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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
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Trimethylglycine
--------------------------------------------------------------------------------
Trimethylglycine (TMG), also called betaine, is a substance
manufactured by the body. It helps break down another
naturally occurring substance called homocysteine.
In certain rare genetic conditions, the body cannot dispose
of homocysteine, resulting in its accumulation to extremely
high levels. This, in turn, leads to accelerated
cardiovascular disease and other problems. Oral TMG is an
FDA-approved treatment for this condition. It "methylates"
homocysteine, removing it from circulation.
Meaningful, but not altogether consistent, evidence suggests
that the relatively slight elevation of homocysteine that
can occur in healthy people is also harmful.6 On this
basis, it has been suggested that TMG might reduce heart
disease risk in healthy people as well. However, this has
not been proven, and TMG has shown the potential for having
adverse effects on cholesterol profile, which could counter
any possible benefit via homocysteine.
Note: TMG is similar chemically to betaine hydrochloride,
but it has entirely different actions.
--------------------------------------------------------------------------------
Sources
TMG is not required in the diet because the body can
manufacture it from other nutrients. Grains, nuts, seeds,
and meats contain small amounts of TMG. However, most TMG in
food is destroyed during cooking or processing, so food
isn't a reliable way to get a therapeutic dosage.
After TMG has done its work on homocysteine, it is turned
into another substance, dimethylglycine (DMG). Some
manufacturers will tell you that DMG is identical to TMG,
but this isn't true. DMG is not a methylating agent, so it
can't have any effect on homocysteine. (See also Therapeutic
Uses below.)
--------------------------------------------------------------------------------
Therapeutic Dosages
Optimal therapeutic dosages of TMG are not known. Common
recommendations range from 375 to 3,000 mg daily.
--------------------------------------------------------------------------------
Therapeutic Uses
There is no doubt that TMG greatly reduces homocysteine
levels and improves health among people with the rare
disease cystathionine beta-synthase deficiency (as well as
related conditions).1 TMG also appears to reduce
relatively mild homocysteine elevations in people without
genetic defects.10-11 However, as noted above, TMG
also seems to worsen cholesterol profile, and this may
counteract any possible benefits.12 For this reason,
if you have elevated levels of homocysteine, it may make
more sense to reduce it by taking supplemental folate,
vitamin B6, and vitamin B12; these supplements are known to
reduce homocysteine levels, and, unlike TMG, they provide
nutritional benefit as well.
TMG may help protect the liver against the effects of
alcohol, perhaps by stimulating the formation of
SAMe.2,3,4,7 In addition, it may be helpful for
non-alcoholic forms of fatty liver (non-alcoholic steatosis)
as well.8,9
TMG has also been suggested as a less expensive substitute
for SAMe in other condition for which SAMe is used (such as
osteoarthritis and depression). However, there is no
evidence to show that it is effective.
A substance labeled pangamic acid or vitamin B 15 has been
extensively used as a performance enhancer by Russian
athletes and has also become popular among American
athletes. However, it is not clear there really is any such
substance; or, to state it another way, various substances
have at various times been given that name. Most recently,
the term has been associated with a mixture of calcium
gluconate and DMG; one small study failed to find this form
of pangamic acid effective for enhancing sports
performance.5
--------------------------------------------------------------------------------
Safety Issues
The only known safety issue with TMG is regarding
cholesterol profile, as already mentioned. People with high
or borderline-high cholesterol should use TMG only with
caution.
Maximum safe dosages for young children, pregnant or nursing
mothers, or those with severe liver or kidney disease have
not been established.
--------------------------------------------------------------------------------
References[ - ]
1. Wilcken DEL, Dudman NPB, Tyrrell PA. Homocystinuria due
to cystathionine beta-synthase deficiency—the effects of
betaine treatment in pyridoxine-responsive patients.
Metabolism. 1985;34:1115-1121.
2. Barak AJ, Beckenhauer HC, Tuma DJ. Betaine, ethanol and
the liver: a review. Alcohol. 1996;13:395-398.
3. Barak AJ, Beckenhauer HC, Junnila M, et al. Dietary
betaine promotes generation of hepatic S-adenosylmethionine
and protects the liver from ethanol-induced fatty
infiltration. Alcohol Clin Exp Res. 1993;17:552-555.
4. Murakami T, Nagamura Y, Hirano K. The recovering effect
of betaine on carbon tetrachloride-induced liver injury. J
Nutr Sci Vitaminol. 1998;44:249-255.
5. Gray ME, Titlow LW. The effect of pangamic acid on
maximal treadmill performance. Med Sci Sports Exerc.
1982;14:424-427.
6. Mangoni AA, Jackson SH. Homocysteine and cardiovascular
disease: current evidence and future prospects. Am J Med.
2002;112:556-565.
7. Kanbak G, Inal M, Baycu C. Ethanol-induced hepatotoxicity
and protective effect of betaine. Cell Biochem Funct.
2001;19:281-285.
8. Abdelmalek MF, Angulo P, Jorgensen RA, et al. Betaine, a
promising new agent for patients with nonalcoholic
steatohepatitis: results of a pilot study. Am J
Gastroenterol. 2001;96:2711-2717.
9. Angulo P, Lindor KD. Treatment of nonalcoholic fatty
liver: present and emerging therapies. Semin Liver Dis.
2001;21:81-188.
10. Schwab U, Torronen A, Meririnne E et al. Orally
administered betaine has an acute and dose-dependent effect
on serum betaine and plasma homocysteine concentrations in
healthy humans. J Nutr. 2005;136:34-38.
11. Olthof MR, Van Vliet T, Boelsma E et al. Low dose
betaine supplementation leads to immediate and long term
lowering of plasma homocysteine in healthy men and women. J
Nutr. 2003;133:4135-4138.
12. Olthof MR, Vliet TV, Verhoef P et al. Effect of
homocysteine-lowering nutrients on blood lipids: results
from four randomised, placebo-controlled studies in healthy
humans. PLoS Med. 2005;2:e135. 
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Oral Hypoglycemic Agents for Diabetes in
Pregnancy- An Appraisal of the Current Evidence for Oral
Anti-Diabetic Drug Use in Pregnancy
Francis LW Ho, MD,
Choon-Fong Liew, MBBS (Lond) FAMS (Endocrinol,)
Elaine C Cunanan, MD,
Introduction:
Tight blood glucose control has always been emphasized in
the treatment of pregnant women with diabetes to increase
the treatment of pregnant women with diabetes to increase
the likelihood of successful pregnancy outcomes. Studies
have documented that uncontrolled diabetes in pregnancy
increases the incidence of congenital anomalies form 2% to
3% in non-diabetic women to around 7% to 9%.” However, most
clinicians have been limited to the use of insulin in
controlling the blood sugar levels in this group of patients
because it has been the drug deemed absolutely safe for use
in pregnancy.
The major concerns regarding the use of oral hypoglycemic
drugs in pregnancy have been fetal anomalies, neonatal
hypoglycemia and the development of pre-eclampsia. Studies
done by Smithberg and Smoke on mice showed that
first-generation sulphonylureas, such as tolbutamide and
chlorpropamide, were associated with congenital
malformations. Similarly, Denno and Sadler also sowed that
phenformin was embryotoxic in rats, and metformin was
associated with a delay in neural tube closure and reduced
yolk sac protein values. There are also case reports
of congenital malformations associated with the use of, or
exposure to, oral hypoglycemic agents in human pregnancy.
However, in a randomized study done by Notelovitz in 1971
where he compared the use of tolbutamide, chlorpropamide,
diet, and insulin in 208 subjects, there were no significant
differences among the different groups in terms of perinatal
mortality and congenial anomalies when glycaemic control was
optimal. The author concluded that it was the poorly
controlled glycaemic state that was associated with the
development of fetal anomalies and note the agents used to
control blood sugar levels.
Neonatal hypoglycemia has been a concern with the use of
oral hypoglycemic agents because Zucker and Simon found
tolbutamide and chlorpropamide to cause profound and
prolonged hyperinsulinemia hypoglycemia among neonates born
to women who took these drugs during pregnancy. In fact,
they found the cord-serum concentrations of chlorpropamide
to be similar to those in maternal serum, and the half-life
of the drug in infants was similar to that in their mothers.
In another paper by Kimball et al, there were 4 patients
with prolonged symptomatic neonatal hypoglycemia associated
with maternal sulphonylurea drug usage. All 4 infants had
evidence of increased and inappropriate insulin secretion,
suggesting beta-cell hyperplasia, Of the 4 hypoglycemic
infants, prolonged elimination of chlorpropamide was
observed in 3 of them and chlorpropamide was detected up to
11 days after birth in these neonates.
In a cohort study by Hellmujth et al consisting of 118
diabetic pregnant women on oral hypoglycemic agents, 50 of
whom were treated with metformin and 68 with a sulfonylurea,
the prevalence of pre-eclampsia was found to be
significantly higher in the metformin group as compared
to the sulphonylurea group ( 32% vs 7%, P<0.001).
The perinatal mortality was also noted to be significantly
higher in the met forming group compared to the
sulphonylurea group 911.6 vs 1.3%, P<0.02).
With all the findings in the studies mentioned, physicians
have been hesitant in using oral hypoglycemic agents in
pregnant women. However, more recent evidence and studies
showing the efficacy and safety of oral agents in pregnancy
suggest that the use of these agents for gestational
diabetes should be re-examined.
Glibenclamide (Glyburide):
Differences in placental transfer of the different
sulphonylureas were first documented by Elliot et al using a
single human placental cotyledon perfusion model to study
drug transfer between maternal and fetal circulation.
Tolbutamide was found to diffuse across the placenta freely.
However, there was no significant transport of glibenclamide
in the maternal –to-fetal and fetal- to maternal directions.
Even increasing the glibenclamide concentration to 100 times
the therapeutic level did not alter transport significantly.
Glibenclamide remained undetected when cord blood was
analyzed using high- performance liquid chromatography. At
least- 99.8 % of the glibenclamide was bound to protein so
it was neither metabolized nor appropriated by the placenta.
Glipizide, on the other hand, although a second-generation
sulphonylurea like glibenclamide, was found to cross the
placenta in small amounts that were significantly higher
than glibenclamide. With these findings, there has been a
rise in interest in the use of oral agents in pregnant
diabetics, and most of the more recent studies involving
sulphonylurea use in pregnancy have been done using
glibenclamide.
In a randomized, controlled trial by Langer et al, a
comparison was made on the use of glibenclamide and insulin
in women with gestational diabetes who were unable to
achieve adequate metabolic control with diet and exercise
alone. Four hundred and four women were randomly assigned to
take either of the two treatments. The primary end point was
the achievement of good glycaemic control and the secondary
end points included maternal and neonatal complications. The
result showed that 82% of the glibenclamide group and
88% of the insulin group achieved good
glycaemic control, but there was less maternal hypoglycemia
in the glibenclamide group 92%) as compared to the insulin
group ( 20%). There were no significant differences
between the 2 groups in the incidence of pre-eclampsia,
macrosomia, neonatal hypoglycemia, congenital
anomalies, perinatal mortality, cord-serum insulin
concentrations and the rate of Caesarean section. Moreover,
glibenclamide was not detected in the cord serum of any
infant in the glibenclamide group. This was a well-conducted
randomized, controlled trial involving a large number of
subjects making it a very significant study.
In a recent prospective cohort study by Kramer et al, where
73 patients with gestational diabetes were treated with
glibenclamide, 81% achieved satisfactory glucose control.
This was similar to the proportion achieved by Langer et al.
however; no anomalies were identified in all of the newborn
infants. Although this was not a randomized, controlled
trial and the number of subjects was quite small, it
supports the findings of Langer.
Metformin:
The use of metformin in pregnancy has been quite
controversial with early reports of adverse effects in those
exposed to this drug. However, with the advent of its use in
the treatment of women with polycystic ovary syndrome
(PCOS), it is postulated to alleviate key pathogenesis
mechanisms such as hyperinsulinaemic insulin resistance,
hyperandrogenaemia, and obesity which may cause miscarriages
in women with PCOS. In fact, it is believed that decreasing
hyperinsulinemia insulin resistance with metformin during
pregnancy in women with the disorder would reduce the rate
of early pregnancy loss; several studies have documented the
beneficial effects and safety of metformin use in women with
PCOS who became pregnant.
Metformin and Early Pregnancy Loss:
In a retrospective study by Jakubowicz et al, a comparison
was made between the pregnancies while taking
metformin and remained on metformin throughout their
pregnancy and the pregnancy outcomes of 31 women who also
had PCOS but did not take metformin during pregnancy. The
early pregnancy loss rate in the metformin group was only
8.8%, as compared to 41.9% in the control group (P<0.001).
In fact, the pregnancy loss rate of the metformin group was
quite similar to the rate of 10% to 15% reported for
clinically recognized pregnancies in normal women.
They also did a subset analysis of the women in each group
with a prior history of miscarriage and found that the early
pregnancy loss rate was only 11.1% in the metformin group,
as compared to 58.3% in the control group (0=0.002). This
shows that even in women with previous early pregnancy
losses, metformin is still beneficial in preventing its
recurrence. Although the number of subjects in this study
was not very large, the percentage of reduction of early
pregnancy loss with metformin was significantly high
and the benefits of using metformin were consistent between
those with and without a history of miscarriages as
compared to those who did not use metformin at all.
Metformin and Insulin, insulin Resistance and Testosterone
Levels:-
Glueck et al did a prospective observational study of 42
pregnancies in women with PCOS who took metformin throughout
their pregnancy. In this study, they examined the effects of
metformin on maternal insulin levels, insulin resistance,
insulin secretion and testosterone levels. They measured and
compared the different parameters at the pre treatment and
preconception baseline, at the last preconception visit on
metformin and during the first, second and third trimesters
on metformin. This study demonstrated that there was a
median percentage reduction of 40% in serum insulin at the
last preconception visit, which did not increase in the firs
tor second trimester 9P>0.05), but rose only 10% in the
third trimester. There was also a 46% median percentage
reductions in insulin resistance at the last preconception
visit with no significant increase (P=0.05), in the first,
second or third trimester. Testosterone also decreased at
the last preconception. Visit by 30% (P=0.01), but rose to
75%, 61% and 95% during the first, second and third
trimesters respectively. However, the median testosterone
level during the third trimester did not differ
significantly from the pre-treatment levels. Therefore, by
reducing the preconception insulin levels, insulin
resistance, and testosterone levels, and by maintaining
these insulin-sensitizing effects thought-out pregnancy,
metformin reduces the likelihood of diabetes developing and
prevents androgen excess for the fetus. These findings are
consistent with metformin known effects on improving insulin
resistance in non- pregnant diabetics.
Metformin and development of Gestational Diabetes:
In a study by Glueck et al comparing 33 non- diabetic women
with PCOS who were on metformin during pregnancy with 39
non-diabetic women with PCOS without metformin therapy
during pregnancy, gestational diabetes developed in only 3%
of the women who took metformin as compared to 27% of those
who did not. Based on the number of pregnancies, gestational
diabetes developed in only 1 out of the 33 pregnancies (3%)
in those women who took metformin as compared to 14 out of
60 (23%) pregnancies in those who did not take metformin. In
addition, there were no fetal malformations nor fetal
hypoglycemia noted in the metformin group. In another study
by the same authors, which compared 119 pregnant women with
PCOS taking metformin with 251 healthy controls without
PCOS, gestational diabetes occurred in 7.6% of the metformin
group as compared to 15.9% of the controls (P=0.027).these
results show that there is a significant reduction in the
incidence of gestational diabetes with the use of metformin
in pregnancy.
In the first study, although there was a significant
difference in the rates of gestational diabetes between
users and non-users of metformin in women with PCOS, the
sample sizes were generally small. The subject in the
second study were not evenly matched in terms of numbers
between the study group and the controls, but, the
interesting point is the comparison of the incidence of
gestational diabetes between PCOS women taking metformin and
healthy control subjects without PCOS. Even though it
is expected that women with PCOS will generally have a
higher incidence of gestational diabetes because of the
inherent insulin resistance when compared to healthy
subjects, this study demonstrated a significantly lower rate
of gestational diabetes in those with PCOS who took
metformin when compared to the healthy controls.
Metformin and Pre-eclampsia:
In contrast to the earlier findings of Helmut et al which
showed a high prevalence of pre-eclampsia in pregnant women
taking metformin, Gluck et al showed that there was no
significant difference in the rates of pre-eclampsia between
those taking metformin (5.2%) and the controls (3.6%)
(P=0.5) when they compared 97 pregnancies of women with PCOS
taking metformin with 252 pregnancies of healthy women.
Even when they did a subgroup analysis comparing only
pregnancies of primigravida in both groups, the incidence
rate of pre-eclampsia was the same for both at 4.4% each.
Ina further study by the same authors, 122 PCOS pregnancies
taking metformin were compared to 252 pregnancies of healthy
women without PCOS. The incidence of pre-eclampsia did not
differ between the metformin group and the control group
(4.1% vs 3.6%, P=0.8).
Metformin and Fetal Outcomes:
Even in 1979, Coetzee et al from South Africa had already
reported in a study of 33 metformin-treated pregnant women
that infant morbidity was low and mortality rates were
not higher in the metformin-treated patients compared to
insulin- treated patient 96/1000 vs 105/1000). The
same authors also sowed in another study involving 171
pregnant women with established type 2 diabetes mellitus
that the overall perinatal mortality was definitely lower in
the metformin- treated group compared to the untreated group
9 42/1000 vs 264/1000).
In 2 recent studies, one involving 126 infants and the other
100 infants, Gluck et al demonstrated that the use of
metformin in pregnant women with PCOS did not increase the
risk of developing major birth defects as compared to the
USA national rate reported by the Centers for Disease
Control and prevention (CDC) (1.6% vs 1.9%), and therefore
concluded that there was no evidence that metformin in
teratogenic. The prematurity rate of infants was not
significantly different from controls (20% vs 18%) and the
birth weight percentiles were also similar between the
neonates of metformin-treated PCOS patients and community
controls. Moreover, they had neither second or third
trimester fetal losses nor neonatal hypoglycemia. Jakubowicz
et al also demonstrated in their study that of the 62
metformin-treated pregnant women with PCOS who had live
births, all of the delivered neonates were normal with
appropriate size for gestational age, except for 1 infant
born with achondrodysplsia, which is an inherited disorder
unlikely to be related to metformin therapy.
Metformin and Infant Development:
To further document metformin safety for use in pregnancy,
Glueck et al prospectively assessed the growth and
motor-social development during the first 18 months of life
of 126 neonates born to 109 women with PCOS who conceived
while taking metformin and continued taking it through their
pregnancy. The lengths and weights of the metformin exposed
infants were compared with gender-specific CDC infants over
18 month. There were also no motor-social developmental
delays noted in the drug-exposed infants. The importance of
this study lies in the fact that it shows no harmful effects
of metformin on infants even beyond the neonatal period.
Acarbose:
The use of acarbose in pregnancy seems to be a good option
because it primarily acts in the gut by delaying
carbohydrate absorption and is not absorbed, thereby having
no systemic effects. However, this drug has not yet been
studied well in pregnancy. In a small study by Zarate et al,
6 pregnant women with moderately elevated levels of fasting
and postprandial blood glucose were treated with acarbose,
after which, the fasting and postprandial glucose levels
normalized. The pregnancies were uneventful and the newborn
babies were normal. Although this study shows promising
results, it is till a very early and small study on acarbose
use in pregnancy, and therefore, no plausible and definitive
conclusions can be drawn from it in terms of the safety and
efficacy of acarbose use in gestational diabetes.
Rosiglitazone:
Rosiglitazone has not been recommended for use in pregnant
women because it has been shown that treatment with the drug
during mid to late gestation was associated with fetal death
and growth retardation in animal models. It is classified as
Category C by the Food and Drug Authority (FDA) for use in
pregnancy, which means the risk of adverse outcomes cannot
be ruled out. However, there have been 2 reported cases of
rosiglitazone exposure during pregnancy. The first patient
was a diabetic and hypertensive woman who took 4 mg/day of
rosiglitazone for the first 7 weeks of gestation when she
was not aware that she was pregnant. Her treatment was
changed to insulin when the pregnancy was confirmed and she
gave birth to a normal healthy infant at the 36th
week of gestation. The second patient was a multigravida,
diabetic woman who had been managed on diet and exercise
alone, and had not received any drug therapy until the 13th
week of her sixth pregnancy. She was started on
rosiglitazone 4 mg/day from the 13th to the 17th
week of gestation, during which she was discovered to be
pregnant. Rosiglitazone was stopped and insulin was
initiated. She delivered a healthy baby boy without any
malformations on the 37th week of gestation.
Although these 2 reports did not show any adverse effect
from the brief exposure to rosiglitazone it would be
difficult to make any conclusions regarding the safety of
its use in pregnancy at the moment.
A study on the placental transfer of rosiglitazone in the
first trimester of pregnancy was recently reported by Chan
et al. In this study, rosiglitazone was given to 31 pregnant
women between the 8th
to 12th weeks of gestation who were undergoing
surgical termination of their pregnancy.
Rosiglitazone was detected in 19 fetal samples 9 61.3%).
This shows that there is a high risk of placental transfer
and fetal exposure to the drug.
Conclusions:
There is now a changing trend in the acceptability of using
oral hypoglycemic agents in non-insulin dependent pregnant
diabetics. Recent evidence (Table10 has shown that there are
some oral hypoglycemic drugs which may be safe and,
therefore, useful, especially for those who are only mildly
to moderately hyperglycemic and who do not desire multiple
daily insulin injections. In some countries where the
use of insulin may not always be possible, the option of
using oral hypoglycemic agents may be particularly
attractive.
Among the sulphonylureas, only glibenclamide has been shown
not to cross the placenta. Moreover, the best and strongest
evidence available so far in terms of safety and efficacy is
that of glibenclamide as sown in a randomized controlled
study involving a large number of subjects 9n=404) and a
direct head –to-head comparison with the gold standard use
of insulin in the treatment of gestational diabetes.
However, it would be reassuring to have more of such
randomized controlled studies comparing
glibenclamide and insulin to confirm these findings.
Metformin has been documented in several trials to be safe
for use in pregnancy, and in fact, even beneficial in terms
of decreasing the incidence of early pregnancy loss and the
development of gestational diabetes, reducing insulin levels
and insulin resistance, and preventing androgen excess in
women with PCOS. However these studies had all been done on
non-diabetics. Moreover, none of these studies had been
randomized controlled trials and most of them involved
relatively small number of subjects.
The efficacy of metformin in gestational diabetes is
presumably attributed to its insulin sensitizing effects,
thereby improving glucose control. However, there is no
direct evidence yet from good studies documenting the safety
of it use in patients with gestational diabetes. A large
prospective, randomized controlled trial called “metformin
in gestational diabetes. (MIG) “Comparing the use of
metformin and insulin gestational diabetes is currently
ongoing in New Zealand and Australia. This study will
provide us with a significant basis to decide whether or not
we should use metformin in gestational diabetes.
Both glibenclamide and metformin are currently classified by
the FDA as Category B drugs for use in pregnancy, which
means that there is no evidence of risk in humans. With
the present safety profile of the 2 drugs, Langer proposed
the following treatment plan fro gestational diabetes
medical nutrition for patients with a fasting blood glucose
level of <95 mg/dl (5.3mmol/L), or HbA 1c of <7%: oral
hypoglycemic agent therapy 9 glibenclamide and/or
metformin ) or a random blood glucose
level of < 140 mg/dl 9 7.8 mmol/L, or a random blood glucose
level of <140 mg/dl ( 7.8 mmol/L, or HbA 1c of > 8%: and
insulin therapy for a fasting blood glucose level of>140
mg/dl (7.8 mmol/L , or a random blood glucose level of >180
mg/dl ( 10mml/L), or a random blood glucose level of >180
mg/dl 9 10 mmol/L, or Hba 1c of >12%. However, the ranges of
the blood sugar levels and HbA 1c values that determine the
specific treatment option in this treatment plan
are not very clear and well-defined, and the threshold for
the HbA 1c value to stat insulin treatment is quite
high ( HbA 1c >12%). Therefore, we suggest the treatment
plan for gestational diabetes to be as illustrated in figure
1.
Acarbose shows promise in its use for gestational diabetes
because this drug is not absorbed in the gut significantly
and, therefore, has no systemic effects. However, with just
one small study, it is still too early to determine how
effective and safe this drug is for treating gestational
diabetes. As with the other oral hypoglycemic agents, large
randomized controlled trials with head-to head
comparison with other oral agents and insulin will help
determine the sue of acarbose for gestational diabetes. This
drug is also currently classified as Category B by the FDA
for use in pregnancy.
Oral hypoglycemic agents, which have been previously
regarded as unsafe for pregnancy are being re-evaluated for
their use in non-insulin dependent pregnant diabetics. Most
of the evidence available so for suggests that some of these
drugs, when used in their normal non-pregnancy doses, may be
safe and beneficial women with gestational diabetes.
However, further well-conducted, large-scale clinical
studies will be needed to confirm the safety and efficacy of
these drugs for use in pregnant diabetics and to
gather widespread acceptability in the medical community. At
present, we still advocate caution in the use of oral
hypoglycemic agents in pregnancy, and one should always
consider the benefits and risks of giving these drugs.
Table 1, Selected Studies Using Oral Hypoglycemic Agents in
Pregnancy:
Drugs
Authors
Years Number Study design
Outcomes
Glibenclamide Langer et al
2000 404
RCT
Glyburide’s was comparable to
(Glyburide)
insulin in the cont-
l
role of blood sugar levels. There were no
signifi-
Cant differences in the neonatal outcomes between the 2
groups.
Kremer et al
2004 73
Prospective
No congenital anomalies were
found in the neonates of those treated with glyburide.
Metformin
Jakubowicz et al 2002
96
Retrospective Reduced
the rate of early
pregnancy loss in women with PCOS.
Gluck et al
2002 70
Prospective
Reduced the development of
gestational And Retrospective diabetes in women with PCOS
with no fetal Malformations in the neonates of the treated
subjects.
Gluck et al
2004 42
Prospective
Reduced preconception insulin
levels, insulin resistance and testosterone levels while
maintaining insulin-sensitizing effects throughout
pregnancy.
Gluck et al
2004 349
Prospective
No significant difference in pre-
eclampsia rates between treatment and control groups.
Gluck et al
2004 126
prospective
No systematic differences in growth
between the drug-exposed and non-exposed infants. There were
also no motor-social developmental delays noted in the
infants of treated subjects.
Acarbose
Zarate et al
2000 6
Prospective
Bloods sugar levels were
adequately controlled. The pregnancies were uneventful and
the newborn babies were normal.
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