage, rupture of the uterus, fetal deaths and permanent CNS or brain damage of the infant due to various causes have been reported to be associated with the use of parenteral oxytocic drugs for induction of labor or for augmentation in the first and second stages of labor."

In addition to the more benign effects of uterine stimulants, such as nausea and vomiting, the manufacturer of Pitocin (oxytocin) points out in its package insert that oxytocin can cause:

     

  1.  maternal hypertensive episodes
  2. subarachnoid hemorrhage
  3. anaphylactic reaction
  4. postpartum hemorrhage
  5. cardiac arrhythmias
  6. fatal afibrinogenemia
  7. premature ventricular contraction
  8. pelvic hematoma
  9. uterine hypertonicity
  10. uterine spasm
  11. tetanic contractions
  12. uterine rupture
  13. increased blood loss
  14. convulsions
  15. coma
  16. fatal oxytocin-induced water intoxication."

In regard to the fetus and newborn, the manufacturer also acknowledges that the following adverse effects of maternally administered oxytocin have been reported in the fetus or infant:

  1. bradycardia
  2. premature ventricular contractions and other arrhythmias
  3. low 5 minute Apgar scores*
  4. neonatal jaundice
  5. neonatal retinal hemorrhage
  6. permanent central nervous system or brain damage and
  7. fetal death".

*    The manufacturer fails to mention the 1 minute APGAR score, which is more likely to reflect the condition of the fetus in utero.

Uterine stimulants which foreshorten the oxygen-replenishing intervals between contractions, by making the contractions too long, too strong, or too close together, increase the likelihood that fetal brain cells will die.

Biochemical factors as well as dosage determine a drug's effect

The fetal effects of a drug administered to or taken by the pregnant or parturient (laboring) woman depend on many factors:

Hopefully, if all biochemical factors are favorable, the development of the exposed offspring may not be affected, or at least not to any discernible degree. Unfortunately, it is impossible to predetermine how an individual fetus will be affected by a drug or combination of drugs administered to the pregnant woman.

Can one get a list of those drugs approved by the FDA for use in obstetric care?

The FDA Office of Consumer Affairs confirms that the Agency has no system that can single out those drugs the Agency has approved for use in obstetrics. Until recently the FDA did not appear to show particular concern regarding the adverse effects on the fetus of the various drugs ingested by or administered to pregnant and parturient women.

FDA categories of obstetric drug risk tends to give a false sense of safety

The FDA has established five categories to indicate a drug's potential for causing birth defects. However, even drugs in Category "A", the category of least risk, have not been tested to determine whether or not there are delayed, long-term risks to the physical and neurologic development of the exposed offspring.

 

ULTRASOUND IN OBSTETRIC CARE

FDA has made no effort to investigate whether there are delayed, long term adverse effects of diagnostic levels of ultrasound on human development.

The FDA approved the use of ultrasound (high frequency sound) for fetal imaging (sonogram), doppler, electronic fetal monitoring during labor without requiring manufacturers to divulge the level of energy produced by the device.

As early as 1979 FDA officer Marion Finkel summarized the FDA's concern regarding the safety of diagnostic ultrasound used in obstetrics when she stated:

"Increasing concern has arisen regarding the fetal safety of widely used diagnostic ultrasound in obstetrics. Animal studies have been reported to reveal delayed neuromuscular development, altered emotional behavior, EEG (brain wave changes, anomalies, and decreased survival. Genetic alterations have also been demonstrated in in vitro systems."

In 1984 an FDA/NIH panel of experts issued a statement recommending against the routine use of ultrasound in obstetrics. The panel recommended that ultrasound be used only when there is a valid medical indication.

Several major research studies have failed to show that routine electronic fetal monitoring (EFM) improves maternal and infant outcome except in very high-risk mothers (probably because the use of EFM has not reduced intervention oriented obstetric care).

This author recently questioned David Feigal, M.D., Director, Center for Devices and Radiological Health as to what is known about the long term effects of ultrasound on human development. His answer was very clear,

"No one knows the long term effects of ultrasound on human development".

Tell your physician or midwife if you are concerned about the safety of ultrasound. If you decide to have a sonogram you can minimize your baby's exposure to ultrasound if you tell the sonographer of your concerns and that you want the shortest possible exposure necessary to obtain the information needed.

 

For further information read the report of the FDA's Center for Devices and Radiological Health entitled An Overview of Ultrasound: Theory, Measurement, Mechanical Applications, and Biological Effects. HI-IS Publication, FDA 82-8190, U.S. Govt. Printing Office, Washington, DC 20402.

 

WHAT YOU CAN DO

The information in the PDR is the same as that in the package insert. However, keep in mind that the information, while approved by the FDA, is actually written by the manufacturer. Some drugs are not listed in the PDR, or if listed, the text of the package insert is not included. The FDA does not require manufacturers to list their drug products in the PDR.

If your pharmacist refuses to give you the package insert or to allow you to read it or the relevant pages in the PDR, find another pharmacist who will allow you to read the information. Feel free to return the unopened drug for a refund if, after reading the package insert information (from another source), you decide against taking the drug.

An information leaflet from the pharmacist is not a substitute for the manufacturer's package insert since the leaflet may omit information regarding adverse drug reactions.

If your public library does not have the latest PDR, which is published annually, ask the librarian to order it.

Keep a record of all drugs taken - brand name, generic name, amount prescribed, number of times taken and the date(s) the drug was taken.

In the case of pregnancy, keep a record of all drugs taken during pregnancy (beginning with the date of the last menstrual period), labor, birth, and breast feeding. Remember, the overwhelming majority of drugs have never been evaluated for use in obstetrics.

 

INFORMATION SOURCE

Center for Drug Evaluation and Research, FDA: Tel: (301) 594-5400

For information unavailable elsewhere, or to report an adverse drug reaction or a suspected drug-related birth defect, write to:

Office of Consumer Affairs, FDA: (301) 827-5006

5600 Fishers Lane, Rockville, Maryland 20857

Freedom of Information Act Office, FDA: (Tel:(301) 827-4583

The Freedom of Information Act requires the FDA to comply with a citizen's request for a drug's "Approval Packet". The packet contains a transcript of the deliberations of the FDA Advisory Committee that approved the drug for marketing.

DRUGS AND THE ELDERLY

If you have a member of your family in a nursing home or institution, ask to read the package inserts of the drugs he or she is being given. Over-medication or improper medication can produce "chemical senility."

If the drugs are supplied by an independent pharmacist who refuses to let you have or read the package insert, withholding payment to the pharmacist until the desired information is provided frequently brings quick results.

Additional Reading

Check with your local library for consumer-oriented books which discuss drug actions and interactions (i.e., "The People's Pharmacy", "Pills, Politics and Profits","Pills That Don't Work", etc.

For additional information regarding the potential risks of various drugs used in pregnancy, labor, birth, and lactation, log on to Drugs Used in Labor and Birth: Their Effects on Mother and Baby" at the web site of AIMSUSA.org.

 

Author's Acknowledgment

Many FDA officers, staff members, and advisors contributed to the information in this report. The author is especially grateful for the encouragement and counsel of Sumner J. Yaffe, M.D., former Chairman of the Committee on Drugs of the American Academy of Pediatrics, and Director, Center for Research for Mothers and Children, National Institute of Child Health and Human Development.

Doris Haire, President, American Foundation for Maternal and Child Health and Chair, Committee on Maternal and Child Health, National Women's Health Alliance