Statement by Doris Haire, President of the American
Foundation for Maternal and Child Health, New York to
the FDA Science Board November 17, 2000
I appreciate this invitation to share my concerns with the members of the FDA Science Board, and to ask the Board to urge the FDA to create an Interdisciplinary Obstetric Advisory Board comprised of pediatricians, pediatric neurologists, behavioral scientists, midwives, obstetric nurses and obstetricians to evaluate the safety of drugs to be administered to pregnant and parturient women. The FDA can not expect a Maternal Health Drug Advisory Committee made up almost exclusively of obstetricians to be objective about the drugs they have administered to their patients. Such a group does not have the training or expertise to determine the delayed effects of the drugs they administer to parturients on the long-term neurologic development of the exposed offspring.
I have heard obstetricians in that committee remind the group that there could be “serious repercussions” for obstetricians if the committee were to recommend that a drug previously approved by that committee be removed from the market.
The fact that the makers of Pitocin, Marcaine, Sublimaze and other drugs commonly used in obstetric care have chosen to remove their labels from the Physicians Desk Reference only adds to our conviction that they wish to withhold ready information regarding the risks of their drugs, not only from the public, but the doctors and other health care providers themselves. Most nurses and midwives who are asked to administer these drugs are refused when they ask the hospital pharmacy for a copy of the package inserts.
I am concerned that as the number of children with learning disability, autism, dyslexia, attention deficit, and hyperactivity continue to mount to a frightening number, the FDA does not appear to be making a strong endeavor to see if obstetric related drugs contribute to these problems. For some reason scientists seem to have let the science of human parturition slip through the cracks. As evidence of this scientific vacuum, a recent Report of the Task Force on the NIH Women’s Health Research Agenda for the 21st Century failed to mention the need to improve the safety of childbirth for the woman and her baby and the need to determine the potential adverse effects of obstetric drugs and interventions on the neurologic development of the exposed offspring.
In light of the soaring rate of autistic (500% is some states) and otherwise neurologically impaired children during the last ten years, it behooves the FDA to question whether cervical ripeners, uterine stimulants and the various pain relieving drugs administered to the parturient permanently alter the brain chemistry of the fetus and newborn sufficiently to interfere with the normal dendritic arborization within the infant’s brain. Virtually all of the drugs administered to the parturient cross the placenta, enter the circulatory system and brain of the fetus and newborn infant where the drugs or their metabolites remain for days, if not weeks.
It is ironic that women who do not wish to become pregnant are provided a package insert with their contraceptive drugs to insure that they understand the risks of taking the drug. Yet the woman who wishes to have a safe birth experience for her baby, as well as herself, receives no package insert advising her of the known or potential risks to her and her baby.
I urge the FDA Science Board to recommend that the FDA require that package inserts be made a available on request to all expectant mothers who wish to know about the drugs they will be offered during pregnancy, labor, delivery, and postpartum.
OXYTOCIN: Consider the information the doctor receives regarding the risks of Oxytocin. The manufacturer of Oxytocin warns the provider in the package insert:
“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 American manufacturer of Pitocin (Oxytocin) points out in its package insert that Oxytocin can cause:
(a) maternal hypertensive episodes
(b) subarachnoid hemorrhage
(c) anaphylactic reaction
(d) postpartum hemorrhage
(e) cardiac arrhythmias
(f) fatal afibrinogenemia
(g) premature ventricular contraction
(h) pelvic hematoma
(i) uterine hypertonicity
(j) uterine spasm
(k) tetanic contractions
(l) uterine rupture
(m) increased blood loss
(n) convulsions
(o) coma
(p) fatal induced-induced water intoxication
The following adverse effects of maternally administered Oxytocin have been reported in the fetus or infant:
(a) bradycardia
(b) premature ventricular contractions and other arrhythmias
(c) low 5 minute Apgar scores
(d) neonatal jaundice
(e) neonatal retinal hemorrhage
(f) permanent central nervous system or brain damage
(d) fetal death
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. The situation is somewhat analogous to holding an infant under the surface of the water, allowing the infant to come to the surface to gasp for air, but not to breathe. All of these effects increase the possibility of neurologic insult to the fetus. No one really knows how often these adverse effects occur because there is no law or regulation in any country which requires the doctor to report an adverse drug reaction to the country’s drug regulating agency, even if the patient dies. I was pleased to note that this flaw in our system made the front page of yesterday’s Los Angeles Times.
There are now growing indications that Oxytocin may contribute to the incidence of autism. But is it the Oxytocin or is it the drug used in epidurals that then precipitates the need for Oxytocin.?
EPIDURAL ANESTHESIA
Consider the following information which the U.S. Food and Drug Administration currently requires the manufacturer of bupivacaine hcl (Marcaine) to provide those care givers licensed to administer epidural anesthesia. The government approved labeling for bupivacaine hcl (Marcaine) reads:
“LABOR AND DELIVERY:
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…”
“ADVERSE REACTIONS. Neurologic” the official labeling continues:
“Neurologic effects following epidural or caudal anesthesia may include spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia; paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control all of which may have slow, incomplete or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; and 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.”
EPIDURAL ANESTHESIA AND CESAREAN SECTION
A randomized controlled prospective trial carried out by Thorp and colleagues has shown a ten fold increase in the rate of cesarean section among mothers who received a labor epidural. Separate investigations by Newton and others have shown that epidural analgesia can cause disruptions in normal uterine function that cannot be completely corrected by the use of Oxytocin and can double the rate of stress incontinence.
Drug manufacturers would have you believe that the incidence and degree of toxicity of a drug depends only upon the procedure performed, the type and amount of drug used, and the technique of drug administration. What they fail to tell the provider is that gestational age, condition of the fetus, previous and concomitant exposure to other drugs, relative hypoxia and various pathological conditions can affect how a drug given to the mother will affect her fetus during labor, birth and the infant’s development following birth. Hypoxemia and a resulting build up of lactic acid in the fetal blood during labor and birth can increase the uptake of a maternal drug by the fetal brain and heart.
EFFECT OF EPIDURAL ANESTHESIA ON NEWBORN
Rosenblatt and her fellow investigators found that bupivacaine administered to the mother during labor can have prolonged adverse effects on the subsequent development of the exposed offspring. The investigators found that newborn infants with greater exposure to bupivacaine in utero were more likely to be cyanotic and unresponsive. They also found that visual skills and alertness decreased significantly with increases in the cord blood concentration of bupivacaine, particularly on the first day of life, but also throughout the next six weeks. Adverse effects of bupivacaine levels on the infant’s motor organization, his ability to control his own state of consciousness and his physiological response to stress were also observed. In 1992 Sepkoski and colleagues carried out a similar investigation which supports the earlier findings of Rosenblatt et al.
These findings underscore the importance of managing the woman’s labor in a way that will avoid the need for Pitocin and the pain relieving drugs that are often administered to help the women cope with the chemically intensified contractions.
As early as 1975 the FDA acknowledged in its “General Considerations for the Clinical Evaluation of Drugs in Infants and Children” that drugs trapped in the infant’s brain at birth have the potential to adversely affect the rapidly developing nerve circuitry of the brain and central nervous system by altering:
a) the rate at which the nerve cells in the brain mature,
b) the process by which the brain cells develop individual characteristic and capacity to carry out specific functions,
c) the process by which the brain cells are guided into their proper place within the brain and central nervous system,
d) the interconnection of the branch-like nerve fibers as the circuitry of the brain is formed, and
e) the forming of the insulating sheath of myelin (fat-like) substance around the nerve fibers which help to assure that the nerve impulses – the message to and from the brain – will travel their normal routes at the normal rate of speed.
Now the work of Zheng, Heintz, and Hatten reaffirms 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.
At no other time in an individual’s life is his or her brain more vulnerable to alteration, trauma, and permanent injury than during the hours which surround that individual’s birth. The nerve circuitry of the brain and central nervous system of the fetus is rapidly developing as labor begins, making these complex structures vulnerable to permanent alteration or damage from the drugs and procedures administered to the mother during that time.
If the FDA is to be truly responsible to the citizens the agency is charged to protect, then the FDA Science Board should mandate that the makeup of the FDA advisory committees not be dominated by those health care providers involved in the administration of the drugs to be considered.
However well-intended, drugs, including Oxytocin, administered to the mother during labor and birth rapidly filter through the placental membrane and enter the blood and brain of the fetus in a matter of seconds or minutes. Once the infant is born and the cord is clamped, those drugs or their metabolites which are present in the newborn infant’s blood and brain are essentially trapped in the infant’s circulatory system for days or longer.
The package inserts or labeling of most of the drugs commonly administered to women during labor note that the drugs can cause an increase in fetal cerebral spinal fluid pressure. What does this alteration mean to the subsequent neurologic development of the exposed offspring whose brains are unduly compressed during labor as a result of artificially ruptured membranes, chemically intensified contractions, skull fracture resulting from forceps or vacuum extraction of the baby’s head?
The FDA Science Board must insist that the FDA disallow ambiguous wording in the drug labeling that implies that a drug is safe for a given condition when in fact the FDA has never required that a drug to be administered to a parturient must be proven safe for the baby.
I understand that the FDA uses its own definition of “Safe”. But that is not the definition understood by the general public. To the vast majority of Americans, “Safe” means “free from harm or injury”.
The FDA permits some pharmaceutical manufacturers to include in their labeling a statement which reads, in effect:
“Safe use in pregnancy, other than during labor and delivery, has not been established.”
That is a statement that former Commissioner Schmidt might well have referred to as “weasel wording”. Where is the documented scientific evidence that drugs such as bupivacaine, fentanyl and Oxytocin are safe for the exposed fetus when used in obstetric care?
Research now suggests that Oxytocin administered to the parturient during labor and birth may contribute to the incidence of autism in the exposed offspring. But is it the Oxytocin that is causing the autism, or the epidural that frequently precipitates the need for Oxytocin to stimulate the uterine musculature made ineffective by the bupivacaine?
It is ludicrous that scientists in the United States are still having to hash through the 40 year old Collaborative Perinatal Project to investigate the possible effect of obstetric drugs on human development. I have been told by several physicians who participated in that project that the Collaborative Project contained no control group of healthy, undrugged mothers and their babies who could have been used as controls against which to measure deviations from normal.
The FDA Science Board owes it to the American public to mandate that the FDA make every effort to require pharmaceutical manufacturers to document that their products will have no adverse effect on the immediate and long-term well-being of the children exposed to their products in utero, or provide with their products a package insert that clearly spells out the potential risks to the mother and her baby.
Industry must be reminded that they and the FDA are working in an electronic glass house. The FDA Science Board must urge the FDA to require more extensive evaluation when considering for approval a drug or device to be used in obstetric care. It is time that the FDA encourage manufacturers of drugs approved for use in obstetric care to submit data that demonstrates that the drug will not cause a delay in the newborn infant’s time to sustained respiration, or interfere with the newborn infant’s ability to see, to hear or suckle immediately after birth. Parents, as well as health care providers, need to be advised as to whether a drug will interfere with the newborn’s normal ability to adapt to extrauterine life.
Concern regarding the long term effects of chemically altering brain chemistry was expressed two decades ago by Dr. Donald Towers, Director of the National Institute of Neurologic Disorders and Stroke, who cautioned:
It is the biochemical circuitry – the biochemical messengers and relevant nerve cells in the brain – that form the basis for mankind’s behavior”
Around the same time neurobiologist Joseph Altman, speaking at a Washington conference examining the possible precursors of learning disability, expressed concern that the development of the human brain appears to be programmed so that certain cells and nerve fibers must develop in synchrony, in order to make appropriate connections within the central nervous system. He cautioned that drug-induced alterations of the chemical components within the brain may interfere with the synchrony of cell and nerve fiber growth, causing subtle or gross misconnections within the developing brain circuitry.
The Neurologic and Adaptive Capacity Score (NACS), used in the past to assess the safety of obstetric drugs has been shown to be unreliable, and there is no documentation to support an Apgar score of 7 or above as indicating the baby has been unaffected by its mother’s obstetric drugs. It is time for the FDA Science Board to develop its own neurologic assessment scale to evaluate the effect of obstetric related drugs on neurologic development. Even the leaders of the Society for Obstetric Anesthesia and Perinatology, of which I am a member, agree that the Brazelton Assessment Scale is the Cadillac of such assessment. The FDA assessment scale should be no less reliable.
As president or chair of several organizations concerned with the less than stellar quality of research in obstetric related drugs, I am here to ask why the FDA has shown so little interest in investigating the effects of obstetric related drugs on the development of the children exposed in utero to these drugs. In 1975, after the publication of The Cultural Warping of Childbirth, which I authored, I was invited to spend 3 months in a college of medicine, observing obstetric care in that highly regarded medical center. Since that time I have visited obstetric services in more than 70 countries and try to keep reasonably current on research dealing with obstetric drugs and procedures. I have found that there is very little effort to determine the adverse effects of commonly employed obstetric drugs and procedures.
I have organized and testified at two congressional hearings and instigated a GAO investigation, all of which pointed out the flaws in the testing of safety for obstetric drugs and devices, yet nothing seems to change. The FDA has not upgraded its “General Considerations for the Clinical evaluation of Drugs in Infants and Children” in more than a quarter century. And even the sound recommendations in that document have been ignored by the FDA advisory committees.
NORMAL PH DOESN’T MEAN OPTIMAL PH
A normal PH at birth does not mean that a newborn infant has come through unscathed. Animal research in New Zealand, carried out by Mallard and colleagues, investigated the neuronal effects of isolated and standardized brief periods of umbilical cord occlusion in utero. They found that brief periods of cord occlusion can cause neuronal damage in the offspring, mainly in the hippocampus region of the brain, with persistent functional changes in cortical activity, even though there was rapid recovery of other potential indicators of fetal asphyxia. Follow up of animals exposed to such brief periods of occlusion indicates that there is often a subsequent progressive decline in function.
Mallard EC, Gunn AJ, Williams CR, Johnston BM, Gluckman P: “Transient umbilical cord occlusion causes hippocampal damage in the fetal sheep” Am J Obstet Gynec 1992;157:1423-30.
EPIDURAL ANESTHESIA AND CESAREAN SECTION
A randomized controlled prospective trial carried out by Thorp and colleagues has shown a ten fold increase in the rate of cesarean section among mothers who received a labor epidural. Separate investigations by Newton and others have shown that epidural analgesia can cause disruptions in normal uterine function that cannot be completely corrected by the use of Oxytocin and can double the rate of stress incontinence.
Drug manufacturers would have you believe that the incidence and degree of toxicity of a drug depends only upon the procedure performed, the type and amount of drug used, and the technique of drug administration. What they fail to tell the provider is that gestational age, condition of the fetus, previous and concomitant exposure to other drugs, relative hypoxia and various pathological conditions can affect how a drug given to the mother will affect her fetus during labor, birth and the infant’s development following birth. Hypoxemia and a resulting build up of lactic acid in the fetal blood during labor and birth can increase the uptake of a maternal drug by the fetal brain and heart.
EFFECT OF EPIDURAL ANESTHESIA ON NEWBORN
I suggest that before approving a drug for use in obstetric care that the FDA require an investigation into the potential of the drug to produce creatine phosphokinase (CPKs) in the blood of newborns 18 to 24 hours after birth.
A study by neonatologist Susan Combs found a correlation between CPKs and CPK isoenzymes in the blood of the newborns who experienced asphyxia during labor. Increased creatine phosphokinase (CPK) and its isoenzymes reflect damage to cells caused by ischemia, hypoxia, trauma and metabolic disorders. CPK1 is found mainly in brain tissue, CPK2 in heart, and CPK3 in muscle. Her study underscores the need to use evidence of CPK and CPK isoenzymes as a measure of cellular damage in asphyxiated infants.
Interestingly, infants with moderate-severe fetal heart rate decelerations had chemical evidence of more cellular damage to brain and heart than to muscle compared to infants with normal FHR tracings or those with only mild variable decelerations. As decelerations worsened, a smaller percentage of total CPK arose from muscle and thus more from brain and heart. The data thus add further support to abnormal fetal heart rate patterns as an indicator of fetal asphyxia.
Research carried out by Stirrat and colleagues at the Bristol University in England has shown that an epidural disrupts the newborn’s neurologic control of respiration for at least the first 48 to 72 hours after birth.
I have attended enough FDA advisory meetings to know that the questions posed to the new drug applicants are worded to avoid any implication that the baby may be adversely affected by the drug under deliberation. Some years ago neonatologist Jack Scanlon reminded the Society of Obstetric Anesthesiology and Perinatology (SOAP) that they were not actively looking for adverse fetal effects resulting from obstetric anesthesia. His ended his comments by saying,
“If you don’t look, you wont find”.
Again, I appreciate this opportunity to share my concerns with you. I have a very large collection of scientific papers dealing with the effects of obstetric drugs on the newborn and would be happy to share information with you. I am submitting a copy of the paper I presented for UNICEF in Thailand entitled “DRUGS USED IN LABOR AND BIRTH: Their Effects on Mother and Baby” and would welcome your constructive criticism and comments. Thank you for your attention.
Addendum:Nov.25, 2000
* The package insert must:
a) advise the reader that fetal hypoxia increases the transfer of most drugs from the maternal compartment to the fetal circulation.
b) define the FDA’s version of Safe”.
c) avoid the phrase “Safe use in pregnancy, other than in labor, has not been determined”.
QUESTIONS OF DRUG SAFETY:
The FDA Science Board must develop standards for both maternal and fetal safety when the FDA is evaluating the potential risks versus the safety of any drug being considered for use in pregnancy or parturition.
DOES THE DRUG BEING EVALUATED BY THE FDA FOR SAFE USE IN PREGNANCY, PARTURITION, OR LACTATION INCREASE THE PARTURIENT’S:
need for external or internal electronic fetal monitoring?
disruption of her gag reflex?
need for intravenous feeding?
discomfort from pruritus?
intrapartum and/or postpartum urinary retention requiring catheterization?
the length of the first and second stage of labor?
shoulder dystocia?
likelihood that she will experience an increase in internal temperature or a disruption in
(a) peripheral vascular tone,
(b) normal thermoregulation, and/or
(c) cardiac function?
need for uterine stimulants, cervical ripeners or other drugs to counteract the effects of a previously administered drug?
incidence of:
a) disrupted internal temperature
b) disrupted peripheral vascular tone
c) disrupted normal thermoregulation
d) anaphylactic reaction
e) postpartum hemorrhage
f) cardiac arrhythmias
g) fatal afibrinogenenemia
h) hypertensive episodes
i) subarachnoid hemorrhage
j) high or total spinal block
k) brain embolism
l) premature ventricular contraction
m) pelvic hematoma
n) uterine hypertonicity
o) uterine spasm
p) tetanic contractions
q) nerve damage
r) uterine rupture
s) increased blood loss
t) headache and or backache
u) drug induced headache requiring blood patch
v) convulsions
w) aspiration of vomitus
x) coma
y) fatal induced-induced water intoxication
z) or subsequent fecal and urinary incontinence?
or inhibit the normal effectiveness of the pelvic musculature to rotate the fetus into the normal position for birth and expel the baby?
inhibit the mother’s normal expulsive efforts to bear down for birth, and to expel the placenta without the need for fundal pressure?
persistent anesthesia and/or paresthesia (perverted sensation)?
weakness and/or paralysis of the lower extremities?
the need for fundal pressure?
the need for an episiotomy?
the incidence of 2nd, 3rd, and 4th degree tears resulting from extensions of parturients’ episiotomy?
the intensity, as well as the incidence, of postpartum hemorrhage?
loss of sphincter control?
the incidence of central nervous system infection in the parturient or the newborn?
the incidence of cesarean section
the need for uterine stimulants to counteract the effects of the epidural or other forms of pain relief)?