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Challenges in obstetric prescription
Food, Drug & Medico - surgical committee
FOGSI
Chairperson-Dr. Ragini Agrawal2009-2011
EditorsDr Ragini Agrawal
Dr Tamkeen Rabbani
• 2009• President-• Dr C.N.Purandare• Vice president• Dr H.R. Patnaik
• 2010• President-• Dr Sanjay Gupte• Vice president• Dr Jaideep
Malhotra
Dr Ragini AgrawalDr Tamkeen Rabbani How To Prescribe Antibiotics In Pregnancy
Dr Seema Hakim Counseling for Prescribing in Pregnancy
Dr. Nasreen Noor Drug Abuse During Pregnancy
Dr Sabahat Rassool Teratology Dr Shaheen Categorization of Drugs in Pregnancy
Dr Alami Zeba Safe Drugs for Common Diseases in Pregnancy
Dr Zehra Mohasin Vaccination In Pregnancy
Contributors— Challenges of obstetrics
prescription –A conceptual consideration
Challenges of obstetrics
prescription –A conceptual
consideration
Dr Ragini Agrawal , M.S.
Chairperson, FOGSI (Food , Drug & Medico surgical committee )
• The aim of ante natal care is to improve the health of mother & babies by preventing birth defects, premature birth and infant mortality.
•Pregnancy is most joyous period of woman
•But It is a “stress test for life” also
Unfulfilled dreams
• The developing organism is unique in its responsiveness to drugs and predictability of therapeutic effectiveness based on the adult can lead to grave consequences in the neonate and child. It should be emphasized that fetal adverse drug effects are not always manifested immediately as in the case of maternal thalidomide ingestion. It is important to note that fetal abnormalities can occur after several months as seen with clonidine or in the case of DES vaginal adenocarcinoma can take 20 years to develop. Based on limited reported effects in humans and more extensive studies with animals, drugs are classified as to the risk of induction of fetal toxicity in categories ranging from A (safe) to D (contraindicated in pregnancy). A separate extremely toxic category X is also used.
Int J Clin Pharmacol Ther. 1994 Jul;32(7):335-43.• Fetal consequences and risks attributed to the use of prescribed and
over-the-counter (OTC) preparations during pregnancy.
• Kacew S, Department of Pharmacology, University of Ottawa, Faculty of Medicine, Ontario, Canada.
Very high doses of vitamin A, D and E in pregnancy have been linked to birth defects. Professor Owens said doctors should not underestimate the dosage of vitamin supplements that some pregnant women consumed, particularly if they used high-potency multivitamins.
Professor Julie Owens, from Adelaide University's school of pediatrics and reproductive health,
Immunosuppressant Drug Causes Birth Defects
American Journal of Medical Genetics.
Insect repellent linked to birth defects
Pregnant women may wish to avoid insect repellent after a study found a link to an increasingly common birth defect, experts say
Some prescription meds can harm fetusNovember 17, 2009 More than six percent of expectant mothers in Quebec consume prescription drugs that are known to be harmful to their fetuses, according to a Université de Montréal investigation published in the British Journal of Obstetrics and Gynaecology. .
Asthmatic children: Did mom use her pump during pregnancy?October 5, 2009 Expectant mothers who eschew asthma treatment during pregnancy heighten the risk transmitting the condition to their offspring, according to one of the largest studies of its kind published in the European Respiratory Journal. A research team from the Université de Montréal, the Hôpital du Sacré-Cœur de Montréal and Sainte-Justine University Hospitl Research
Center found that 32.6 percent of children born to mothers who neglected to treat their asthma during pregnancy developed the respiratory illness themselves.
Sexually transmitted disease, urinary tract infections may be bad combination for birth defectJune 20, 2008
[B]Chances of gastroschisis increase fourfold in babies whose moms have both infections[/B] University of Utah researchers report in the online British Medical Journal.
Epilepsy drug may increase risk of birth defectsJuly 21, 2008
Taking the epilepsy drug topiramate alone or along with other epilepsy drugs during pregnancy may increase the risk of birth defects, according to a study published in the July 22, 2008, issue of Neurology, the medical of the American Academy of Neurology
y
Local health investigation sheds light on gastroschisis birth defectNovember 6, 2009 Results of an investigation conducted by University of Nevada, Reno researchers, public health officials and area physicians published this week in the Archives of Pediatrics & Adolescent Medicine, indicate that Washoe County experienced a cluster of a particular birth defect, gastroschisis, during the period April 2007 - April 2008. This study added significant
support to the findings of other studies that certain infections, such as colds and sore throats; use of cold medications, such as pseudoephedrine; and some recreational drugs, may be contributing factors in the development of gastroschisis.
Concerns during pregnancy
• Fear of teratogenesis• Need to safeguard the smooth
progress of pregnancy and delivery
• Need to prevent withdrawal effects in the neonate
• Concerns about subtle effects on the infant’s neurodevelopment
Concerns & considerations
• congenital abnormalities caused by human teratogenic drugs accounts for less than 1% of total congenital abnormalities.
• About 8% of pregnant women need permanent drug treatment due to various chronic diseases and pregnancy-induced complications.
Concerns & considerations
• Moreover in India, due to easy availability of drugs coupled with inadequate health services, increased proportions of drugs are used as self medication (for common complains and infective conditions), as compared to the prescribed drugs.
Concerns & considerations
• Woman always face the threat of adverse drug reactions and drug interactions between active hidden ingredients of both herbal and allopathic drugs.
• Un planned pregnancy is a bigger issue as she is already on potential teratogenic medicine or had inadvertently during early period of conception
Concerns & considerations
• Careful consideration of the benefit to the mother and the risk to the fetus is required while prescribing drugs during pregnancy
Concerns & considerations
• Reducing medication errors and improving patient safety are the important areas of discussion
• The use of drugs during pregnancy calls for special attention because in addition to the mother, the health and life of her unborn child is also at stake.
Concerns & considerations
• The drugs given to pregnant mothers for therapeutic purposes may cause serious structural and functional adverse effects in the developing child .
Concerns & considerations
• Since it is very difficult to determine the effects on the fetus before marketing new drugs due to obvious ethical reasons, most drugs are not recommended to be used during pregnancy
Concerns & considerations
• Since there are numerous gaps in knowledge about deleterious consequences for the fetus, prescription drug use by pregnant women should be viewed as a public health issue.
• Pharmaco-epidemiological studies can measure the extent of prescription and teratogenic drug use in pregnant women.
Prescription drugs and pregnancy.
• Prescribing drugs in pregnancy is an unusual risk-benefit situation.
• Drugs that may be of benefit or even life-saving to the mother can deform or kill the fetus. However, the risk to the fetus should not be exaggerated.
Important points
• There are only approximately 20 groups of drugs which are known to cause birth defects in humans.
• For one of these drugs to cause birth defects, a number of criteria must be fulfilled.
Important points
• The drug exposure must take place at a critical stage of pregnancy
• The dose must be high enough to cause a threshold of exposure for an appropriate duration of time.
• For most of the known human teratogens, > 90% of pregnancies exposed during the first trimester result in normal offspring.
Important points
• Although only a few drugs are known to cause birth defects in humans, uncertainty about the safety of the majority may lead to under prescribing for pregnant women and women of childbearing age.
Important points
• Epidemiological studies of pregnancy outcome after specific drug exposures are often superficially reassuring, but most are severely limited in their power to detect adverse outcomes.
Important points
• Safety in animal studies may also be reassuring but species differences demand caution in this interpretation.
• Concerns about prescription drugs in the first trimester, when they can cause birth defects, are mostly quite different to concerns about use in the second and third trimesters.
Important points
• As the fetal organ systems mature, the fetus can be affected by the pharmacological activity of the drug in the same way as the mother.
• Many drugs have pharmacological effects on the fetus in the second and third trimesters but in most cases, they are well recognised and can be managed or avoided.
Important points
• Communicating the risk-benefit situation to the patient is always a challenge for physicians with limited time and sometimes limited knowledge.
Important points
• Fear of litigation is an unfortunate and an unwanted parameter in the assessment.
• Better knowledge of the parameters that determine teratogenicity may allow physicians to feel more confident in assessing the risks and benefits associated with prescribing in pregnancy
Drug classification • Although the pregnant mother may require treatment of
certain disorders, there are a number of drugs which are absolutely contraindicated including those agents in risk category X and the socially unacceptable drugs of abuse.
• A limited use for drugs in category D under close supervision may be necessary .
• .Prescribed drug use in pregnancy should be dissuaded. Further ingestion of over-the-counter (OTC) preparations should be limited and deemed to be used with caution.
• It is generally accepted that the pregnant mother provides a fetus an environment in which to develop. However, drug exposure in utero is far more deleterious than in the growing child as the fetus lacks the ability to cope with pharmaceutical agents entering its biosphere.
Objective For Discussion
• Rational use of drugs in pregnancy
• Clear understanding of Teratogens & birth defects
• Substance abuse effects on pregnancy
• Role of Counselling for Prescribing in Pregnancy
• Clear concept of Categorization of Drugs in Pregnancy
Objective For Discussion
• Safe Drugs for Common Diseases in Pregnancy
• Vaccination In Pregnancy
• To achieve healthy mother & healthy baby
Categorization of Drugs in Pregnancy
Dr ShaheenAssistant Professor Deptt of OBG
JNMC , AMC ,Aligarh
Introduction
• Pregnancy is a physiological condition where drug treatment presents a special concern.
• The concern has been influenced by historical events, including Thalidomide crisis in 1960’s & Di-ethyl stilboestrol in 1971.
Introduction contd.
• Hence in 1979 in the USA, Food & Drug Administration (FDA) developed a system that determines the teratogenic risks of drugs.
Introduction contd.
• There are other organizations such as Australian Categorization of Risk of drugs use in pregnancy.
• But the most widely used system are the FDA & TERIS (Teratogen information system) pregnancy risk classifications.
The FDA Categorization of Drugs in Pregnancy
• Category A- Controlled studies in women fail to demonstrate a risk to the fetus in the any trimester and the possibility of fetal harm appears remote
The FDA Categorization of Drugs in Pregnancy
• Category B- Animal studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women,
or
Animal studies have shown an adverse effect that was not confirmed in controlled studies in women in any trimester
The FDA Categorization of Drugs in Pregnancy
• Category C- Studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women
or studies in women and animals are
not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
The FDA Categorization of Drugs in Pregnancy
• Category D- There is positive evidence of fetal
risk, but the benefits from use in pregnancy may be acceptable despite the risk
e.g. if the drug is needed in a life-threatening situation for which safer drugs cannot be used or are ineffective.
The FDA Categorization of Drugs in Pregnancy
• Category X- Studies in animals or humans have
demonstrated fetal abnormalities, or
there is fetal risk based on human experience or both, and the risk clearly outweighs any possible benefit.
The drug is contraindicated in women who are or may become pregnant.
Drug Safety System: the problems
• Pregnant women are excluded from pre-licensure clinical trial, for fear of harming the mother or developing fetus
• Most drugs are marketed with limited information on their safety during pregnancy and therefore are not recommended for use by pregnant women.
Drug Safety System: the problems
• Passive mechanism of spontaneous reporting of adverse drug effects are inadequate for detecting drug induced fetal risk or lack of such risk
Drug Safety System : the problems & solutions
• Therefore the U.S. FDA has overhauled safety issues related to drugs by provisions in the FDA Amendments Act (FDAA)
• The legislation instructs FDA to establish a system that can access drug safety data on 25 million patients by 2010 and 100 million by 2012
Drug Safety System : the problems & solutions
• The US FDA and the European Medicine Agency recommend active surveillance, such as the use of Pregnancy Exposure Registers (PERs)
• Another important component of the sentinel system is a more modern and expanded FDA Spontaneous Adverse Event Reporting System (AERS).
Drug Safety System : the problems & solutions
• The FDA is collaborating with the Center for Disease Control and Prevention (CDC) and the National Institute of Health (NIH) on a standard and common reporting method of adverse events for all FDA regulated products.
Drug Safety System : the problems & solutions
• The FDA also plans to combine safety-signal detection and analysis for drugs, biologics, medical devices, and other regulated products into an agency – wide FDA Adverse Event Reporting System (FAERS) and a user friendly Medwatch plus portal
Drug Safety System : the limitations
• Resources for routine pharmaco-vigilance are rare and automated data sources generally do not exist in developing world
• In industrialized countries the drug information can be derived from medical records and automated databases, including medical or pharmacy insurance claims
Drug Safety System : the limitations
• Troubling news about several high-profile drugs saps confidence in the system for assuring the supply of safe ones and
flushing out dangerous medicines
• No drug is ever fully safe. The safety net isn't designed to catch rare side effects until drugs reach the market.
• By then, regulators are often powerless to spot mistakes
Drug Safety System : the limitations
The massive import of drugs also poses problems.
The FDA conducts inspections of plants, amid explosive growth in imports from India and China, to ensure that the drugs are of high quality.
Drug Safety System : the limitations
The low level of follow up inspection, combined with the huge amount of imports, greatly increases the potential that consumers will get products that have impurities or ineffective ingredients.
Brant Zell pastchairman of the Bulk
pharmaceuticals Task force
• Rare harmful effects pop up only with mass consumption. Doctors are merely encouraged to report them, and the FDA forces the industry to carry out relatively few studies of drugs on the market.
"If a plane crashes off the coast of New York, we don't leave the investigation to the controllers that were controlling the plane and the airline that was flying it,"
Dr. Alastair Wood, a Vanderbilt University pharmacologist and FDA
drug safety adviser.
New drug trials in pregnancy:
A recent review found that only 17 medications for maternal health are are being developed world wide, and many advocates say that the “drought” of new medications to treat pregnant women is unlikely to change any time soon,
USA today reports
This building is on very shaky ground. Would I condemn it ? No but I would tell
people, ‘ you go in at your risk’
Dr Cathrine De Angel , Editor, JAMA
The answer to the problems is to have an evidence based review system for guiding prescribing in pregnancy
Despite such limitations thousands of Americans survive or lead better lives
thanks to effective and safe drugs.• "Medicines that receive FDA
approval are among the safest in the world,"
Acting Commissioner Lester Crawford
• The FDA has commissioned the independent non-profit Institute of Medicine to study drug safety and recommend improvements.
Evidence Based Review System
The FDA’s evidence based review system
• Identifies scientific studies that evaluate the substance/disease relationships
• Identifies surrogate endpoints of disease risk
• Assesses the quality of scientific studies
Evidence Based Review System
• Evaluates the totality of the scientific evidence
• Assesses SSA (significant scientific agreement)
• Analyzes the specificity of the claim language of a QHC (Qualified health claim)
• Revaluates existing SSA claim and existing QHCs
AHFS drug information
• AHFS DI is an attested and proven source of comparative, unbiased and evidence based drug information for safe and effective drug therapy
REPRORISK System
The single most comprehensive compilation of Reproductive Risk Information Databases
Benefits:• Provides guideline for reducing
exposures.• Helps to prevent possible medical
and legal complications
REPRORISK System
• Equips patients with information needed to make informed decisions and take preventive measures.
• Facilitates identification and reporting of hazardous health effects.
REPROTEXT
A Reproductive Hazard Reference
• Presents reviews on health effects of industrial chemicals encountered in the work place.
• Describes effects on human reproduction of acute and chronic exposures and reproductive, carcinogenic, and genetic influences
• Includes unique dual health hazard ranking system for general society and “grade card” scale suggesting level of reproductive hazard.
REPROTEXT
• Covers physical agents including heat, noise, and radiation.
• Helps set risk – reducing priorities by combining hazard rankings with exposure estimates.
• Assists with development of program to improve employee protection guidelines
REPROTOX
Reproduction Hazard Information –
From the reproductive toxicology centre, Bethesda, MD, covers the impact of the physical and chemical environment on human reproduction and development.
Covers all aspects of reproduction including fertility, male exposures and lactation
REPROTOX
• Discusses reproductive influences of industrial and environmental chemicals, naturally occurring radioactive materials, prescription non-prescription, and recreational drugs and nutritional agents
Includes the latest, most relevant teratology articles
TERIS
• Teratogens Information System developed by the university of Washington.
• Provides current information on the teratogenic effects of drugs and environmental agents.
TERIS
TERIS documents include:
• Agent name and number.• Summery of teratogenic effects• Magnitude of risk• Quality and quantity of data• Comments• References
Conclusion
• The most widely used system for categorizing drug risk during pregnancy in the United States are the FDA and TERIS pregnancy risk classification.
• Controlled data on using medication during pregnancy and lactation are lacking, making firm recommendations more difficult.
Conclusion
• Only fair agreement on risk category assignment exists when comparing common pregnancy risk classification systems within and between countries
Conclusion
• Pregnancy risk categories should be used as general guide lines to help choose safer medications alternatives.
• Useful print and internet resources
help guide national medication selection during pregnancy and lactation
Counseling for Prescribing in
Pregnancy
Dr Seema HakimProfessor Of Obstetrics & GynaecologyJ N Medical College,Aligarh Muslim University
Aligarh, U.P.
Introduction
• 40-90% women are exposed to drugs in pregnancy
• The safety of more than 60% of these drugs for the fetus and the mother is unknown
• Known teratogens sometimes are required for the pregnant patient to treat life-threatening conditions
The Problems:
• Some pregnant women are exposed to drugs inadvertently because they do not know they are pregnant at the time of intake
• Often women requesting counseling for prenatal drug exposure have misconceptions regarding the risks
The Problems:• The problem is compounded by
referral sources who exaggerate the risk and offer termination.
• Inaccurate reports in the lay press further cause panic.
• Most women report for counseling only after exposure rather than coming for prenatal counseling
The Problems:
• The drug manufactures label almost all drugs as unsafe in pregnancy to avoid litigations
• Most women have no idea
about the background risk of congenital anomalies
Why counseling:
• The health of the fetus and concomitantly pregnant female’s health is at risk
• Patients are more receptive to adverse effects if they are already aware and well informed about them
Effective counseling
Results in:• Improved understanding • Increased recall of information• Reduced anxiety• Decreased uncertainty• Increased satisfaction• Improved compliance
Concerns during pregnancy
• Fear of teratogenesis• Need to safeguard the smooth
progress of pregnancy and delivery
• Need to prevent withdrawal effects in the neonate
• Concerns about subtle effects on the infant’s neurodevelopment
Concerns during pregnancy
Pregnancy likely to unmask occult chronic diseases e. g. glucose intolerance, hypertension
Pregnancy is a “stress test for life”
Obstetric complications and increasing maternal age will add to overall rates of poor outcome.
Prenatal Counseling
• Drugs may be needed for certain conditions like epilepsy, diabetes, hypertension which predate pregnancy.
Prenatal Counseling
• Counseling should include both the fetal risk from the drug as well as the teratogenic risk of the condition for which the drug is being prescribed e.g epilepsy and diabetes which are associated with a higher malformation rate per se.
Prenatal Counseling
• The manner in which the information is given affects the perception of the risk e.g.. Women given negative information– such as a 1-3% chance of having a malformed baby are more likely to perceive an exaggerated risk as compared to women given positive information– the 97-99% chance of having a normal baby
Prenatal Counseling
• Most commonly used drugs can be prescribed with relative safety in pregnancy
• All women have a 3% chance of having an abnormal baby
Prenatal Counseling
• Exposure to a known teratogen may increase this risk, but it is usually increased by only 1-2%, or at the most doubled or tripled.
• Counseling should emphasize relative risk
• The concept of risk versus benefit should also be introduced before prescribing
Counseling After Exposure
• Counseling a woman exposed to drugs specially during the critical period of organogenesis is a challenge.
Certain questions need to be answered---
• Is the drug a known teratogen?• What are its potential adverse
effects on the fetus and neonate?
• What are the risks to the mother if the drug is withheld?
Certain questions need to be answered---
• What are the implications of the disease itself for which the drug is to be given regarding risk of anomaly?
• What are available sources of information about its use in pregnancy and its effects on the fetus?
How to proceed with counseling---
• After looking for answers to these questions proceed by giving the following information to the woman:-------
-----Etiology Of Malformations
• Cause is unknown in 60-70% of malformations
• It is estimated that---- - 20-25% are genetic - 3-5% due to intra-uterine
infections - 4% due to maternal disease
like diabetes, epilepsy
---fewer than 1% are due to prescribed drugs!
• However patients, physicians, lawyers often suspect that drugs caused a malformation in any exposed infant.
Next we should evaluate the risk of teratogenicity.
Evaluating the Risk
• Few drugs are known teratogens but no information is available for more than 60% of the drugs to allow an assessment of the risk to the fetus
• Major text books, FDA categorization, computerized data-bases such as TERIS, REPROTOX etc. provide information for assessment of potential risks.
But are these methods appropriate & adequate for risk
evaluation?
Limitations of FDA Categorization
• Hard to remember
• May be misleading–Up to 60% of category X
drugs have no human data–Few drugs listed in category
A e.g Ampicillin is category B
Limitations of FDA Categorization
Rarely updated, does not reflect current scientific data e.g oral pills still in category X though teratogenicity has been disproved
No information on degree of risk
The system bases drug ratings on limited animal data or case reports.
Therefore should not be considered as a primary directive for prescribing in pregnancy.
Counseling the Patient
• Detailed medical history and physical examination required before proceeding further with counseling.
History
• LMP for accurate gestational dating
• Detailed information regarding
class, dose, route of administration, timing of exposure according to gestational age, disease being treated
• Detailed family history and genetic pedigree
History
• Co-morbidities to be ruled out which may affect risk of malformations
• USG to be done for gestational
dating, as menstrual age and gestational age have a difference of 2 weeks
• The period of 2 weeks between fertilisation and implantation follows ‘all & none’ law– either fetus aborts or pregnancy continues without any harm.
History
• it can be confirmed that the exposure was before conception or organogenesis then the counseling may simply consist of reassuring the patient.
• Determine whether the drug is absorbed in circulation or has only local effect and then will not harm the fetus eg. Laxatives, local Antacids
History
• Determine whether agent crosses the placenta eg even LMW Heparin does not cross and so no fetal effects.
• For known teratogens eg. Isotretinoin having established risk of anomaly and when exposure in a given period of gestation has been documented --termination may be offered.
counseling
The counselor may explain the risk as follows---
“ although a small risk cannot be ‘ruled out’, the risk of spontaneous anomalies is probably greater than any risk that can be estimated from available information for most medications that have been studied.”
counseling
• Finally if the initiation of therapy for a pregnant lady may be delayed for the period of organogenesis without risking her life then this may be considered as an option.
counseling
• If delay is unsafe, treatment should be started, even if risk is involved and termination may be offered after counseling e.g.chemotherapy for acute leukemia should be initiated as soon as diagnosis is confirmed irrespective of gestational age.
Prescribing in pregnancy
• Consider non drug options
• Avoid drugs if possible during weeks 6-10
• Do not start any medication unless clearly indicated
• Do not discontinue medicines that successfully maintain the maternal condition unless there are clear indications to do so
Prescribing in pregnancy
• Ask about and document non-prescription medicines
• Have a pregnancy medication reference available
• Favor older medicines with longer record of use
• Keep doses low before delivery if possible
Prescribing in pregnancy
• Consult with pediatrician.• Educate your patient• Report adverse outcomes• Always consider the effect of
not treating• Remember that few drugs are
absolutely contraindicated
Avoid polypharmacy in pregnancy
• Optimize non-pharmacologic alternatives
• Determine whether each medication:– Is necessary– Is effective– Is at lowest effective dose–Does not adversely alter
other medication effect
Rational management to avoid polyfarmacy
Simple–Use generics
–Use least frequent dosing needed
–Tie to scheduled daily activities, meals, sleep/wake
–Provide legible written instructions
•Support–Educate-- all medicines, even
over-the-counter have adverse effects, report all products used
–Encourage use of one pharmacist
–Avoid seeing multiple physicians
–Enlist help of family, friends, caregivers
– Medication organization equipment
• Survey-Periodic review
5 `rights' of medication:
-- right patient
– right drug
– right dose
– right route
– right frequency
Process of Rational PrescribingDefine the patient’s problem
Specify the Therapeutic objective
Verify if treatment is suitable for this patient
Start the Treatment
Give information, instructions and warnings
Monitor and stop treatment
Conclusions
Constantly update your knowledge
Give time to your patient
Evaluate the condition
Make a prudent decision
Wisdom and knowledge are the key to good counseling and prescribing in pregnancy!
Teratology
Dr Sabahat Rasool, MBBS, MS JNMC, AMU, Aligarh
Objectives
• To define teratology and teratogens
• Evaluate potential teratogens• Genetic mechanisms, including
Homeobox genes• Physiological mechanisms• Perinatal pharmacology
Little Angels
These Rotten Things…
And These…
And These…
Teratology – A Historical
Perspective• 15th & 16th centuries –
malformations caused by the devil: mother & child killed
• 1900’s –malformations related to genes
• 1941 –malformations linked to rubella virus
• 1960’s – Thalidomide Tragedy• 1970’s – Fetal Alcohol
Syndrome
Chemicals & teratogenicity
• Approximately 80,000 chemicals listed by EPA in the USA
• Most of them not tested for developmental toxicity
• For example, High Production Volume (HPV) chemicals
• Mercury & lead are good examples
Teratology
• A Teratogen is any agent acting during embryonic or fetal development to produce a permanent alteration of form or function (Shepard, 1998)
• Teratogenesis is derived from the Greek words gennan which means to produce, and terata, which means monster
Teratogen – Types
• Hadegen – named after the God Hades, agent that interferes with normal maturation and function of organ
• Trophogen – an agent that alters growth
• Teratogen – an agent that produces structural abnormalities
• Most authors use the term teratogens to describe all three: hadegen, trophogen, and teratogen
Definitions
• Malformation- structural defect from a localised error of morphogenesis
• Disruption- specific abnormality due to disruption of normal developmental process
• Deformation- an alteration in shape/ structure of a previously normal organ
• Syndrome- a recognised pattern of malformations with a specific agent/ etiology
Teratogens--Classification• Viruses (rubella, toxoplasma,CMV)• Chemicals (methyl mercury,
pesticides, PCBs, alcohols)• Environmental agents (alcohol,
tobacco, cocaine)• Physical factors (radiation,
hyperthermia, atomic fallouts)• Drugs (phenytoin, thalidomide,
retinoids, warfarin, DES)• Maternal factors (hyperthermia,
diabetes)
Consequences of Teratogen Exposure
• Death• Malformation• Growth restriction• Functional defects
Wilson’s Six Principles
• 1. Susceptibility to teratogens depends on the genotype of the conceptus and the manner in which this interacts with adverse environmental factors
Wilson’s Six Principles
2. Susceptibility to teratogenesis varies with the developmental stage at the time of exposure.
3. Teratogenic agents act in specific ways on developing cells and tissues to initiate sequences of abnormal developmental events
Wilson’s Six Principles
4. The access of adverse influences to developing tissues depends on the nature of the influence.
5. There are four manifestations of deviant development (Death, Malformation, Growth Retardation and Functional Defect)
Wilson’s Six Principles
• 6. Manifestations of deviant development increase in frequency and degree as dosage increases from the No Observable Adverse Effect Level (NOAEL) to a dose producing 100% Lethality (LD100)
Criteria for Proof of Human
Teratogenicity• Careful delineation of clinical
cases
• At least three reported cases of rare environmental exposure associated with rare defect
Shepard, 2001, Czeizel & Rockenbaeur, 1997 & Yaffe and Briggs 2003)
Criteria for Proof of Human
Teratogenicity
• Proof that the agent acts directly or indirectly on the embryo or fetus
• Proven exposure to agent at a critical time in prenatal development
Criteria for Proof of Human
Teratogenicity• A biologically plausible
association
• Consistent findings by two or more high quality epidemiological studies
• Teratogenicity in experimental animals, especially primates
Timing of Organogenesis
1 2 3 4 5 6 7 8 12 16 20 38
Implantation
Prenatal Death
Emryonic period
Major Morphological abnormalities
Fetal Period
Physiological and Functional Defects
Central Nervous System
Heart
Ears
Eyes
Limbs
Palate
External Genetalia
Timing of organogenesis during
the embryonic development
• Pre-implantation period starts from 2 weeks from fertilisation to implantation
• Also known as the ‘all or none’ period
• Any insult at this stage leads to
embryonic death.
Timing of exposure- pre-implantation stage
• Exposure of embryos to teratogens during the pre-implantation stage usually does not cause congenital malformations, unless the agent persists in the body beyond this period.
Embryonic period
• Embryonic period starts from the 2nd week through the 8th week following conception. This is the most critical period encompassing organogenesis.
Fetal Period
• Fetal period starts after 9 weeks post fertilisation till term. Exposure during this period will affect fetal growth (e.g., intrauterine growth restriction), the size of a specific organ, or the function of the organ. The term fetal toxicity is commonly used to describe such an effect .
Factors affecting drug
Transfer:Transfer across placenta depends on:
–Placental surface area–Placental metabolism
Factors related to drugs affecting drug
transfer:
–Molecular weight–Lipid solubility–Ionization–Protein binding–Chemical Structure–Size –High blood concentration
The Thalidomide Disaster
• Thalidomide introduced in 1956 as an anti-anxiety, sedative-hypnotic and antiemetic medication for use in the first trimester
The Thalidomide Disaster
• During late 50s and early 60s, more than 10,000 children in 46 countries were born with deformities such as phocomelia, as a consequence of thalidomide use.
• Withdrawn in 1961
• Thalidomide tragedy led to stricter testing being required for drugs before they can be licensed
Thalidomide- The most notorious teratogen
Fetal Alcohol Syndrome
Genetic & Physiological Mechanisms of Teratogenecity
• Folic acid metabolism disruption
• Toxic oxidative intermediates• Fetal genetic makeup• Homeobox genes• Maternal diseases or paternal
exposures
Folic Acid
• Disruption of folic acid metabolism may lead to neural tube defects (NTDs), cleft lip & palate, and even Down’s Syndrome
• Folic acid is needed for production of methionine, and methylation of proteins, lipids and myelin
• (Hernandez Diaz et al, 2000, NEJM)
Anticonvulsants
• Anticonvulsants act as folic acid antagonists, leading to oral clefts, cardiac and urinary tract defects
Oxidative Intermediates
Drugs- Hydantoin Carbamazapine, Phenobarbital
Epoxides – Carcinogenic, Mutagenic
FETALEpoxide hydroxylase - weak
No detoxification
Epoxides Accumulate
ADULTEpoxide hydroxylase
Detoxified
Microsomes
Fetal Genetic Makeup
• Interaction of environment and certain altered genes may lead to malformations
• MTHFR 677C → T mutation is associated with NTDs, but only when folate intake is inadequate
Hwang et al, 1995, Am J Epidemiol)
cigarette smokers
• Polymorphisms in gene for TGF-1 are linked to producing isolated cleft palate in cigarette smokers
Homeobox Genes
• A homeobox is a DNA sequence found within genes that is involved in the regulation of development (morphogenesis) in animals
• These are regulatory genes encoding nuclear proteins, and controlling expression of developmentally important genes
Mutations to homeobox genes can produce easily visible
phenotypic changes
• Arrangement of the genes along the chromosome corresponds to the arrangement of the body areas they control
• Genes at the 3-prime end of the chromosome control the cranial region and are expressed before those at the 5-prime end, which control the caudal region (Faiella et al, 1994, Proc Natl Acad Sci USA)
Homeobox Genes and Teratogens
• Some teratogens, (retinoids) activate homeobox genes prematurely, leading to chaotic expression at different sensitive stages of development, especially causing abnormalities of limb buds and hindbrain
• Valproate alters the expression of Hox d8, d10 & d11 genes, preventing normal closure of posterior neuropore
Maternal diseases
• Interaction of maternal disease with fetal genetic composition determines some drug effects e.g alcoholic mothers have nutritional deficiencies and also abuse other drugs. Fetuses exposed to these combined adverse effects will be at higher risk of malformations.
Paternal exposures
• Paternal exposure to teratogens can act by inducing gene/ chromosomal abnormality in sperm.
• Another possibility is that a drug in seminal fluid may directly contact the fetus during intercourse.
Drugs and the lactating mother:
• The physiologic processes that govern the excretion of drugs in breast milk are the same as that which determine the transfer of drugs through placenta.
• Toxicity therefore depends on pharmacological characteristics of the drug
Conclusion
• Toxicity most of the time is reversible and is related to prolonged and continuous use of drug
• But there are exceptions where a single dose may be associated with fetal / newborn toxicity e.g narcotic analgesics close to delivery may cause sinusoidal fetal heart rate pattern or respiratory depression of newborn
Conclusion
• Therefore when a woman requires drug therapy during pregnancy or lactation, particularly prolonged / continuous use, the lowest possible dose should be used and monitoring should be done to detect any signs of toxicity.
Safe Drugs for Common Diseases in Pregnancy
Dr Alami Zeba MBBS, MD, Aligarh
Introduction
The safety of more than 60% of the medications in pregnancy remains unknown.
40-90% pregnant women are exposed to medications during gestation.
Introduction
• 90-97% pregnant women take medications prescribed by their physician and two thirds take over the counter medications without medical advice.
Objectives
• To summarize the safest drug for treating common conditions in pregnancy
• To discuss the teratogenic potential of drugs which sometimes must be prescribed in pregnancy to treat life-threatening conditions.
Frequently used drugs in pregnancy:
• Vitamins, anti-emetics, analgesics, antipyretics, sedatives, antibiotics, laxatives, antacids, diuretics, antihistamines
Medications used to manage serious medical
complications / pregnancy complications:
• Hypertension, PIH, diabetes, cardiac disease, bronchial asthma, thyroid disease, cancers, poly-hydramnios, pre-term labor, general and local anesthetics,coagulation disorders, auto-immune disorders, epilepsy etc.
Considerations
• Pharmokinetics are affected by physiologic changes of pregnancy and dose adjustments are needed to optimize the clinical outcome.
• Teratogenetic potential of the drug should be considered while prescribing
• Some may directly affect the fetus, others may cause harm by affecting maternal physiology e.g diuretics
Analgesics
Salicylates and Acetaminophen
- Increase the risk of early spontaneous abortion.
- 1st trimester use may cause fetal gastroschisis.
- There is theoretical concern of premature closure of ductus arteriosus.
185
CLASP Study 1994
• Did not report any fetal anamoly with low dose aspirin [60 mg] given to pregnant women for prevention of PIH and IUGR
Analgesics
• Indomethacin
• Used to treat hydramnios, and for tocolysis. May casue premature closure of ductus arteriosus and pulmonary hypertension in neonate. This effect is reversible if drug is not given after 34 weeks. Other adverse effects are – intraventricular hemorrhage, necrotizing enterocolitis and bronchopulmonary dysplasia
Analgesics cont…
Narcotic analgesics :
- Chronic maternal ingestion may cause neonatal withdrawal syndrome.
- They may also cause neonatal respiratory depression and sinusoidal heart rate pattern in -utero.
188
morphine, codine, meperidine, propoxyphene
Not known to be teratogenic
Analgesics cont…
Ergotamine and sumatriptan:
- Used for treatment of migraine headache.
- Use of ergotamine in 1st trimester may cause neural tube defect and leads to fetal bradycardia due to uterine contraction and decreased uterine blood flow.
- .189
Sumatriptan does not cause fetal anomalies and spares uterine vessels so better during pregnancy
Antiemetics
Doxylamine : Non-teratogenic, safe in pregnancy
Piperazine and phenothiazines
[Metoclopramide. Chlorpromazine]
: Not associated with anomalies.
Ondansetron : Reserved for treatment of hyperemesis refractory to other medications as no human studies , [category B].
190
Antacids Aluminum, Calcium, Magnesium
Magaldrate, Sodium Bicoarbonate. - These are not teratogenic safe if used in
moderation Long term high dose use may lead to maternal or fetal hyper-calcacemia, hyper-magnesemia or hypocalcaemia.
H2 receptor antagonists: (ranitidine)
- Not associated with congenital malformations even if used in 1st trimester though cross the placenta
Proton pump inhibitors: (Omeprazole)
- Can be used safely even in 1st trimester 191
DecongestantsPseudoephedrine:-The most preferred decongestant as proven to be safe in pregnancy.
Phenylephrine and phenylpropanolamine:-Used in nasal sprays and eye drops.-No increased risk of anomalies but may interfere with uterine blood flow and should be avoided in pregnancy with decreased uterine blood flow (e.g.PIH)
192
Decongestants cont…
Oxymetazoline, Xylometazoline:
-used in long acting nasal sprays-No increase in the frequency of congenital malformations.
193
Antihistamines
• Ethanolamine, Piperidine, Butyrophenone and Piperazine derivatives :
All are non- teratogenic . Parenteral use of ethylamine
derivatives [Clemastine, Diphynhydramine] may have oxytocic effect.
Antihistamines cont….
Non-sedating antihistamines:- Loratadine: No study to address its safety in pregnancy.-Cetrizine: There is no risk of congenital anomaly.-Astemizole and Fexofenadine are non teratogenic .-Chromolyn Sodium: safe even in 1st trimester
195
Antitussives
Dextromethorphan: Not associated with congenital anomalies if used in first trimester.Narcotic containing: Neonatal withdrawal syndrome and respiratory depression may occur on long term use. Alcohol containing: Short term use has no adverse effect.
196
Expectorants
Guaifenesin: - Most commonly used agent in expectorants- It does not increase the risk of birth defectsIodide containing expectorants:- Should not be used after 10 weeks as these may cause fetal goiter.
197
Cardiac Medications
Digoxin:- Cardiac glycoside used to treat heart failure, atrial fibrillation or flutter and other supraventricular tachycardias.-Readily crosses the placenta but has no adverse fetal effects, -Successfully used to treat fetal arrythmias also.
198
Cardiac Medications cont…
Quinidine:- Used as antiarrhythmic drug.- Dose used to treat arrhythmia is one tenth the dose used to treat severe malaria and has not been associated with fetal abnormalities.
199
• Many local anesthetics are used as anti-arrhythmics e.g Lidocaine, Procainamide.
• These cross placenta but do not increase congenital malformations
• However short term use is different from long term use to treat arrhythmias as long term studies not available but we have to see risk-benefit ratio as arrhythmias may be life threatening.
Cardiac Medications cont…
Amiodarone:Used for life-threatening arrhythmias
-Structurally similar to thyroxine
-May cause fetal and neonatal hypothyroidism if given after 10 weeks.
201
Anti anginals:
Nitro-glycerine: Is used during general
anesthesia in hypertensive and cardiac patients.
No epidemiologic studies available to confirm safety but do not withhold in life-threatening cases.
Verapamil: Used as antianginal,
antihypertensive and for arrhythmias.
Is associated with decreased
uterine flow, cardiac depression and cardiac arrest in neonates so give only if condition is life threatening and other agents are ineffective
Antihypertensives
Methyldopa:- Most commonly used drug to treat hypertension during pregnancy.- Its many years of use attest its safetyHydralazine:- Used to treat hypertension in later half of pregnancy without adverse fetal effects.
204
Antihypertensives cont….
Sodium Nitroprusside:- Readily crosses the placenta. - May lead to accumulation of cyanide in fetal liver.
Clonidine:- An α-adrenergic antagonist.- Has no adverse fetal effects.
205
Antihypertensive cont…
β-blockers:
- long term use possibly associated with fetal growth restriction and neonatal hypoglycaemia.- May cause transient mild hypotension and symptomatic β- blockade in exposed newborns.
206
Antihypertensives cont…
Calcium channel blockers:
- May block the calcium dependent embryonic processes theoretically.
- Nifedepine has been associated with fetal loss in some studies
Verapamil:- Associated with limb defects and hypertrophic cardiomyopathy.- Causes cardiac depression and arrest if used with digoxin.Nifedipine:- Associated with fetal limb defects and pregnancy loss if used in early pregnancy .
Antihypertensives cont…
208
Antihypertensives cont…
ACE inhibitors:-Decrease fetal renal perfusion which leads to oligohydramnios if used in II and III trimester.-Resulting oligohydramnios causes lung hypoplasia and limb contractures known as ACE inhibitor fetopathy
-Contra-indicated in pregnancy 209
Diuretics Thiazides:-May cause neonatal thrombocytopenia, bleeding and electrolyte disturbances if given near term.Furosemide: •-May increase incidence of PDA in preterm newborns. •Crosses placenta increasing fetal urine production.• Increase utero-placental insufficiency and IUGR. •Given only when benefits outweigh risks as in pregnancy with heart disease or in pulmonary edema.
210
Diuretics cont…
Spironolactone:-anti-androgenic and shown to cause feminization of male rats and delayed sexual maturation of female rats in-utero. Not been studied widely in pregnancyAcetazolamide:-Has been associated with limb defects in rodents but not in primates or humans. 211
Anticoagulants
Warfarin: -Readily crosses the placenta.-Exposure between sixth and ninth week causes warfarin embryopathy characterized by nasal and midface hypoplasia and stippled vertebral and femoral epiphyses.-Second and third trimester exposure causes hemorrhage in several organs leading to disharmonic growth and deformation.-Contra-indicated in 1st trimester of pregnancy
212
Anticoagulants cont…
Heparin:Has large and highly polar molecules that do not cross the placenta and thus are not associated with fetal anomalies, low birth weight or stillbirthMay cause maternal osteopeniaSafe in pregnancy
213
Antiepileptics Phenytoin: -Fetal hydantion syndrome,10% of infants exposed will have major defects and 1/3rd will have minor defects. Carbamazepine: -Fetal hydantion syndrome and neural tube defect risk is 1% as compared to .1% for general population, but safest in pregnancy as compared to other drugs
214
Valproate: Used for petit mal seizures Neural tube defects 1-2% risk of neural tube defects
which is 8-10 times more than the general population
Trimethadone and Paramethadone:
Craniofacial anomalies, microcephaly, growth deficiency and cardiac defects.
Antiepileptics cont…Phenobarbital:Clefts, cardiac anomalies, urinary tract malformations.
Lamotrigine:Lower teratogenic risk than other antifolate anti convulsants.
Topiramate:Should be avoided in pregnancy.
216
Asthma Medications
Epinephrine and Terbutaline:- Not associated with adverse
fetal effects.
Theophylline:- Safe in pregnancy, all
trimesters.
217
Asthma Medications
Beclomethasone and Prednisone:
- Have no adverse fetal effects. Given as inhalers for long term use and short term, parenteral for exacerbations.
Avoid Triamcinolone in
pregnancy as teratogen for animals
Thyroid Disorder Drugs
Propylthiouracil: - May cause fetal goiter and
hypothyroidism- Clinically significant effects are
uncommon with the therapeutic doses.
Methimazole:- Associated with scalp defects,
esophageal and choanal atresia.
219
Potassium Iodide & Sodium Iodide:
can be used for short term e.g for thyroid surgery or thyroid crisis but long term use may cause goitre in infant.
Thyroid Replacement drugs: Thyroxin does not cross
placenta significantly and is not associated with anamolies
Anti Neoplastic Drugs
- Breast carcinoma, melanoma and Hodgkin’s lymphoma are the most common malignancies in pregnant women.
- Most chemotherapeutic agents impede cell growth and cell division.
- Cause congenital anomalies and growth retardation.
221
Anti Neoplastic Drugs
All are Category D drugs but potentially life- saving therapy cannot be withheld in pregnancy
Hormones
Androgens:- Masculinization of female fetus.
Testosterone and anabolic steroids:
- First trimester exposure may cause labio-scrotal fusion.
- Phallic enlargement may occur in late exposure.
223
Hormones cont…
Medroxyprogesterone acetate:- Virilization of female fetuses and feminization of male fetuses in rats but not in humans.
Norethindrone:- Female fetus masculinization in 1% exposures.
224
Hormones cont…
Danazole:- Causes clitorimegaly, fused labia and urogenital sinus malformation.
Oral Contraceptives:- Not associated with congenital anomalies
225
Diethylstilbestrol:- Vaginal clear cell
adenocarcinoma.- Cervical ectropion and vaginal
adenosis.- Hypoplastic, T-shaped uterine
cavity.- Cervical collars, hoods, septa
and coxcombs.- Exposed males may have
epididymal cysts, microphallus, cryptorchidism, testicular hypoplasia and hypospadias.
226
Psychotropics
Diazepam:- Most widely used tranquilizer.- Increased risk of cleft palate, limb
malformation and other defects in rodents.
- It’s teratogenic effects in humans is controversial.
- Neonatal depression and withdrawal symptoms on long term use.
227
Psychotropics cont…
Lithium salts:- Ebstein anomaly- May also cause diabetes insipidus, hypothyroidism and hypoglycemia.
Selective Serotonine Reuptake Inhibitors:- Not associated with fetal losses and malformations- can be used safely as antidepressant in pregnant women.
228
Psychotropics cont…
Tricyclic Antidepressants:- Safe in pregnancy.
Phenothiazines:- Teratogenic potential is minimal.
229
Immuno Suppressives
Azathioprine:- Growth restriction, immune suppression and pancytopenia may occur in exposed neonates.
Should not be with held from pregnant patients as given for prevention of rejection in renal transplant
230
Immuno Suppressives cont…
Cyclosporine:- Causes maternal nephro-toxicity but safe for fetus, cannot be withheld in pregnancy as prescribed for life-threatening conditions
Tacrolimus:- Cause abortions and anomalies in animals but not in humans.- May lead to preterm delivery, hyperkalemia growth restriction and nephrotoxicity. 231
Others
Antifungals: Local agents like Clotrimazole and
Nystatin are safe. Fluconazole parenteral in high doses is associated with anomalies like brachycephaly, heart defects, cleft palate. Single oral dose is not associated with increased frequency of anomalies.
Griseofulvin not safe in pregnancy
Antivirals
• Ziduvidine for AIDS and a Acyclovir for Herpes are safe in pregnancy
• Ribavarin used for treating resiratory viral infections as aerosol is highly teratogenic.
• No human data available for Idoxuridine, Gangcyclovir, Indinavir, Lamivudine, Nevirapine etc
Antiparasitic drugs
• Metronidazole for Trichomoniasis and Amebiasis safe even in 1st trimester
• Chloroquine used for Malaria is safe• Quinine for falciparum malaria in
large doses often used as abortifacient increases risk of congenital abnormalities or when taken in 1st trimester.
• Mefloquine may cause stillbirth in 2nd or 3rd trimester
Antiparasitic drugs
• Spiramycin, Pyremethamine, Sulphadiazine used for Toxoplasmosis are safe in pregnancy but concurrent administration of folic acid is needed with Pyrimethamine
• Mabendazole and Pyrantel pamoate safe in pregnancy
Herbal Preparations
• It is difficult to estimate the risk of herbal remedies as the quantity and quality of the ingredients in these preparations are not known.
• Pregnant mothers should therefore be counseled to avoid these.
Some known teratogens:
• Alcohol• Antiepileptics- phenytoin,
carbamazepine, valproate, phenobarbital, trimethadione, lamotragine
• Warfarin compounds• ACE-inhibitors• Retinoids• Hormones- androgens, danazole,
anabolic steroids, DES, androgenic progestogens
Some known teratogens:
• Antineoplastic drugs- cyclophosphamide, methotrexate,
• Antimicrobials - tetracyclins, streptomycin, sulphonamides,
• Antifungals- griseofulvin, fluconazole
• Antivirals- ribavirin• Antimalarial- mefloquin
How To Prescribe Antibiotics In
Pregnancy
Dr. Tamkin Rabbani MD, DNB, MICOG
Department of OBG, J.N. Medical College, AMU Aligarh.
When I look upon the past, I can only dispel the sadness which falls upon me by gazing into that happy future when infection will be banished as a cause of maternal death and disability.
Philip
Sammuel Weiss
Infection
• Infection is the commonest and single most important problem encountered by obstetricians during pregnancy
• Sepsis still remains an important cause of maternal mortality and morbidity.
In a study of almost 9000 Medicaid prenatal patients Piper and colleagues (1987) reported that each woman received an average of 3.1 prescriptions of drugs with antibiotics as the commonest group.
Indian scenario is expected to be grimmer due to:
-Lack of regulatory agencies , -Poor enforcement of existing
regulations, --Lack of awareness of general population about teratogenic potential of various drugs.
It important that as
obstetricians we should know how to prescribe antibiotics correctly.
Spectrum of problems
• Common infections encountered are cystitis, acute pyelonephritis, upper and lower respiratory tract infections, amnionitis, septic abortion, puerperal sepsis
• Typhoid, hepatitis, malaria and TORCH group of infections sometimes also present a therapeutic dilemma for us!
• Surgical prophylaxis for cases like ovarian cystectomy, Mc Donald stitches, Bartholin abscess, Cesarean section, episiotomy etc. is required.
• Prevention of chorioamnionitis in both term and PTL with PROM also needs antibiotics
• Prophylaxis for prevention of streptococcal infection of neonates is needed.
Most of these infections are straight forward to treat but may become life threatening if not treated adequately.
Today we have a whole array of antibiotics at our disposal but despite this sudden explosion in the number of antibiotics an obstetrician’s choice is limited because of the risk of teratogenecity and emergence of resistance against the tried and tested ones!
The problem is that almost every drug we are using today has this
warning in the accompanying insert----
• This drug has not been proven safe for pregnant and lactating women!
The infamous thalidomide tragedy is the background for these warnings.
This has made antibiotics big business for lawyers.
Nobody, specially the FDA wants a repeat of the benedictin episode ---- drug was withdrawn not because it was a teratogen but because it was a LITOGEN!
• Predicting human teratogenicity from animal studies is difficult if not impossible!
• Package inserts do not provide guidance as to whether termination is indicated if a pregnant lady has inadvertently ingested that drug.
• Simply mentioning that a particular drug crosses the placenta does not indicate potential fetal harm as:
-Drug may cross but may not harm
-Drug may not cross but have deleterious effects on fetus by affecting maternal physiology
The present system of testing, marketing and categorizing drugs has created a population of ‘therapeutic orphans’– the pregnant and potentially pregnant women.
We are supposed to make the intelligent decisions!
----And responsibility shifts to us, the obstetricians to decide the risk- benefit ratio subjecting us to an unfair and unrealistic burden.
Prescribing in pregnancy--- the obstetrician’s burden!
? Whether to prescribe at all
When to prescribe
What to prescribe
For how long to prescribe
Commandments
• Discourage pregnant ladies from self medication.
• Warn pregnant ladies against smoking and drug abuse, environmental factors etc.
• All prescriptions should be evidence based.
• Avoid poly pharmacy in pregnancy.
Antibiotics with potentially adverse fetal
effects• Tetracyclins- yellow-brown discoloration of
deciduous teeth• Aminoglycosides- oto-toxicity, 8th cranial nerve
damage and sensori-neural deafness in fetuses reported with streptomycin given in high doses for long-term use, risk of damage is 1-2% which is 20 times than that for general population
Tetracyclin induced teeth discoloration
Antibiotics with potentially adverse fetal
effects
Nitrofurantoin- Transient hemolytic anemia in
newborn specially those with G-6-PO4 Deficiency and others as well.
Avoid near term.
Antibiotics with potentially adverse fetal
effectsSulfonamides and
trimethoprim-• Cross placenta and compete with
biliruben in fetus and in late gestation cal lead to neo-natal hyper-bilirubenemia.
• Avoid in pregnancy
Antibiotics with potentially adverse fetal
effects• Fluroquinolones- irreversible arthropathy in animals,
so use only for resistant cases.
• N-methyl thio tetrazole containing cephalosporins-
testicular hypopasia in rats , no human studies
Antibiotics with potentially adverse fetal
effects
Chloramphenicol-• Crosses placenta in high levels
causing peri-natal problems like ‘gray baby syndrome’ in newborn.
• Avoid in pregnancy
Safe antibiotics in pregnancy
Penicillins- Ampicillin, Penicillin, Amoxicillin are
safe. Newer penicillins– Mezlocillin,
Piperacillin and those combined with Clavulanic Acid and Sulbactum not adequately studied in pregnancy so should be avoided.
All cross placenta and achieve high levels so used for treating fetal syphilis.
Safe antibiotics in pregnancy
Cephalosporins- All cross placenta and achieve
high levels in fetus.1st generation cephalosporins and cefoxitin from 2nd generation cephalosporins are a better choice as they do not contain the side chain N-methyl thio tetrazole
Safe antibiotics in pregnancy
• Erythromycin- does not cross placenta in
significant amount so does not prevent congenital syphilis. Azithromycin and Clarithromycin are probably safe and few studies available do not show an increased risk of anomalies if given in 1st trimester
Safe antibiotics in pregnancy
• Aztreonam-• Monobactum with same spectrum of
activity as aminoglycosides and given category B in pregnancy by FDA.
Safe antibiotics in pregnancy
Clindamycin- No human studies, but reaches fetus
in high levels so do not use except for local tablets for bacterial vaginosis. CDC states that clindamycin vaginal preparations should only be used during the first half of pregnancy.
But remember absence of evidence is not evidence of absence!
Because for most newer antibiotics there are no human studies.
Evidence based treatment of some common infections in pregnancy: [WHO recommendations].
Asymptomatic bacteriuria: - Amoxicillin 3gms stat or - Ampicillin 2gms stat or - Nitrofurantoin 200 mg stat or - Cephalosporin 2gms stat or Single dose treatment is as
good as a 3 day course
Cystits: - Amoxicillin 500 mgs TDS 3days - If treatment fails / recurs more
than 2-3 times send C/S and treat accordingly.
- For prevention of further attacks:
Co-trimaxazole / NFT 100 mgs/ Amox 250 mgs HS till delivery and 2 weeks of puerperium.
Acute pyelonephritis:
- Ampicillin 2g IVI 6 hrly plus Gentamycin 5 mg /kg b wt
IVI OD till she is fever free for 48 hrs.
- If poor clinical response after 72 hours reevaluate and add anaerobic coverage.
- After treatment give Amox 1gm TDS 14 days,then 250 mgs HS till 2 weeks post partum.
Amnionitis: - Amp 2 gms IVI 6 hrly plus GM
5 mgs /kg B WT OD. - Discontinue if she delivers
vaginally. - If delivers by c/s add
metronidazole and stop antibiotics once fever
free for 48 hrs.
Pneumonia Community acquired infection is
usually caused by pneumococcal, Mycoplasma or Chlamydia so DOC is:
-Erythromycin 500- 1000 mgs 6 hrly x 7days orally or IVI depending on
severity. If no response: 3rd generation cephalosporin to be
started as cause may be Hemophilus or
staphylococcal infection.
Typhoid
- Ampicillin 1gm x 6 hourly or Amoxycillin 1gm x 8 hourly for a total of 14 days.
- However, Cephalosporins may be
used as first line drugs according to local sensitivity patterns.
Acute Gastro-enteritis
• Mostly self limiting• Strict maintenance of fluid and
electrolyte balance is mandatory by oral Re hydration therapy or Parenteral fluids according to the condition of the patient.
- Attempt should be made for a specific diagnosis by simple stool examination and cephalosporin or metronidazole should be added accordingly.
Septic Abortion
-Ampicillin 2gm IVI x 6 hourly plus Gentamycin 3-5 mg / kg body weight/day plus Metronidazole 500 mg IVI x 8 hourly till patient is fever free for 48 hours.
-Surgical management according to case.
Metritis
-Use combination of antibiotics ampicillin plus gentamycin and metronidazole till fever free for 48 hrs.
- surgical management for retained products– D&C, laparotomy, hysterectomy according to situation
Pregnancy with heart disease
• Ampicillin 2 gm IVI plus Gentamycin 1.5 mg per kg wt( max.80 mg.) IVI / IMI ½ hour prior to procedure followed by Amp 1gm IVI 6 hours of initial dose..
• Amoxicillin 3 gms orally stat then 1.5 gms after 6 hrs in low risk cases.
Preterm PROM
• Use amoxicillin and erythromycin IVI for 48 hrs then orally for 7-10 days to prevent sepsis in mother.
• Do not use clavulanic acid as risk of necrotising entero-colitis in neonate.
• Ampicillin 2g iv 6 hourly or Penicillin G 2 m.u. IV 6 hourly for prevention of group B streptococcal infection of neonate.
Term PROM Membranes ruptured >18 hours,
Ampicillin 2g IVI 6 hourly or Penicillin G 2 M.U.IVI 6 hourly for prevention of group B streptococcal infection of neonate.
• Stop antibiotics if she delivers normally and has no fever.
• Add metronidazole if she undergoes c/s and continue antibiotics till she is fever free for 48 hours
Summary of treatment practices:
-As 1st line defence against serious infections give a combination of Amp 2gms 6 hrly plus Gentamycin 3-5 mg /kg b wt od and metronidazole 500 mg 8 hrly.
-If infection is not serious start Amoxicillin 500 mg 8 hrly plus Metronidazole 500 mg tds orally.
If clinical response is poor after 48 hrs ensure proper dosage , look for another cause of fever and change antibiotic (according to culture report) after 72 hrs.
-If staphylococcal infection is suspected give Cloxacillin 1 gm 4 hrly.
-If clostridia or group A
hemolytic is suspected give Penicillin 2 million units ivi 4 hrly
-If above are not a possibility then switch over to Ceftriaxone 2gm IVI OD
-Continuation of antibiotics after
patient is fever free for 48 hrs has not been proven to have any additional benefit.
-Women with blood stream
infections however need antibiotics for a minimum of 7 days.
Process of writing a rational prescription—
1. Define the patient’s problem.
2. Specify the therapeutic objective i.e. what do you want to achieve with the treatment.
3. Verify the suitability of your treatment i.e. check effectiveness and safety.
Process of writing a rational prescription—
4. Start the treatment.
5. Give information instructions and warning, ask the patient to paraphrase.
6. Monitor the therapy and stop if required.
While writing the treatment avoid polypharmacy--
-----and jugglery!
Give: information, instruction, warning.
Keep uptodate
• Knowledge and ideas keep changing.
• New drugs are developed and experience with existing ones expand.
• Side effects become better known.
• New indications are discovered.
Lack of knowledge can not be an excuse for the physician and is liable to be held responsible, so make good use of internet and library.
The most important type of inefficiency in treatment is a combination of two separate groups, the use of ineffective therapies and the use of effective therapies at the wrong time.
--Archibald Leman Cochrane
To remain true to our Hippocratic oath we should remember our promise to ourselves as we entered the medical school---
I will apply for the benefit of the sick all measures that are required , avoiding the twin traps of over treatment and therapeutic nihilism.
Drug Abuse During Pregnancy
Dr. Nasreen Noor Assistant Professor, Department of
Obs. & Gynae
J.N.M.C.,
Why do people take drugs ?
• It’s pleasurable
• Experimentation
• Introduction by
partners family or
friends• Low self
esteem• Mental Health
• Coping mechanism
• Escaping• Overwhelming• Emotions.• Managing
depression or anxiety
• Managing trauma
A Major Reason People Take a Drug is they Like
What It Does to Their Brains
The first use is usually voluntary
Impact of drug abuse
Maternal dis-inhibition and personality alteration can further impair the welfare of the fetus.
Effects of Substance Use During Pregnancy
What are the consequences of substance use or exposure?
• Complications during birth
• Physical deformities
• Mental retardation
• Developmental Disorders
Women who use substances may:
• Feel anxious about becoming a parent.• Wonder what they can offer a child.• Need to explore the impact of the
pregnancy on their life style.• Have concerns about being stigmatised
or
judged in a hospital setting.
Negative Heritage
Emotional Instability
PARENTING DYSFUNCTION
Vulnerable Infant
Deficits in Social
Support
Four Factors in ParentingDysfunction in ChemicallyDependent Women
Alcohol• Teratogen – risk of foetal alcohol
syndrome • Not known what is ‘safe level’ of
consumption, seems, binge drinking more problematic.
• (2007) English Dept of Health guidelines ‘no alcohol is safe,so avoid if pregnant or trying to conceive.
• Abstinence ‘ideal’ • Breast feeding : alcohol enters breast milk
but not stored.
Fetal Alcohol Syndrome
• Low birth weight• Central nervous system effects• Facial dysmorphology
FASD
Fetal Alcohol Spectrum Disorders
“ an umbrella term describing the range of effects that can occur in an individual whose mother drank during pregnancy. These effects may include physical, mental, behavioral, and/or learning disabilities with possible lifelong implications.”
Bertrand et al, 2004
Epicanthal folds
Flat nasal bridge
Low set ears
Flat philtrum
Receding jawThin upper lip
Short, upturned nose
Flattened midface
Short palpebral fissures
Microcephaly
Tobacco Increased likelihood of: miscarriage and
threatened miscarriage, prematurity, LBW, accidental haemorrage & perinatal death
• Ask if woman smokes• Advise (non confrontationally) to quit• Assess stage of change, level of
dependence• Assist (eg provide information, explore
persons doubts, tobacco cessation group)• Arrange follow up (eg at next A/N visit)
Cocaine
• Associated with IUGR, placental abruption and premature rupture of the membranes
• Developmental problems observed.• Advise cessation, harm minimisation,
offer counseling• Breastfeeding: express and discard for
24hours after use
Amphetamines
• Appetite depressant – poor maternal nutrition – low birth weight.
• If IV drug use – infection risks..• Possible link with cerebral ischemic
lesions • Advise cessation, counselling may be
of use• Breast feeding: Express and discard
for 24 hours
Maternal Effects of Amphetamine During
Pregnancy• Increased maternal blood pressure• Increased maternal heart rate• Increased risk of premature birth• Constricts blood flow in the placenta,
thereby impacting oxygen flow to the fetus
Effects of Amphetamine on the Developing fetus/infant
• Poor fetal growth—small for gestational age
• Elevated fetal blood pressure (stroke)• Birth defects (6 times the normal rate)
• Cleft palate/lip• Heart disease• Kidney disease• Omphalocele• Premature birth
• Placental hemorrhage
Managing substance abuse in pregnancy
Antenatal care -Goal is to stop or reduce use of
recreational drugs • Detailed history including partner’s drug use &
sexual history• Consultation with a trainee in addiction
medicine• Consultation with anaesthesist may be
beneficial for labour analgesia• Specialist in USG to rule out structural
anomalies, defects and syndromes.
Intrapartum care
• Need constant intrapartum monitoring
• Disturbances in fetal heart rate and rhythm observed with some drugs.
Postnatal Care
• Pediatricians should be informed detailed history .
• Careful newborn examination for birth defects or withdrawal effects
• Early liaison with social work team is vital.
• Maternal withdrawal symptoms should be
looked for.• Sedative or replacement therapy if
indicated.
Avoiding Relapse
It is also important to keep in mind that substances can continue to cause significant health problems to children after birth…
• Transmission through breast milk
• Environmental exposure to smoke
Heroin
Short half life – mother and foetus experience withdrawal – may increase pre maturity, miscarriage associated with IUGR
• Illicit – unknown additives• If used IV – infection & life style issues .• Detoxification not advised - very high risk
of relapse, preferred treatment: stabilise women on methadone, counseling and psychosocial support
• Breastfeeding: not recommended
Avoiding Relapse
• Many new mothers report that they resuming substance use following delivery
• Particularly true of tobacco products and alcohol
A Strategy for Avoiding Relapse
–Make a plan
–Return for follow-up
–Tell others you have quit
–Ask for help from family and friends
Message
Care of women abusing recreational substances can be exasperating, but is worthwhile.
Although the mother’s health needs must be met,the well being and development of the fetus must not be neglected by her care taker.
Vaccination In
Pregnancy
Dr. Zehra MohsinAssistant ProfessorJNMC, AMU, Aligarh
Introduction
• Vaccination is the single most important public health achievement of the 20th century.
• The word vaccination was first coined by Edward Jenner from the Latin word vacca for cow as the first vaccine was derived from the cowpox virus
• No evidence exists of risk from vaccinating pregnant women with inactivated vaccines or toxoids.
• Benefits of vaccinating pregnant women usually outweigh potential risks when the likelihood of disease exposure is high.(1)
Killed Vaccines / Toxoids
• Usually multiple doses are required.• Periodic booster required.• May be given in pregnancy if needed.• No vaccine is recommended in the 1st
trimester.
Live Vaccines
• Provide long-lasting immunity. Single dose required.
• Contraindicated in pregnancy as they pose a theoretical risk of infection to fetus.
• If inadvertently given in pregnancy termination is not indicated as yet no vaccine related side effects are reported
• Tetanus Toxoid(TT)/ Tetanus + Diphtheria (Td)
Indian national immunization schedule and WHO recommend 2 doses given IM, 4 weeks apart in the 2nd trimester (16-20 weeks)
In those who have been vaccinated,a single booster is adequate if next pregnancy is within 3 years (2).•
• CDC recommends 3 doses of TD in un-immunised women.
• First 2 doses, 4 weeks apart, starting in 2nd trimester and 3rd dose 6 months after 2nd dose (postpartum).
• Single dose booster is recommended for women who have received TD vaccination within the last 10 years.(3)
Hepatitis B Vaccine • Purified HbsAg produced by
recombinant technique.
• Recommended in ‘at risk’ women: Having more than 1 sex partner during the previous 6 months, evaluated or treated for STD, IV drug user or with a HbsAg +ve partner.
• Dose : 3 doses at 0, 1 and 6 months, IM (4).
Hepatitis B Immunoglobulin
• Post exposure prophylaxis in newborn along with hepatitis B vaccine.
• To be given preferably within 12 hours of birth.
Influenza Vaccine • Trivalent killed virus vaccine
recommended for women who are pregnant in influenza season (Oct-March) but live attenuated influenza vaccine is contraindicated (5).
• Single dose – IMI
• Also contra indicated in those allergic to eggs
Meningococcal Vaccine
• Mpsv4 is quadrivalent polysaccharide vaccine. Single dose - subcutaneous, recommended for those at risk for infection
• Mcv4 a quadrivalent conjugate vaccine may be given but data regarding safety is not available
MMR Vaccine
• Live virus vaccine
• Pregnancy contraindicated for upto 28 days after vaccination.
• Routine pregnancy testing before vaccination in not necessary, if given inadvertently termination not recommended.
Varicella Vaccine
• Live attenuated viral vaccine
• Can cause congenital Varicella in 2% fetuses
• VZ IG should be strongly considered for susceptible pregnant women who have been exposed
BCG VaccineHerpes Zoster Vaccine
• Not recommended in pregnancy
HPV Vaccine
• The quadrivalent vaccine does not contain live virus and is categorized as category B drug by FDA
• If the woman is found to be pregnant after vaccination the remaining of the 3 dose regimen are to be given after delivery
Vaccines Recommended in
Special Cases
Hepatitis A Vaccine
• Inactivated viral vaccine
• Two dose schedule 6 months apart
• Pre-exposure and post-exposure for women at risk of infection
Rabies Vaccine
• Killed virus vaccine
• Post exposure prophylaxis can be given.
• Pre exposure prophylaxis might also be indicated in those at risk of exposure.
Pneumococcal Vaccine
• Polyvalent polysaccharide vaccine (ppv23) given in a single dose, SC or IM , repeat dose after 6 years
• Recommended in women with : Chronic lung disease, cardiovascular disease, Diabetes mellitus, chronic liver disease, chronic renal failure, asplenia / post spleenectomy, immunosuppressive disease, cochlear implants.
Yellow Fever Vaccine
• Live attenuated viral vaccine
• Dose: single ,subcutaneous
• To be administered only if travel to an endemic area is unavoidable
Anthrax Vaccine
• Prepared from cell free filtrate of bacillus anthracis
• Recommended only for those who work directly with
-animal hides
-Potentially infected animal
Typhoid Vaccine
• Killed vaccine given as 2 doses 4 weeks apart, SC.
• Recommended in women following exposure or traveling to endemic areas
• Not much data regarding safety• Live oral vaccine ty21a not
recommended
Japanese Encephalitis Vaccine
• Inactivated viral vaccine
• Not routinely recommended
• Only if traveling to endemic areas or during outbreaks
Novel influenza A [H1N1]
Both seasonal flu shots and 2009 H1N1 flu shots are recommended for pregnant women at any time during pregnancy