Some FDA Approved Important Obstetrics Drugs: Their Effects On Mother And Baby

FDA APPROVED OBSTETRICS DRUGS:
THEIR EFFECTS ON MOTHER AND BABY
(Thanks: Doris Haire, President, American Foundation for Maternal and Child Health and Chair, Committee on Maternal and Child Health, National Women's Health Alliance)

FDA USES ITS OWN DEFINITION OF SAFE
Most Americans, including many health care providers, assume that if the FDA approves a drug for marketing then the FDA has determined that drug is free from harm or injury to the person receiving the drug. They do not know that the U.S. Food and Drug Administration (FDA) bases its approval of a drug on whether, in the Agency's opinion, the benefits of the drug outweigh the risks. Unfortunately the FDA has no way of knowing the true incidence of risk to the patient because there is no law or regulation that requires a doctor or other health care provider to report an adverse drug reaction to the FDA, even if the patient dies.

NO WRITTEN FDA STANDARDS FOR EVALUATING DRUG SAFETY
The Director of the FDA's Center for Drug Evaluation and Research (CDER) acknowledges that the FDA has no written standards for evaluating or documenting the safety of drugs approved for use in obstetric care. The Neurologic and Adaptive Capacity Score (NACS), formerly accepted as a reliable tool for evaluating the neurologic state of the infant, has now been found to be unreliable.

LITTLE MORE THAN A DOZEN DRUGS HAVE BEEN APPROVED BY FDA FOR USE IN OBSTETRIC CARE and more than half of these drugs have had their FDA approved labeling removed from the PHYSICIANS DESK REFERENCE (PDR) by their manufacturers.

The manufacturers of these drugs apparently prefer that the information regarding the inherent risks of these drugs be withheld from convenient review by health care providers and consumers.

WHAT IS THE PHYSICIANS DESK REFERENCE (PDR) and WHY IS IT IMPORTANT? The PDR is the only publication that must publish the text of an FDA approved label of a drug exactly as it appears in the drug's package insert.
All other printed sources of drug information can, if they choose, omit mention of risks. The fact that a manufacturer can choose to omit the label of his product from the PDR points to the need for a Federal pharmacopeia that includes the labels of all drugs approved by the FDA.
At the end of this document we have listed some of the drugs that are NOT FDA approved for use in obstetric care, but are nevertheless used for that purpose.
We have also provided a Glossary, defining technical terms you may read in the labeling of the drugs you are offered.
To insure your safety and that of your family it is important that you understand that:
• The FDA acknowledges that there is major underreporting of adverse drug effects, so neither the FDA nor the public has any way of knowing how frequently adverse drug effects occur. As a consequence, few women realize the inherent risks of oxytocic drugs to themselves and their babies.
• NONE of the drugs used in obstetric care has been proven safe for the fetus exposed to the drug in utero. None of the pharmaceutical manufacturers of those drugs approved by the FDA for use in obstetrics has carried out periodic neurological examinations of children exposed to their drug products in utero. The FDA has not required companies to provide such data.
• Most drugs approved by the FDA have never been tested on women.
• The FDA acknowledges that drugs trapped in the infant's brain at birth have the potential to adversely effect 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 function;
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 messages to and from the brain - will travel their normal routes at the normal rate of speed.

• Research now confirms that the migration of neurons along the fibers within the brain can be altered by changing the normal chemistry of the rapidly developing brain. Yet the FDA does not require, as part of the approval process, that the manufacturer of a drug to be approved for obstetric use commit to carrying out a follow-up study to determine the delayed, long-term effects of the drug on the neurologic development of offspring exposed to the drug in utero.
Health care providers often state that the predominant cause of neurologic impairment in children occurs before labor begins. There is no scientific documentation for this statement.
Please take the time to read "Just How Safe Is 'Safe': How the FDA Determines the 'Safety' of Drugs", also at this web site, to understand why one cannot assume that the FDA approval of a drug means that the drug is free from harm or injury to the mother or her baby.
 

As you read the information in this document keep in mind that:
• Virtually all drugs administered to the mother, including oxytocin, rapidly filter across the placental membranes and enter the blood, brain and other major organs of the fetus within minutes of administration to the mother during pregnancy, labor and birth. There is no such thing as a placental "barrier".
• There have been no adequate and well-controlled studies carried out to determine if this drug may cause fetal harm or damage to the developing fetal brain if administered to a pregnant woman.
• The idea that a maternally administered drug, chemical or food additive can harm the fetus only during the period of organogenesis (the first three months of pregnancy) is scientifically inaccurate.
• As the time of birth nears, the fetal brain is relatively large and rich in blood vessels, and the cerebral blood flow is relatively high in comparison with that of the adult brain. These factors increase the transfer of drugs given to the mother to the fetal circulation, brain and central nervous system. If drugs slow the fetal heart rate and the oxygen saturation of the fetal blood is depleted below the physiologic level, the transfer of drugs administered to the mother, and hence to the fetus, is increased. The one minute APGAR score and the newborn's time to sustained respiration are important barometers of how the fetus fared in utero.
• The fact that the fetal brain's myelin content, the fat-like substance that protects the nerve fibers of the brain, is low when compared with that of the adult brain, makes the fetal and newborn brain and central nervous system more vulnerable to the effects of a drug taken by or administered to the mother.
• The gestational age, the condition of the fetus, and the simultaneous exposure of the fetus to other drugs can influence the ways in which a drug given to the mother affects the unborn or newborn baby.
• A six week follow up of newborn infants in the U.K. found that bupivacaine, administered in the form of an epidural block, adversely altered brain function in a significant number of newborn infants throughout the six week testing period. A subsequent evaluation in the U.S. found essentially the same results.
CHECK THE OFFICIAL FDA LABEL OF THE DRUG
• To check whether or not a drug has been approved by the FDA for the treatment of your condition ask your pharmacist or doctor for a copy of the drug's official "package insert", or read the FDA approved label in the PHYSICIANS DESK REFERENCE (PDR).

MANY DRUGS ARE USED "OFF-LABEL".
• "Off-label" is pharmaceutical jargon meaning that the drug is being used to treat a condition for which the FDA has NOT approved the drug for that treatment. Terbutaline, for example, has not been approved by the FDA to treat premature contractions, yet the drug is frequently used "off label" to treat the condition, rather than use Ritodrine, which has been approved for such treatment.
• Please see the list of drugs frequently used off-label by physicians and other health care providers in the care of maternity patients.
ALWAYS READ THE "INDICATIONS" SECTION OF THE PACKAGE INSERT FIRST
• If, for example, the words "obstetrics", "pregnancy", "labor", "delivery", or "lactation" are NOT mentioned in the INDICATIONS section of the package insert, the FDA has NOT approved the drug for use under those conditions.
If those conditions are mentioned elsewhere in the text, such as for example, under "Labor and Delivery", that does not mean that the drug has been approved by the FDA for such use

There are many drugs given to or administered to pregnant women that are not approved for such use by the FDA. While drugs such as codeine, morphine, hydromorphone, promethazine, codeine, fentanyl citrate, phenergan, terbutaline, etc, are sometimes used "off label" in obstetric care, they have not been approved by the FDA for obstetric use.

• No drug should be administered to a woman during pregnancy, labor and birth, unless the woman is fully informed of the known risks and the relevant areas of uncertainty regarding the effects of the drug on the physiologic and neurologic development of the woman or her baby. Whenever possible non-technical terms are used to help you and your health care provider discuss the risks as well as the advantages of the drug in question.
• If you have any questions about the drugs listed below, call the manufacturer of that drug and ask to be sent a copy of the package insert for the drug in question. Drug companies, as well as patients, benefit when patients understand the risks, as well as the benefits, of the drugs they are considering. Manufacturers are not accustomed to answering consumer requests for information, so be polite, but firm in your questions.

NORMAL BLOOD GASES AT BIRTH ARE NO GUARANTEE NEWBORN IS UNSCATHED
Research in animals 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 animals exposed to such brief periods of occlusion indicates that there is often a subsequent progressive decline in function.
Research in newborn infants has shown that a drop in fetal heart rate during labor, which reflects a drop in fetal oxygenation, correlates with evidence of CPK enzymes in the newborn's blood indicating damage to the brain, heart and tissue.
The FDA does not require pharmaceutical manufacturers to advise the physician or the patient if the use of a product is likely to precipitate the need for cascade of obstetrical interventions such as intravenous infusion, catheterization, chemical stimulation of labor, artificial rupture of membranes, cesarean section, episiotomy (incision to enlarge the vaginal opening), fundal pressure (external pressure on the uterus), forceps or vacuum extraction, uterine atony and hemorrhage) or surgical correction to correct postpartum urinary or fecal incontinence.
Nor does the FDA require a drug manufacturer to note in the drug label if the drug is likely to precipitate (a) fetal hypoxia, (b) fetal bradycardia or tachycardia (slowing or speeding of the fetal heart rate), (c) tentorial hemorrhage (blood covering the brain), (d) newborn resuscitation, (e) Erb's Palsy, (f) newborn jaundice, or (g) the need to perform a spinal tap on the newborn to rule out meningitis.

YOUR PHYSICIAN OR OTHER HEALTH CARE PROVIDERS ARE LEGALLY OBLIGATED TO ADVISE YOU OF DRUG RISKS AND TO OBTAIN YOUR INFORMED CONSENT PRIOR TO TREATMENT and you have an obligation to tell the doctor if you know you are pregnant.
FOLLOWING IS A LIST OF DRUGS APPROVED BY THE FDA FOR USE DURING SOME, BUT NOT ALL, OBSTETRIC PROCEDURES.
This document is to assist the reader in identifying the specific FDA approved uses of the drugs listed below and to help the reader understand the risks to both the mother and her baby inherent in their use. For your protection, and that of your family, make sure you understand the risks and let your doctor or other health care providers know whether you wish to accept or forgo the drugs being offered to you.

Each drug is listed alphabetically by its brand name, the generic (chemical) name, and the name of the drug's manufacturer. If the drug is also manufactured by other pharmaceutical companies, we have also noted their names.

If possible, we have included the full name and mailing address of the pharmaceutical company and the telephone number to call for information. Many companies have chosen to remove their label information, their address and their telephone number from the PDR, so we will make them available to the public as soon as they become available to us.

BUPIVACAINE HYDROCHLORIDE
FDA approved Marcaine for use in labor and delivery.
For information see the MARCAINE entry below.
DELAYED LONG TERM EFFECTS: There have been no adequate and well-controlled studies to determine the delayed, long term effects of Bupivacaine on pregnant women, or on the neurologic, as well as general, development of children exposed to Bupivacaine in utero
Dinoprostone PGE2
LABEL IS IN THE PDR, PAGE 1261
Approved by FDA as a cervical ripener in patients at or near term in whom there is a medical or obstetrical indication for the induction of labor.
It is NOT approved for the elective induction of labor, when there is no medical reason for the induction.
Dinoprostone vaginal insert is a thin flat, rectangular polymeric slab with a long tape to serve as a retrieval system. Dinoprostone is inserted into the vagina in order to "ripen" the cervix. The patient must remain in the recumbent position for two hours after insertion. The drug gradually causes the rigid cervix to become softened, yielding and dilated to allow passage of the fetus through the birth canal.

The use of Dinoprostone is not without risk. Therefore the drug should only be administered by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities. Since Dinoprostone is a prostaglandin that can augment the activity of oxytocic drugs, the two drugs should not be administered at the same time. Dinoprostone must be removed before oxytocin administration is initiated and the patient's uterine activity must be carefully monitored for uterine hyperstimulation. The label also notes that uterine hyperstimulation, sustained uterine contraction, fetal distress, or other fetal or maternal adverse reactions should be a cause for consideration of removal of the insert.

Dinoprostone should not be administered to women with a history of previous cesarean section or uterine surgery in light of the potential risks for uterine rupture and associated obstetrical complication. If uterine hyperstimulation is encountered, or if labor commences, the vaginal insert should be removed. Dinoprostone should also be removed prior to amniotomy (the artificial rupture of membranes). If the mother's membranes have ruptured, the chemical stimulation of contractions can increase fetal intracranial pressure. Dinoprostone is contraindicated when prolonged contractions of the uterus may be detrimental to uterine integrity and fetal safety.

During a normal contraction the maternal blood vessels that carry oxygenated blood through the uterine wall to the placenta are constricted. During these periods of diminished blood flow the oxygen in the mother's blood, stored up in the placenta's intervillous space between contractions, maintains the fetal brain with a relatively constant supply of oxygen. Any uterine stimulant or drug which foreshortens these oxygen-replenishing intervals between contractions, by making the contractions too long, too strong, or too close together, increases the likelihood that fetal brain cells will be adversely affected. Uterine activity, fetal status and the progression of cervical dilatation and effacement should be carefully monitored.

DELAYED LONG TERM EFFECTS: There have been no adequate and well-controlled studies to determine the delayed, long term effects of Dinoprostone on pregnant women, or on the neurologic, as well as general, development of children exposed to Dinoprostone in utero

Meperidine
Approved by FDA for obstetrical analgesia
Meperidine called Pethidine in Europe, is a narcotic analgesic used to relieve moderate to severe pain. The drug has multiple actions similar to those of morphine. Demerol crosses the placenta and enters the fetal circulation, brain and other organs within minutes of administration to the mother. Demerol also appears in breast milk.

The major risks of Meperidine, as with other narcotic analgesics, are respiratory distress, circulatory depression, respiratory arrest, shock and cardiac arrest. Overdose of Meperidine can result in hypertension, severe respiratory depression, cyanosis, coma and death. Therapeutic doses of Meperidine have occasionally precipitated unpredictable, severe and occasionally fatal reaction in patients who have received such agents within 14 days. Other adverse reactions noted in the label/package insert are hyperexcitability, convulsions, bradycardia or tachycardia (slowing or speeding of the fetal heart), hyperpyrexia (high fever), hypertension or hypotension (high or low blood pressure), coma, severe respiratory depression, and cyanosis (bluish discoloration of skin due to diminished oxygen).

If Meperidine is given intravenously, the injection should be given very slowly, preferably in the form of a diluted solution. Rapid intravenous injection of narcotic analgesics, including Meperidine, increases the incidence of adverse reactions such as severe respiratory depression, apnea, hypotension, peripheral circulatory collapse and cardiac arrest. Meperidine should not be administered intravenously unless a narcotic antagonist and the facilities for assisted or controlled respiration are immediately available.

The package insert states that the major hazards of Meperidine, as with other narcotic analgesics, are respiratory depression, circulatory depression, respiratory arrest, shock and cardiac arrest.

Under "Nervous System" the package insert cites adverse effects such as euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, severe convulsions, transient hallucination and disorientation, and visual disturbances. The inadvertent injection of the drug about a nerve trunk may result in sensory-motor paralysis which is usually, but not always, transitory.
Under "Cardiovascular" the package insert cites adverse effects such as tachycardia, bradycardia, palpitation, hypertension, syncope, and phlebitis following intravenous injection.

Urinary retention and pruritus (itching) are also noted by the manufacturer.

FETAL EFFECTS:
The FDA has allowed the manufacturer to imply, by the following ambiguous paragraph, that Meperidine has been proven safe for the fetus when administered to the mother during labor. Under Usage in Pregnancy and Lactation the package insert states:

"Meperidine should not be used in pregnant women prior to the labor period unless in the judgment of the physician the potential benefits outweigh the possible hazards, because safe use in pregnancy prior to labor has not been established relative to possible adverse effect on fetal development. When used as an obstetrical analgesic, Meperidine crosses the placental barrier (editor's note: the placenta is not a barrier) and can produce depression of respiration and psychophysiologic function in the newborn. Resuscitation may be required."

The manufacturer does not describe in the package insert the type of psychophysiologic dysfunctions that may be precipitated when the fetus is exposed in utero to Meperidine during labor and delivery. The ambiguity of the statement arises from the fact the drug has never been subjected to a long-term, scientifically controlled follow-up to evaluate the effect of the drug on the subsequent neurologic development of the offspring exposed to the drug during labor and delivery.

Meperidine rapidly filters across the placental membranes and enters the blood, brain and other organs of the fetus within seconds or minutes of administration to the mother. Drug induced alterations in the brain chemistry of the fetus can cause the fetal heart to slow or to speed up to non-physiological levels. The drug's official label notes that Meperidine, like all pain relieving drugs, tends to increase cerebral spinal fluid pressure.
We have no way of knowing how frequently these adverse effects occur under normal clinical conditions because, as mentioned earlier, the law does not require physicians or other health care providers to report adverse drug reactions to the FDA, even if the patient dies.

The FDA has allowed the manufacturers of Meperidine to provide only a minimum of information in the label in regard to the drug's adverse effects on the fetus and newborn infant. The label acknowledges that the drug does cross the placenta and can increase the likelihood that the newborn infant will require resuscitation. However, the label does not make it clear that:
(a) Meperidine given to the mother during labor can impede the normal transfer of oxygen from the mother's circulation to that of her fetus,
(b) Prolonged oxygen depletion can cause the fetal brain to swell,
(c) The drug can interfere with the newborn infant's normal ability to self- regulate his/her internal temperature, or
(d) A severely narcotized newborn infant is more prone to aspirate its gastric fluids if the drug has blunted or paralyzed his protective gag reflex.
DELAYED LONG TERM EFFECTS: There have been no adequate and well-controlled studies to determine the delayed, long-term effects of Demerol on pregnant women, or on the neurologic, as well as general, development of children exposed to Demerol in utero or during lactation

MARCAINE (Bupivacaine)
FDA approved Marcaine for use in labor and delivery.
The FDA approved labeling for Bupivacaine (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..."

Under "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 analgesia can cause disruptions in normal uterine function that cannot always be completely corrected by the use of oxytocin. The package insert does not mention that such disruption can precipitate the need for forceps or vacuum extraction of the baby, or the use of fundal pressure (external pressure applied to the mother's lower abdomen) to help push the baby out). Forceps and vacuum extraction carry risks to both mother and baby, as does fundal pressure. Fundal pressure increases the likelihood of uterine inversion, and that an episiotomy will be extended into a rectal tear. Fundal pressure has the potential to increase fetal intracranial pressure if the membranes have ruptured.

The incidence and degree of Bupivacaine toxicity depends on the (a) procedure performed, (b) type and amount of drug used, (c) technique of drug administration (d) gestational age of the fetus, (e) condition of the fetus, (f) and 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 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.

Rosenblatt and her fellow investigators in Britain found that Bupivacaine 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. See References at end of document.

DELAYED LONG TERM EFFECTS: There have been no adequate and well-controlled studies sponsored by Abbott to determine the delayed, long-term effects of Marcaine on pregnant women, or on the neurologic, as well as general, development of children exposed to Marcaine in utero or during location
METHERGINE (Methylergonovine maleate)

Approved by the FDA for use only AFTER the delivery of the anterior (front) shoulder
Methergine acts directly on the smooth muscle of the uterus and increases the resting tone, rate and strength of uterine contractions. Methergine is used to induce a rapid and sustained spasmodic uterine contraction to shorten the third stage of labor and reduce blood loss.
The manufacturer of Methergine acknowledges that the drug can result in sudden and severe blockage of blood to the heart. The use of Methergine has diminished because of the drug's action to constrict blood vessels.

The label of Methergine warns against intravenous administration of the drug because of the possibility of inducing a sudden hypertensive or cerebrovascular accident (stroke). Under full obstetric supervision, Methergine may be given in the second stage of labor following delivery of the anterior (front) shoulder. The timing of Methergine administration is of upmost importance, since premature administration can cause the baby's body to become "trapped" by the constricting uterus, making the infant difficult to extract by forceps, vacuum extraction or manually.

The manufacturer of Methergine reports infrequent cases of acute myocardial infarction, transient chest pains, labored breathing, thrombophlebitis (inflammation of a vein resulting from the formation of a stationary blood clot along the wall of a blood vessel, hematuria (blood in the urine), water intoxication (an undue retention of water, marked by vomiting, depression of core temperature, convulsions; hallucinations, leg cramps, dizziness, tinnitus, diarrhea, profuse sweating; irregular heart rate, and coma.

The official label of Methergine mentions that several infants have been accidentally injected with Methergine and that all but one infant recovered. The label provides no information as to the long term effects of the drug on the neurologic development of those infants injected with Methergine.

DELAYED LONG TERM EFFECTS: There have been no adequate and well-controlled studies to determine the delayed, long-term effects of Methergine on pregnant women, or on the neurologic, as well as general, development of children exposed to Methergine in utero
PITOCIN (oxytocin)
PITOCIN has been approved by the FDA for the medical induction and stimulation of labor. Pitocin has not approved for the elective induction or stimulation of labor.

Oxytocin crosses the placenta and enters the blood and brain of the fetus within seconds or minutes. There appears to be a correlation between fetal exposure to oxytocin and autism in the exposed offspring.

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."

Because oxytocin is used so commonly to stimulate labor we note here that, 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:
(a) Maternal hypertensive episodes (abnormally high blood pressure)
(b) Subarachnoid hemorrhage (bleeding in area surrounding spinal cord) (c) anaphylactic reaction (exaggerated allergic reaction)
(d) Postpartum hemorrhage (uterine hemorrhage following birth)
(e) Cardiac arrhythmias (non-normal heart rate)
(f) Fatal afibrinogenemia (loss of blood clotting fibrin)
(g) Premature ventricular contraction(non-normal heart function)
(h) Pelvic hematoma (blood clot in the pelvic region)
(i) Uterine hypertonicity (excessive uterine muscle tone)
(j) Uterine spasm (violent, distorted contraction of the uterus)
(k) Tetanic contractions (spasmodic uterine contractions)
(l) Uterine rupture
(m) Increased blood loss
(n) Convulsions (violent, involuntary muscle contraction(s).
(o) Coma (unconsciousness that cannot be aroused)
(p) Fatal oxytocin-induced water intoxication (undue retention of water marked by vomiting, depression of temperature convulsions, and coma and may end in death.

Fetal and Newborn Effects
The following adverse effects of maternally administered oxytocin have been reported in the fetus or infant:
(a) Bradycardia (slow fetal heart rate)
(b) Premature ventricular contractions and other arrhythmias (non-normal heart function
(c) Low 5 minute Apgar scores (non-physiologic neurologic evaluation)
(d) Neonatal jaundice (excess bilirubin in the blood of the neonate.
(e) Neonatal retinal hemorrhage (hemorrhage within the innermost covering of the eyeball)
(f) Permanent central nervous system or brain damage
(g) 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 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 FDA.

These findings underscore the importance of the midwife 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 woman cope with the contractions intensified by Pitocin.

DELAYED LONG TERM EFFECTS: There have been no adequate and well-controlled studies to determine the delayed, long-term effects of Pitocin on pregnant women, or on the neurologic, as well as general, development of children exposed to Pitocin in utero or during lactation
RITODRINE
Approved by the FDA for use as a tocolytic agent to manage preterm labor in suitable patients.
When administered intravenously, Ritodrine will decrease uterine activity and prolong gestation in the majority of suitable patients. Intravenous infusion of 0.05 to 0.30 mg/min or single oral doses of 10 to 20 mg/min decrease the intensity and frequency of uterine contractions.

Ritodrine Hydrochloride, once sold under the brand name Yytopar, is the only tocolytic drug approved by the FDA to forestall premature labor. The manufacturer cautions that IV administration of Ritodrine should be supervised by persons having knowledge of the pharmacology of the drug and who are qualified to identify and manage complications of drug administration and pregnancy. Beta-adrenergic drugs such as Ritodrine increase cardiac output. Even in a normal healthy heart this added demand can lead to a reduction in the flow of oxygenated blood to the myocardial muscle - the major muscle in the heart. This disruption in blood flow can result in myocardial necrosis (death of heart muscle); non-physiological heart rates, such as arrhythmias, atrial and ventricular contractions, ventricular tachycardia; and heart pain, with or without EEG changes. Because cardiovascular responses are common and more pronounced during intravenous administration of Ritodrine, cardiovascular effects, including maternal pulse rate and blood pressure and fetal heart rate, should be closely monitored.

The label of Ritodrine notes that pulmonary edema (accumulation of fluid in the lungs) has been reported in patients treated with Ritodrine and cautions that patients must be closely monitored in the hospital, and sometimes after the delivery of the infant. Maternal death from this condition has been reported.
Ritodrine contains sodium metabisulfite, a sulfite which may cause an allergic-type reaction, including serious allergic symptoms that can become life-threatening.

When Ritodrine is used for the management of preterm labor in a patient with premature rupture of the membranes, the benefits of delaying delivery should be balanced against the potential risks of development of chorioamnionitis (inflammation of fetal membranes).
Ritodrine crosses the placenta, enters the fetal circulation, brain and other major fetal organs. How this alteration of brain chemistry affects the neurologic development of the exposed offspring is unknown. The label of Ritodrine notes that neonatal symptoms of hypoglycemia and ileus (intestinal obstruction due to inhibition of bowel motility) are infrequently reported. Although clinical studies did not demonstrate a risk of permanent adverse fetal affects from Ritodrine, the possibility cannot be excluded; therefore, Ritodrine should be used only when clearly indicated.

DELAYED LONG TERM EFFECTS: There have been no adequate and well-controlled studies to determine the delayed, long-term effects of Ritodrine on pregnant women, or on the neurologic, as well as general, development of children exposed to Ritodrine in utero

SCOPOLAMINE HYDROBROMIDE
APPROVED FOR USE IN OBSTETRICS
Scopolamine is a sedative and tranquilizing depressant to the central nervous system. The drug can produce restlessness, hallucinations, or delirium, especially in the presence of severe pain.
The manufacturer advises in the label that Scopolamine crosses the placenta and that use during labor may cause respiratory depression in the neonate, and that Scopolamine may contribute to neonatal hemorrhage due to a drug induced reduction in the clotting factor (fibrin) in the neonates blood.
 

DELAYED LONG TERM EFFECTS: There have been no adequate and well-controlled studies to determine the delayed, long-term effects of Scopolamine on pregnant women, or on the neurologic, as well as general, development of children exposed to Scopolamine in utero

Sufentanil citrate
Sufentanil is FDA approved for epidural administration as an analgesic combined with low dose Bupivacaine during labor and vaginal delivery.
SUFENTANILNIL CITRATE
Sufentanil is a potent opioid. The drug can produce muscular rigidity that involves the skeletal muscles of the neck, trunk and the extremities. The manufacturer warns that skeletal muscle rigidity is related to the dose and speed of administration of Sufentanil. The drug can cause respiratory drive to decrease and airway resistance to increase. At high doses, a pronounced decrease in pulmonary exchange and apnea (transient cessation of breathing) may be produced.

The FDA approved label/package insert of Sufentanil cautions that the drug should be administered incrementally and that the proper placement of the needle or catheter in the epidural space is essential. The intravascular injection of Sufentanil can result in a serious overdose including acute muscular rigidity in the trunk area, and apnea (impaired respiration). A intrathecal injection of the full Sufentanil/Bupivacaine epidural dose and volume can result in a serious overdose, including acute truncal muscular rigidity and apnea that can, in turn, produce effects of high spinal anesthesia including prolonged paralysis and delayed recovery and death.

The FDA approved Sufentanil label cautions:
(a) That the drug should be administered only by persons specifically trained in the use of intravenous and epidural anesthetics and the management of the respiratory effects of potent opioids.
(b) That an opioid antagonist, resuscitative and intubation equipment and oxygen should be readily available, and
(c) That the facility should be fully equipped to handle all degrees of respiratory depression, and provide for post operative monitoring and ventilation of

patients administered Sufentanil. Muscular rigidity has been reported to occur or recur infrequently in the extended postoperative period.

The label advises that (a) the most serious and significant effect of an overdose of Sufentanil is respiratory depression, (b) that the intravenous administration of an opioid antagonist such as naloxone should be employed as a specific antidote to manage respiratory depression, and (c) that respiratory depression can recur in the postoperative period.

The patient must be carefully and continuously monitored since the duration of respiratory depression produced by Sufentanil may last longer than the countering effects of the opioid antagonist. If the patient's gag reflex continues to be blunted by the opioid after the effects of the opioid antagonist has worn off, there is increasing possibility that the patient may aspirate her stomach contents, which could result in neurologic injury or death.
Respiratory depression may be intensified when Sufentanil is administered in combination with volatile inhalation agents and or other central nervous system depressants such as barbiturates, tranquilizers, and other opioids.

Indwelling catheters appear to be standard with the use of epidural Sufentanil in order to avoid urinary retention. The return of normal bladder activity may be delayed.

The manufacturer of Sufentanil states that there are insufficient data to critically evaluate the effects of Sufentanil on the neuromuscular and adaptive capacity of the neonate following recommended doses of maternally administered epidural Sufentanil with Bupivacaine. If larger than recommended doses are used for combined local and systemic analgesia during delivery, the impaired neonatal response to sound and light can be detected for 1-4 hours and if a dose of 80 mg is used, impaired neuromuscular coordination can be detected for more than 4 hours.

DELAYED LONG TERM EFFECTS: There have been no adequate and well-controlled studies to determine the delayed, long-term effects of Sufentanil on pregnant women, or on the neurologic, as well as general, development of children exposed to Sufentanil in utero or during lactation