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 September 2003 NCSAC Meeting Hypotheses Submitted by AFMCH

Hypotheses Submitted by AFMCH

Statement by Doris Haire, President
American Foundation for Maternal and Child Health

to the September 15, 2003
Meeting of the
National Children’s Study

I appreciate this opportunity to express my concerns, for I am troubled by the fact that after numerous meetings, there is no clear committment that the National Children’s Study will carefully document each child’s intrapartum exposure to drugs and procedures administered to the mother during labor and birth. The collection of that information is essential to any meaningful environmental study of human development.

I am also troubled by the fact that there appears to be no pediatric neurologist involved in the planning of this study. Such expertise is essential if the study is to make progress in determining whether or not there is a possible correlation between fetal exposure to a specific drug or regimen and the subsequent development of a neurologic disorder in childhood or early adulthood.

With the rate of children with learning disability, dyslexia, autism and other neurologic problems continuing to rise, it is imperative that the Study be designed to look closely and document the newborn infant’s exposure and response to intrapartum drugs. Zheng and colleagues have shown that the migration of neurons along the glial fibers within the rapidly developing brain can be altered by changing the normal chemistry of the brain. Intrapartum drugs trapped behind the newborn infant’s blood brain barrier can continue to alter brain chemistry for several days after birth.

Research carried out by the Maternity Center Association found that most pregnant women, unless they are being cared for by a midwife, are not told the drugs administered to them during labor and birth enter the baby’s brain within seconds or minutes. Nor is she likely to be told that none of the drugs and very few of the procedures, included ultrasound, used in obstetric care have been subjected to properly controlled research and found to be safe for the exposed fetus.

I do not question that genetics and other factors may play a role in the increasing incidence of neurologically impaired children, but that does not negate the need to carefully document the use and effect of drugs administered to the mother during labor, birth and lactation.

I would like to review briefly the 5 hypotheses which I have previously submitted for your consideration and explain why I have submitted them.

Hypothesis 1. The administration of oxytocin to parturients during labor and birth increases the incidence of jaundice in the newborn.

Rarely is a pregnant woman told that the administration of oxytocin to her, in order to induce her labor or augment contractions, may cause problems for her newborn baby. Yet the manufacturer of oxytocin states in its label that oxytocin crosses the placenta and enters the blood and brain of the fetus. The manufacturer further states that such intrauterine exposure to oxytocin during the first and second stages of labor can result in; (a) fetal bradycardia, (b) premature ventricular contractions and other non-normal heart functions, (c) low Apgar scores, (d) neonatal jaundice, (e) neonatal retinal hemorrhage, (f) permanent central nervous system or brain damage, and (g) fetal death.

Oxytocin and other uterine stimulants are not FDA approved for the ELECTIVE induction or augmentation of labor. Uterine stimulants can foreshorten the oxygen?replenishing intervals between contractions because the drug can cause contractions to be too long, too strong, or too close together, increasing the likelihood that fetal brain cells will die. No one really knows how often the adverse effects of oxytocin or any other obstetric drug occur, because there is no law or regulation which requires the doctor to report an adverse drug reaction to the FDA.

Hypothesis #2: The administration of pain relieving drugs to the mother during labor and birth can increase the incidence of resuscitation of the newborn infant.

There is no well-controlled scientific follow-up that has determined that newborn resuscitation is of no importance C a NON EVENT. And no one knows exactly how long a fetal or newborn brain can be deprived of oxygen before brain cells die. I have been privileged to observe obstetric care in more than seventy countries and I am always appalled by our high rate of resuscitation in the United States when compared to other countries.

The creeping omission of the 1 minute APGAR in American obstetric services appears to be one way of camouflaging the rate of newborn resuscitation. Requiring the recording of each infant’s time to sustained respiration, along with the 1 minute and 5 minute Apgar could help the NCS to correlate which drugs precipitate the need for newborn resuscitation and which do not.

Hypothesis #3: Drugs administered to the mother during labor and birth can 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 characteristics 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 around the nerve fibers, which help to assure that the nerve impulses will travel their normal routes at the normal rate of speed.

Normal blood gases at birth are no guarantee that the newborn infant has come through unscathed. Even the word "normal" in relation to blood gases is subject to debate. Research in fetal sheep by Mallard and colleagues has found that cord occlusion resulting in short periods of oxygen depletion in the fetus can cause neuronal damage in the offspring that is not reflected by the blood gases measured in the newborn animal. Follow up of the animals exposed to such brief periods of occlusion indicates that there is often a subsequent progressive decline in function.

Hypothesis #4: Drugs administered to the parturient during labor and delivery can adversely affect the intrauterine environment, the immediate newborn responses and the future neurological development of the offspring exposed in utero to those drugs.

Rosenblatt and colleagues in Britain found that a bupivacaine epidural administered to the mother during labor can have prolonged adverse effects on the early development of the exposed offspring. The investigators concluded:

"Significant and consistent effects of bupivacaine throughout the assessment period can be demonstrated. Immediately after delivery, infants with greater exposure to bupivacaine in utero were most likely to be cyanotic and unresponsive to their surroundings. 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."

A similar investigation carried out by Sepkoski, Brazelton and colleagues supports the earlier findings of Rosenblatt et al. Furthermore, the four year follow up by Sepkoski found that many of the adverse effects of the bupivacaine epidural seen earlier in the neonate still persisted at age four.

Nor can it be assumed that a drug used in obstetrics for years is without harm to the fetus. The manufacturer of meperidine (Demerol) cites the major risks of administering the drug as: (a) respiratory arrest, (b) shock, (c) cardiac arrest, (d) hyperexcitability, (e) convulsions, (f) bradycardia, (g) tachycardia, (h) hyperpyrexia, (i) hypertension, (j) hypotension, (k) coma, (l) severe respiratory depression, and (m) cyanosis.

Hypothesis #5: The elevation of creatine phosphokinase (CPK1, CPK2, CPK3) in the blood of the newborn indicates damage to the fetal brain, heart and muscle respectively.

British obstetrician, Dr. John Spencer, presented data at the FIGO meeting in Montreal showing that a drop in fetal heart rate reflects a concomitant drop in fetal oxygenation. Yet parents are frequently told that there is no need to worry if the fetal heart rate falls.

Neonatologist Susan Combs, working with newborn infants, found that a drop in fetal heart rate during labor correlated with evidence of CPK enzymes in the newborn’s blood, suggesting possible damage to the newborn’s brain, heart and tissue. Testing for CPKs is a relatively simple blood test which should be done as a standard practice. The fact that Dr. Combs’ work was stopped when the obstetric department learned of her research makes the idea of testing for CPKs all the more interesting.

Hypothesis #6 Forceps delivery, vacuum extraction and prolonged bearing down create added trauma to the fetal head and contribute significantly to the rate of urinary and fecal incontinence in the mother.

Pregnant women should be advised that an epidural block for delivery may increase the need for forceps delivery, vacuum extraction or both and increase the likelihood that her baby may develop a caput succedaneum, subgaleal hematoma or intracranial hemorrhage requiring admission to the NICU.

A recent paper in the Journal of Neuroscience indicated that exposure of infant rats to a clinically relevant anesthesia protocol for 6 hours during synaptogenesis causes not only acute deletion of many neurons from the developing brain but also learning/memory disabilities that persist into adolescence and adulthood. Animals exposed to this anesthesia protocol displayed deficits in spatial reference memory capabilities as manifested by slower pace learning acquisition as juveniles and by significant impairments in both spatial reference and working memory as adults".

If you wish to obtain more information regarding the risks of obstetric related drugs to the newborn I refer you to the Foundation’s website: Unfortunately, the official FDA label of several drugs mentioned above have been removed from the PHYSICIANS’ DESK REFERENCE (PDR) by their manufacturers. Their removal is regrettable because the PDR is the only publication that is required to publish the complete text of the official FDA approved labeling for an FDA approved drugs.

In light of these omissions I would like to introduce another hypothesis:
Hypothesis 7: Making all drug labeling approved by the FDA available on the internet will facilitate public access to that information.

Because of the limitations of time I have not included as much detail as I have provided in my presentation to the Science Board of the FDA, which can be found under the title "Improving the Outcome of Pregnancy through Science" on the Foundation’s website: External Web Site Policy.

Jevtovic-Todorivic V, Hartman, R, Yukitoshi I, Benshoff N, Dikranian K, Zorumski C, Olney J, and Wozniak D. "Early exposure to common anesthetic agents caused widespread neurodegeneration in the developing rat brain and persistent learning deficits." J. Neuroscience, 2003; 23(3): 876-882

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.

Rosenblatt D, Belsey E, Lieberman, B, Redshaw M, Caldwell J, Notarianni L, et al: "The influence of maternal analgesia on neonatal behavior: II Epidural bupivacaine". Br J Obstet Gynecol 1981; 88: 407-17.

Sepkoski C, Lester B, Ostheimer G, Brazelton TB: "The effects of maternal epidural anesthesia on neonatal behavior during the first month". Developmental Medicine and Child Neurology 1992; 34: 1072-1080.

Zheng C, Heintz N, Hatten M: "CNS gene encoding astrotactin, which supports neuronal migration along glial fibers". Science 1996; 272: 417-19.