Sa aking mga Minamahal ( alam niyo kung sino kayo),
Pwede ba akong maging mahangin kahit sandali? Konting yabang lang po. Ang di matuwa di kayo required magbasa ng blog ko. Tsupi!
Ibabalita ko lang po that to date I have recently published 3 journal articles in international peer reviewed journals. Sa world of academe kasi this is an important achievement. To publish one paper internationally is hard enough but 3 in one year is really a feat. There is such a term in universities --- PUBLISH OR PERISH. As a professor, to publish original research articles is a must to be retained in the university and to be promoted.Yun lang po. Salamat sa tulong ng lahat ng tao to make these endeavors successful. Who I am right now I owe to a lot of people - my teachers since elementary grade, my UP professors (mentors), my students , my friends, my colleagues and my family. And before I forget, thank you to all my detractors and critics as well.
1. The Role Of Adjuvant Surgery In The Management Of Gestational Trophoblastic Neoplasia (GTN) J Reprod Med 2008; 53: 513-518
2. Sexual Dysfunction As A Complication Of Treatment Of Gestational Trophoblastic Neoplasia (GTN) J Reprod Med 2008; 53: 595-599
3. Efficacy of Methotrexate as Primary Single Agent Therapy for Nonmetastatic and Low risk Metastatic GTN at UP-PGH. Cancer Therapy 2008; 6: 611-616
Thursday, September 11, 2008
DRUGS, MEDICATIONS AND IMMUNIZATIONS DURING PREGNANCY
Outline
I. Introduction
II. Pharmacokinetics in Pregnancy
III. Feto-placental Pharmacokinetics
IV. Principles of Teratogenesis
V. Mechanisms of Teratogenesis
VI. FDA Pregnancy Categories
VII. Representative Human Developmental Toxicants
VIII. Guidelines For Prescribing And Counseling In Pregnancy
IX. Immunization during Pregnancy
X. References
INTRODUCTION
Pharmacotherapeutic decisions in pregnancy take into consideration numerous factors. The ideal drug for treatment in pregnancy is efficacious for the maternal indication, is minimally transported through the placenta and, in the event of transplacental passage, exerts minimal effect on the fetus. Often neglected but of similar importance are drug characteristics that influence tolerability and adherence to dosage and dosing schedule, more so when the drug therapy in question exacerbates conditions common to pregnancy such as emesis, gastrointestinal changes either in the form of diarrhea or constipation, glucose intolerance and hypertension.
PHARMACOKINETICS IN PREGNANCY
Fig 1. Physiologic changes in pregnancy
Physiologic changes in pregnancy significantly affect pharmacokinetics in the pregnant patient (figure 1). These changes include:
1. Cardiovascular changes- increased cardiac output (40%) and increased plasma volume (50%) and total blood volume (40%)
2. Gastrointestinal changes - decreased gut motility, increased gastric pH and nausea and vomiting
3. Respiratory changes - hyperventilation, increased tidal volume, and increased pulmonary blood volume
4. Volume changes -dramatic increases in maternal aqueous and fatty tissue spaces (greatest at 10-30 weeks) and the increase in total body water (mostly extracellular: 40% maternal, 60% feto-placental)
5. Metabolic changes- relative decrease in serum albumin concentration (25%) and elevated levels of steroid hormones competing for protein binding sites, elevated levels of serum progesterone, elevated levels of serum estrogen
6. Renal changes - increase renal blood flow (50%) and the consequent increase in glomerular filtration (50%) 1
Table I. Physiologic changes in pregnancy and their impact on pharmacokinetics of selected agents , ,
PHYSIOLOGIC CHANGES IN PREGNANCY EFFECTS ON PHARMACOKINETICS KEY EXAMPLES
Decreased gut motility, increased gastric pH and nausea and vomiting Variable bioavailability of oral preparations Most oral preparations
Hyperventilation, increased tidal volume, and increased pulmonary blood volume Increased alveolar uptake of inhaled drugs Inhaled anesthetics
Increased cardiac output, and increased plasma volume and total blood volume Increased volume of distribution
Increases in maternal aqueous and fatty tissue spaces (greatest at 10-30 weeks) and the increase in total body water Further increase in the volume of distribution
Relative decrease in serum albumin concentration and elevated levels of steroid hormones competing for protein binding sites Increased free drug fractions of protein-bound drugs Diazepam, phenytoin, sodium valproate (especially in the 3rd trimester)
Elevated levels of serum progesterone Increased cytochrome metabolism of some drugs Phenytoin, carbamazepine, sodium valproate
Elevated levels of serum estrogen Decreased cytochrome oxidase metabolism of some drugs Theophylline and caffeine
Increase renal blood flow and the consequent increase in glomerular filtration Increased renal excretion and creatinine clearance Lithium, Digoxin
Ampicillin (doubled)
The net effect of these changes lead to an expected decreased steady state drug concentration in pregnancy if a normal dose is administered, i.e. a higher dose will be needed to achieve therapeutic levels, although drug-specific exceptions will occur.
Although the changes in pharmacokinetics in the pregnant patient appear to be very important in theory, these changes are often not significant clinically. Notable exceptions are drugs that are exclusively eliminated via the renal route, such as lithium and digoxin. The increase in renal excretion leads to a significant decrease in serum concentrations, and, considering their narrow therapeutic range, may necessitate serum concentration monitoring. Also noteworthy are antiepileptics (carbamazepine, valproic acid and phenytoin) which experience a decrease in effective serum concentrations secondary to increased hepatic and renal elimination, increase in plasma volume, and decreased protein binding. 3, These drugs, however, are more the exception than the rule, because the changes mentioned above are often offset in most conditions.
Thus, very often it is the effects on the developing fetus that are taken into greater consideration in therapeutic decisions in pregnancy rather than maternal factors.
FETO-PLACENTAL PHARMACOKINETICS
Drugs that eventually reach the fetus are (almost) always administered to the mother. For a drug to exert its effects on the fetus, transplacental transport must take place. After maternal administration, drugs first pass through the placenta before reaching the fetal serum. From the fetal serum, drugs are then transferred transplacentally to the mother and are eventually excreted.
Raised areas on the basal surface of the placenta, termed as maternal lobes or cotyledons, are intimately related with several fetal cotyledons, allowing maternal circulation to be virtually superimposed onto the fetus. For materials to pass from mother to fetus, however, solutes must pass through the syncytiotrophoblast, either directly through its cytoplasm, or, less commonly, via a network of specific transporters. The transport of molecules from maternal to fetal circulation thus involves the passage between 3 functional compartments: maternal blood, the tropohoblastic cytoplasm, and finally fetal circulation (figure 2).
The great majority of substances depend on simple diffusion to pass through these compartments. The rate of transport between mother and fetus, then, is dictated by the molecular weight, degree of ionization, protein-binding and finally relative concentrations across these compartments. 2,3,4
Fig 2. Major pathways and interrelations of pharmacokinetics in maternal, placental and fetal units. Size of arrows indicates relative importance of effect. (Re-drawn from an original by Garland M. Pharmacology of drug transfer across the placenta. Obstet Gynecol Clin Nth Am. 1998 25(1) 21-42 )
Several key factors involved in drug transfer across the placenta are:
1. The physicochemical properties of drugs, i.e. lipid solubility, degree of ionization, molecular size and protein binding characteristics. Drugs that are highly lipid soluble, non-ionized, of low molecular weight (<200 daltons) and minimally protein-bound easily cross the placental barrier
2. The transfer of flow-limited drugs are affected by placental blood flow and maternal serum drug concentrations (greater maternal serum concentrations create a greater concentration gradient causing increased placental transport)
3. Compounds that alter blood flow also alter maternal drug disposition and consequently affect placental transfer
4. Placental metabolism (i.e. dealkylation, hydroxylation and demethylation) also influence drug transport through the placenta, although these effects are relatively minor compared to metabolism via the maternal and fetal liver
5. Fetal metabolism may also play a part, but these effects may change during pregnancy 5
.
Fetal pharmacokinetics also plays a role in determining the net effect of drugs on the fetus (i.e. teratogenicity):
1. Maternal blood flow through the placenta gradually increases during gestation (from 50mL/min at 10 weeks of pregnancy to a peak of 600mL/min at 38 weeks AOG), thereby increasing the fetal drug exposure as pregnancy progresses.
2. The protein binding capacity of fetal plasma is significantly lower than that of maternal circulation (fetal plasma albumin concentration may be 15% greater than maternal, but this is offset by the lower levels (37%) of alpha1-acid glycoprotein and the lower affinity for binding of fetal plasma proteins) leading to a greater free fraction for drugs that enter the fetal circulation (especially basic drugs such as propranolol and lidocaine and drugs with poor affinity to fetal proteins such as ampicillin and benzylpenicillin) and consequently, a greater risk for toxicity.
3. The fetal plasma and amniotic fluid are slightly more acidic than maternal blood, favoring the ionization and subsequent ion-trapping of basic drugs in the fetal compartment after transplacental passage. This apparent accumulation in the fetal plasma further predisposes to toxicity.
4. The fetal liver also expresses drug-metabolizing enzymes such as cytochrome oxidases, but the metabolizing capacity is much less than that of the mother. Drugs that pass through the placenta may thereby undergo first-pass metabolism through the fetal liver before reaching systemic circulation, though this effect is modulated by the ductus venosus shunt and may vary by 30-70%.
5. The fetal kidney is immature and glomerular filtration is markedly reduced. Glomerular filtration rate increases with gestational age, but peaks to only 2-4mL/min at term, primarily because the fetal kidney receives only 3% of cardiac output, compared to 25% in the adult. Cation secretion (e.g. cimetidine) is efficient, but the renal excretion of anionic drugs (e.g. penicillin) is very low.
6. Fetal urine enters amniotic fluid, which may be subsequently swallowed by the fetus, and renally excreted drugs and metabolites may subsequently be reabsorbed.2,3,
In general, drugs that exist as large, highly protein bound and/or ionized molecules in maternal plasma and are poorly absorbed into the maternal bloodstream rarely cross the placental membrane and are usually confined to the maternal circulation in therapeutic doses, thus exhibiting minimal effects to the fetus.
Because of decreased protein binding, ion-trapping and poor metabolism and excretion, drugs that do pass to the fetal circulation exhibit a greater potential for toxicity than they do for the mother.
PRINCIPLES OF TERATOGENESIS
By far the greatest concern for both patient and physician in drug therapy during pregnancy are the possible teratogenic effects of drugs on the fetus. Teratogens (from the Greek teratos meaning “monster”) refer to any agent that acts during the embryonic or fetal period and produces a permanent alteration in form or function. These alterations include birth defects, or visible deformities that are congenital in origin, but may occur as metabolic derangements that may be more subtle at birth.
Environmental factors (e.g. maternal conditions, infectious agents, mechanical problems, chemicals, drugs, radiation, hyperthermia, etc.) account for about 10% of all abnormal outcomes in pregnancy. Evaluation of the teratogenic effect of agents depends on the following criteria: 1) proven exposure to agent at critical times in prenatal development, 2) consistent epidemiologic evidence, 3) clearly characterized clinical effects (i.e. syndromes), 4) frequency of clinical syndromes reflecting actual frequency of exposure in the population and 5) the ability of the agent to cross the placenta or sufficiently alter maternal or fetal metabolism to cause significant effects. Other useful but non-essential criteria for evaluating teratogenicity are experimental animal models that mimic the human malformation at clinically comparable exposures and that the mechanisms of teratogenesis are understood and/or results are biologically plausible.1,3, , 7
The timing of exposure to a suspected teratogen plays a crucial role in its effect on fetal development (figure 3). Periods of susceptibility in embryogenesis are characterized by rapid cell division and differentiation.
Fig 3. Sequence of events in normal embryogenesis. (Figure taken from Human Pharmacology: Molecular to Clinical, 2nd ed.)
Fig 4. Outcomes associated with exposure at different stages of reproduction
During the preimplantation or the so called “all or none” period (<15 days from fertilization to implantation), the zygote undergoes rapid cleavage and organization into an outer and inner cell mass (blastocyst formation). Development during this stage can be considered “all or none”, that is, injurious stimuli are either sufficient enough to cause the death of the embryo, or compensation by the uninjured cells are enough to continue normal development (figure 4).
The embryonic period (from the 2nd to the 8th weeks AOG) is the most crucial stage in teratogenesis. Fetal susceptibility to teratogens is greatest at this stage, and is central to the pathogenesis of most structural malformations
The fetal period (from 9 weeks up to term) is characterized by the maturation of fetal organs important to functional development. The fetus remains vulnerable to insult, and exposure to teratogens may still result to defects in function and minor anomalies. An example is the pulmonary hypoplasia caused by any agent that causes a reduction in amniotic fluid volume from 20-25 weeks.
MECHANISMS OF TERATOGENESIS
Some proposed mechanisms of teratogenicity include:
1. Cell death beyond recuperative capacity of the embryo/fetus
2. Mitotic delay; increase in the length of the cell cycle
3. Retarded differentiation
4. Physical constraint and vascular insufficiency
5. Interference with histogenesis by cell depletion, necrosis, calcification, etc
6. Inhibited cell migration and cell communication 6
Other agents have more established physiologic and genetic mechanisms. For example, agents may disrupt the metabolism of folic acid. Folic acid plays an important role in the synthesis of DNA and RNA bases. Drugs that either prevent the absorption of folate or acts as antagonists (e.g. anti-seizure medications: valproic acid, phenobarbital, carbamazepine and phenytoin) predispose to a variety of congenital malformations, the most common of which are neural tube defects.4, 6
Other drugs exert their effects by the production of oxygen free radicals and other oxidative intermediates. Free radicals are often rendered innocuous by cytoplasmic epoxide hydroxylase. This enzyme system, however, is immature in the fetus, leading to the accumulation of these free radicals in fetal tissues, and subsequent carcinogenic and mutagenic effects. Specific examples include phenobarbital, phenytoin and carbamazepine, which are metabolized by hepatic microsomes into epozides and arene oxides.6
The maternal condition itself may play a role in fetal malformations, and provide a synergistic effect with the drug in question. Alcoholism in pregnant women, for instance, is often associated with concomitant use of other recreational drugs and smoking, as well as nutritional deficiencies. Fetuses born to alcoholic mothers, thus, exhibit greater tendencies for congenital defects than would otherwise be explained by exposure to alcohol alone. Likewise, epileptic mothers, even without therapy, carry a greater risk for congenital malformations.
Genetic factors of the fetus also contribute to the teratogenic mechanism of toxins. Previous mutations that alter the functions of certain enzymes, especially those crucial to the removal of toxic agents, may increase the susceptibility of a particular teratogen (e.g. risk of malformation after exposure to phenytoin is increased in fetuses with low activities of epoxide hydroxylase). This interplay of both environmental and genetic factors probably account for most anomalies that are “multifactorial” in origin.1,6,8
Other agents act by the direct alteration of key genetic sequences in embryogenesis. A key example is a group of genetic sequences that direct the future position of numerous structures in the body. These homeobox genes are arranged in a fixed order along the length of the chromosome. This position, in turn corresponds to a particular body region: the 3’ end corresponds to the caudal region, and the 5’ end directs the development of the caudad region. Agents that predispose to a particular homeobox gene (e.g. valproic acid exhibits a predilection to the 5’ end) thus preferentially cause malformations to the corresponding body region (caudally in the case of valproic acid). 4,6,8,9
Finally, paternal factors can also exert effects on malformations on the fetus. Agents that cause germline mutations and genetic maldevelopment of sperm cells can destine the fetus to become malformed even before implantation takes place. Also, drugs or agents taken by the paternal spouse can gain access to the developing fetus during sexual intercourse in pregnancy.4,6,7, 8, 9
The great majority of agents, however, have poorly understood mechanisms of teratogenesis. The difficulties in analyzing the mechanisms of teratogenicity include the following:
1. Normal development is an extremely complex process that even now is not completely understood.
2. Environmental toxicants include a wide range of chemical, physical and biological agents that initiate a wide variety of mechanisms, and exposure to specific toxicants are rarely encountered alone in the clinical setting.
3. Some toxicants may affect only a fraction of individuals in the population, while sparing others from their teratogenic effects.
4. A mechanistic understanding of developmental toxicity involves understanding at several levels of biologic organization 1,2,3,9
FDA PREGNANCY CATEGORIES
As a guide to physicians, the Food and Drug Administration utilizes a lettered classification system with regards to their safety for use in pregnancy. The FDA recommendations are based on the best available clinical evidence, and assigns lettered categories to drugs from “A”, or drugs that have been categorically demonstrated to have no teratogenic effects in humans, to “D” and “X”, or drugs that have been directly linked to congenital malformations in humans. The “X” classification is used for drugs that are absolutely contraindicated in pregnancy, while “D” is usually applied to drugs that are positively teratogenic, but for which no other useful alternatives are presently available.
Table II. Drug FDA categories
FDA Category Interpretation Examples
A Controlled studies in humans show no risk. Adequate, well-controlled studies in pregnant women have failed to demonstrate risk to the fetus. Multivitamins or prenatal supplements
B No evidence of risk in humans. Either animal findings show risk, but human findings do not; or, if no adequate human studies have been done, animal findings are negative. Penicillins
C Risk cannot be ruled out. Human studies are lacking, and animal studies are either positive for fetal risk, or lacking as well. However, potential benefits may justify the potential risk.
D Positive evidence of risk. Investigational or post-marketing data show risk to the fetus. Nevertheless, potential benefits may outweigh the potential risk. Carbamazepine, phenytoin
X Contraindicated in pregnancy. Studies in animals or hmans, investigational or post-marketing reports have shown fetal risk which clearly outweighs any possible benefit to the patient. Isotretinoin, Thalidomide, Diethylsilbestrol
The next table (Table 3) lists drugs that are proven human teratogens. Most drugs in this list are either Category D or X, but some are listed as Category C. When viewing this list, it is important to note that some medications may commonly cause malformations, while others rarely cause them, even when a positive relationship does exist. Also, because drugs are only used when a disease already exists, it is often hard to show whether the birth defects are caused by the agent itself and not the clinical condition. Careful clinical judgment is then necessary to weigh the possible risk and benefits from the use of a particular agent.
Table III. Human Teratogens 7,8,10
• ACE inhibitors (eg, captopril, enalapril) - D • Acetohydroxamic acid (AHA) - X
• Aminocaproic acid - D • Androgens (eg, Danazol) - X
• Angiotensin II receptor antagonists (eg, losartan, valsartan) - D • Antineoplastics (alkylating agents) - D
• Antineoplastics (antimetabolites) - X o 5-Fluorouracil
o Methotrexate o Methylaminopterin
o Cytarabine o Busulfan
o Chlorambucil o Azathioprine
o Cyclophosphamide o Mechlorethamine
o Cisplatin o Bleomycin
• Aminoglycosides (eg, gentamicin, streptomycin) - D • Aspirin - D
• Atenolol - D • Benzodiazepines - D and X
• Flurazepam (X) o Temazepam (X)
o Triazolam (X) • Bromides - D
• Carbamazepine - D • Colchicine – D
• Corticosteroids - C • Danazol - X
• Diethylstilbestrol - Not on market • Ergotamine - X
• Finasteride - X • Fluconazole - C
• Folic acid antagonists o Phenytoin - D
o Methotrexate – X • Lithium - D
• Methimazole - D • Methylene blue - C
• Mifepristone, RU-486 - D • Minoxidil - C
• Misoprostol - X • Mysoline - D
• Penicillamine - D • Phenobarbital or methylphenobarbital - D
• Potassium iodine and medications that effect iodine levels (diatrizoate) - D • Progestins - X (except megestrol and norethindrone - D)
• Raloxifene (Evista) - X • Retinoic acid, isotretinoin (Accutane), acitretin (Soriatane), etretinate, topical tazarotene - X
• Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) - X • Tamoxifen – D
• Tetracycline - D • Thalidomide - X
• Valproic acid - D • Warfarin - X
REPRESENTATIVE HUMAN DEVELOPMENTAL TOXICANTS
The deleterious effects of medications vary depending on the critical periods of development when exposed to said agents. Different organs have different critical periods, although the period from gestation day 15 to day 60 is critical for many organs. The brain and skeleton are always sensitive, from the beginning of the third week to the end of pregnancy and the neonatal period. The heart is most sensitive during the third and fourth weeks of gestation while the external genitalia are most sensitive during the eighth and ninth weeks.1,2,3,4,6,810
One must also consider that genetic mutations and medications may cause similar abnormalities and syndromes. Axial malformations in mice can result from mutations in certain HOX genes or exposure to retinoids in cases of treatment of dermatologic disorders in unsuspected pregnant women. Maternal ingestion of warfarin can result in defective bone mineralization, telebrachydactyly, and facial dysmorphism with nasal hypoplasia. Human X-linked dominant chondrodysplasia punctata (CDPX2), or Happle syndrome, is associated with mutations in the human emopamil-binding protein, a delta-delta-sterol isomerase involved in cholesterol biosynthesis. Happle syndrome is a genetic disease of bone and cartilage whose phenotype is quite similar to the dysmorphism caused by warfarin ingestion. 10
The following table (table 4) lists some representative human developmental and their associated clinical syndromes:
Table IV. Representative human teratogens.
AGENT USE ADVERSE EFFECTS
13-cis retinoic acid Tx of cystic acne Craniofacial, CVS and mental deficits
Aminopterin Folate antagonist Abortion, CNS, craniofacial, growth defects
ACE inhibitors Antihypertensive Skull defects and kidney hemorrhage
Cigarette smoke Stimulant Growth retardation, facial defect
DES Synthetic estrogen Reproductive tract defects and vaginal cancer
Diphenylhydantoin Anticonvulsant Craniofacial, mental defects, fetal loss, growth retardation
Etretinate Psoriasis Limb, ear, cardiac, thymic defects
Lead Environmental contaminant Abortion, growth retardation, CNS defects
Penicillamine Chelator Connective tissue defects
Polychlorinated biphenyls Environmental contaminant Growth retardation, hyperpigmentation, neurobehavioral deficits
Thalidomide Antiemetic Reduction defects in limb and ears
Valproic acid Anticonvulsant Neural tube closure defects
Lithium Bipolar disorders Cardiac defects
GUIDELINES FOR PRECRIBING AND COUNSELING IN PREGNANCY
As a rule of thumb, drug intake in the pregnant patient is generally avoided, especially in the first trimester, when the fetus exhibits the greatest risk for congenital malformations. It is important to consider, then, whether non-pharmacologic treatments are available and equally as effective for the condition (i.e. pain management).
When drug therapy is absolutely necessary, preference must be given to drugs that have a proven safety profile (Category A and B), as opposed to newer agents for which data is lacking or equivocal. Monotherapy is preferred and in instances where drug combinations is the treatment of choice, agents must be introduced one at a time. Exposure of the fetus to the agent must be kept to a minimum: lowest possible dose and shortest possible effective treatment duration. When other routes are available, systemic administration should be avoided (inhalational and topical versus oral and intravenous). And most importantly, the benefits of the use of any drug should clearly outweigh any risks posed to both the fetus and mother.
But because most exposure to drugs in pregnant women occurs even before the pregnancy is known, the physician will often find himself in the position of counseling the patient of the teratogenic risk after exposure. Obstetricians, general practitioners, pediatricians and geneticists as well as other health professionals such as pharmacists, midwives and nurses are frequently asked by concerned pregnant women about the risk of drug intake, other medicinal products and exposure to other substances for the unborn child. In providing such counsel to patients, the physician must always make sure that he has the most current, best evidence about the drug in question. It must always be emphasized that a baseline 3% risk for congenital malformations exists for all pregnancies even without any known exposure to any agent. 1,2,3,7,9,10
It should also be emphasized that except for some important exceptions, most commonly prescribed and over-the-counter medications are relatively safe in pregnancy, and even for those with proven teratogenic potential, the issue of relative risk (an increase in probability versus an all-or-none phenomenon) should always be explained. Also, equal emphasis should be put on the possible risks for malformations associated with the condition for which the drug therapy was indicated (e.g. epileptics have a baseline 5% risk for malformations as opposed to 3% in uncomplicated pregnancies).2,3,7 ,11,12 And lastly, the dilemma of weighing risk versus benefit should also be touched, because some conditions (e.g. fever) carry a greater risk of producing malformations than any theoretical risk associated with the drug therapy in question (e.g. paracetamol).
Table 5 lists some common conditions in pregnancy and the important agents to consider for each:
Table V. Common conditions in pregnancy and associated drugs and interventions. Letters in parentheses indicate FDA categories. , , , ,11,12
CONDITION DRUGS/INTERVENTION
Bacterial Infections Penicillins (B) - preferred agents and probably the safest antimicrobial in pregnancy
Eryhtromycin (B) - for penicillin allergic patients
Use with caution: Cephalosporins (B), Chloramphenicol (B), Metronidazole (C)
Tuberculosis Rifampicin, Isoniazid, Ethambutol - have shown no increased risk for congenital malformation; use with caution
Colds, Coughs Always aim for symptomatic relief with fluids and rest.
Antihistamines with relative safety: Chlorpheniramine (B), Triprolidine (C), and Diphenhydramine (C) (more rapid onset of rebound congestion in pregnancy; use for no longer than 2-4 days)
Pseudoepehdrine (C) - generally considered safe in pregnancy
Cough Suppressants: Guaifenesin (C) or Dextromethorphan (C) (avoid preparations with alcohol and iodine)
Nausea and Vomiting Should always be treated conservatively when effective (rest, small, frequent meals, and acupressure)
Pyridoxine - Vit B6 (A); Pyridoxine in combination with Doxylamine (B); or Emetrol - first-line
Use with caution: Promethazine (C), Metaclopramide (C)
Pain Relief Paracetamol (B) - pain reliever and antipyretic of choice
Ibuprofen (B), Naproxen (B), Aspirin (D) - use with caution
For Severe Pain: Narcotics (Codeine, Demerol, Morphine) may be considered, but addictive potential for both mother and fetus should be recognized (risk for respiratory depression)
Local Anesthetics (Xylocaine) may be used safely, but combinations with Epinephrine are generally avoided
Diarrhea Kaolin and Pectin (B) - anti-diarrheal of choice, not absorbed systemically
Loperamide (B) - most probably safe
Asthma Treatment is the same as with the non-pregnant patient
Theophylline (B), Salbutamol via aerosol (B), Steroids (B) and Leukotrienes (B) are all safe in pregnancy
Epilepsy Always emphasize the increase in risk for malformations (5% in epileptics vs 3% in others) with or without therapy. Avoid drug combinations whenever possible and use therapeutic drug monitoring when necessary
Therapy is ideally maximized before pregnancy and one may consider slowly withdrawing therapy if patient has been seizure free for 2-3 years.
There is absolutely no justification for shifting from a drug with teratogenic risk (e.g. carbamazepine) to one about which even less is known.
Phenobarbital (D) - no increased frequency in minor or major birth defects
Carbamazepine (D) - traditionally the drug of choice in pregnancy, but present data on its teratogenic potential is unclear
Phenytoin (D) - teratogenic potential influenced by genetics (epoxide hydroxylase levels)
Valproic Acid (D) - 1-2% risk of spina bifida, also associated with minor cranio-facial abnormalities
Hypertension Methyldopa (C) - most widely used, unparalleled safety record in pregnancy
Beta-blockers (except Atenolol (D)) - not teratogenic, but may cause growth restriction
Hydralazine - no adverse fetal effects, used for the 2nd-3rd trimesters
Sodium Nitroprusside - readily crosses placenta and in theory, may cause accumulation of cyanide in the fetus; no adequate clinical data
Hyperthyroidism Propylthiouracil - used more often than carbamazepine. Is less lipid-soluble and more protein-bound, thus transported less well to the fetus and breastmilk.
IMMUNIZATION IN PREGNANCY
Vaccination in pregnancy, similar to drug use, is a special scenario in that both the effects on the mother and fetus must be considered together in its administration. Vaccines that generate an immune response in the maternal serum may also become protective to the fetus when maternal antibodies pass through the placenta. This phenomenon, however, may be detrimental when a sufficient amount of maternal antibodies are transmitted as to interfere with the development of natural antibodies in the fetus. Maternal reactions to vaccination, such as fever and hypersensitivity may also adversely affect fetal support and development.
These risks, however, are primarily theoretical. At present, there is no available clinical evidence that vaccination either with inactivated bacteria or viruses or toxoids carries any risk to the fetus. Live vaccines, however, carry a greater theoretical risk of causing fetal disease and are generally avoided in pregnancy. Altogether, the benefits of vaccination in pregnancy generally outweigh the risks of fetal disease, especially when the risk of developing the disease is relatively high (post-exposure prophylaxis) and when the vaccine is unlikely to cause any harm.
Live-viruses (measles, mumps, rubella) are generally contraindicated in pregnancy because of the probable risk of vertical transmission. When a live-virus vaccine is inadvertently given to a pregnant woman, or when a vaccinated woman subsequently becomes pregnant within 4 weeks of the vaccine, counseling about the possible effects on the fetus is indicated. Regardless of whether a live attenuated or killed vaccine is administered, risk versus benefit assessment is still the rule of thumb.1,13,14
Table 6 summarizes the relative safety of common vaccines in pregnancy:
Table VI. Vaccination in pregnancy
VACCINE SAFE IN PREGNANCY? COMMENTS
Tetanus-Diphtheria (Td) Yes Pregnant patients should receive Tetanus toxoid as a booster if there has been no prior administration within the last 10 years. Previously unvaccinated patients should receive a complete series of 3 vaccinations. The preferred schedule is after the second trimester, with each dose given 4 weeks apart. This is the only vaccine routinely indicated for all susceptible pregnant patients
Hepatitis A Not established Because vaccine is a killed vaccine, theoretical risk is low, but safety in pregnancy has not been determined. May be indicated for high risk patients.
Hepatitis B Yes Pregnancy is not a contraindication, and patients at high risk (e.g. >1 sex partner in the last 6 months, concurrent STD, IV drug use, or an HBsAg-positive partner) should be vaccinated. Current vaccines are noninfectious and no data has shown detrimental effects to the fetus.
Human Papillomavirus (HPV) Not recommended Vaccine has been related to some adverse outcomes in pregnancy, but data is limited.
Influenza (Inactivated) Yes Recommended during influenza season, as pregnant patients who become infected are at increased risk for severe complications. No adverse fetal outcomes reported.
Measles, Mumps and Rubella No Risk to fetus of live vaccines cannot be excluded and should not be administered in pregnant patients. Vaccinated women should be advised not to become pregnant for 28 days after administration.
All Rubella containing vaccines are contraindicated because of the risk of developing Congenital rubella syndrome (CRS) in the fetus. But to date, no documented cases of post-vaccination CRS have been reported.
Pneumococcal Not established Safety in pregnancy has not been evaluated, although no adverse effects have been reported.
Polio (IPV) Yes, but avoided No adverse effects reported, but generally avoided due to theoretical risks. High risk patients, however, may be considered for vaccination
Tetanus-Diphtheria- Pertussis (DPT) Yes Pregnancy is not a contraindication to DPT. Maternal Pertussis antibodies may be protective to the infant in early life, and so many practitioners prefer this vaccine over Tetanus toxoid alone.
Varicella No Because effects on the fetus are unknown, Varicella should be avoided entirely in pregnancy. But because of its lower virulence, the risk of transmission (if any) should even be lower than the wild type. VZIG should be strongly considered, however, for pregnant patients exposed to varicella.
BCG Not recommended No harmful effects reported
Typhoid Not established No available data
Rabies Yes, as post-exposure prophylaxis Because the consequences of rabies far outweigh the risk of vaccination, pregnancy is not a contraindication for post-exposure prophylaxis
I. Introduction
II. Pharmacokinetics in Pregnancy
III. Feto-placental Pharmacokinetics
IV. Principles of Teratogenesis
V. Mechanisms of Teratogenesis
VI. FDA Pregnancy Categories
VII. Representative Human Developmental Toxicants
VIII. Guidelines For Prescribing And Counseling In Pregnancy
IX. Immunization during Pregnancy
X. References
INTRODUCTION
Pharmacotherapeutic decisions in pregnancy take into consideration numerous factors. The ideal drug for treatment in pregnancy is efficacious for the maternal indication, is minimally transported through the placenta and, in the event of transplacental passage, exerts minimal effect on the fetus. Often neglected but of similar importance are drug characteristics that influence tolerability and adherence to dosage and dosing schedule, more so when the drug therapy in question exacerbates conditions common to pregnancy such as emesis, gastrointestinal changes either in the form of diarrhea or constipation, glucose intolerance and hypertension.
PHARMACOKINETICS IN PREGNANCY
Fig 1. Physiologic changes in pregnancy
Physiologic changes in pregnancy significantly affect pharmacokinetics in the pregnant patient (figure 1). These changes include:
1. Cardiovascular changes- increased cardiac output (40%) and increased plasma volume (50%) and total blood volume (40%)
2. Gastrointestinal changes - decreased gut motility, increased gastric pH and nausea and vomiting
3. Respiratory changes - hyperventilation, increased tidal volume, and increased pulmonary blood volume
4. Volume changes -dramatic increases in maternal aqueous and fatty tissue spaces (greatest at 10-30 weeks) and the increase in total body water (mostly extracellular: 40% maternal, 60% feto-placental)
5. Metabolic changes- relative decrease in serum albumin concentration (25%) and elevated levels of steroid hormones competing for protein binding sites, elevated levels of serum progesterone, elevated levels of serum estrogen
6. Renal changes - increase renal blood flow (50%) and the consequent increase in glomerular filtration (50%) 1
Table I. Physiologic changes in pregnancy and their impact on pharmacokinetics of selected agents , ,
PHYSIOLOGIC CHANGES IN PREGNANCY EFFECTS ON PHARMACOKINETICS KEY EXAMPLES
Decreased gut motility, increased gastric pH and nausea and vomiting Variable bioavailability of oral preparations Most oral preparations
Hyperventilation, increased tidal volume, and increased pulmonary blood volume Increased alveolar uptake of inhaled drugs Inhaled anesthetics
Increased cardiac output, and increased plasma volume and total blood volume Increased volume of distribution
Increases in maternal aqueous and fatty tissue spaces (greatest at 10-30 weeks) and the increase in total body water Further increase in the volume of distribution
Relative decrease in serum albumin concentration and elevated levels of steroid hormones competing for protein binding sites Increased free drug fractions of protein-bound drugs Diazepam, phenytoin, sodium valproate (especially in the 3rd trimester)
Elevated levels of serum progesterone Increased cytochrome metabolism of some drugs Phenytoin, carbamazepine, sodium valproate
Elevated levels of serum estrogen Decreased cytochrome oxidase metabolism of some drugs Theophylline and caffeine
Increase renal blood flow and the consequent increase in glomerular filtration Increased renal excretion and creatinine clearance Lithium, Digoxin
Ampicillin (doubled)
The net effect of these changes lead to an expected decreased steady state drug concentration in pregnancy if a normal dose is administered, i.e. a higher dose will be needed to achieve therapeutic levels, although drug-specific exceptions will occur.
Although the changes in pharmacokinetics in the pregnant patient appear to be very important in theory, these changes are often not significant clinically. Notable exceptions are drugs that are exclusively eliminated via the renal route, such as lithium and digoxin. The increase in renal excretion leads to a significant decrease in serum concentrations, and, considering their narrow therapeutic range, may necessitate serum concentration monitoring. Also noteworthy are antiepileptics (carbamazepine, valproic acid and phenytoin) which experience a decrease in effective serum concentrations secondary to increased hepatic and renal elimination, increase in plasma volume, and decreased protein binding. 3, These drugs, however, are more the exception than the rule, because the changes mentioned above are often offset in most conditions.
Thus, very often it is the effects on the developing fetus that are taken into greater consideration in therapeutic decisions in pregnancy rather than maternal factors.
FETO-PLACENTAL PHARMACOKINETICS
Drugs that eventually reach the fetus are (almost) always administered to the mother. For a drug to exert its effects on the fetus, transplacental transport must take place. After maternal administration, drugs first pass through the placenta before reaching the fetal serum. From the fetal serum, drugs are then transferred transplacentally to the mother and are eventually excreted.
Raised areas on the basal surface of the placenta, termed as maternal lobes or cotyledons, are intimately related with several fetal cotyledons, allowing maternal circulation to be virtually superimposed onto the fetus. For materials to pass from mother to fetus, however, solutes must pass through the syncytiotrophoblast, either directly through its cytoplasm, or, less commonly, via a network of specific transporters. The transport of molecules from maternal to fetal circulation thus involves the passage between 3 functional compartments: maternal blood, the tropohoblastic cytoplasm, and finally fetal circulation (figure 2).
The great majority of substances depend on simple diffusion to pass through these compartments. The rate of transport between mother and fetus, then, is dictated by the molecular weight, degree of ionization, protein-binding and finally relative concentrations across these compartments. 2,3,4
Fig 2. Major pathways and interrelations of pharmacokinetics in maternal, placental and fetal units. Size of arrows indicates relative importance of effect. (Re-drawn from an original by Garland M. Pharmacology of drug transfer across the placenta. Obstet Gynecol Clin Nth Am. 1998 25(1) 21-42 )
Several key factors involved in drug transfer across the placenta are:
1. The physicochemical properties of drugs, i.e. lipid solubility, degree of ionization, molecular size and protein binding characteristics. Drugs that are highly lipid soluble, non-ionized, of low molecular weight (<200 daltons) and minimally protein-bound easily cross the placental barrier
2. The transfer of flow-limited drugs are affected by placental blood flow and maternal serum drug concentrations (greater maternal serum concentrations create a greater concentration gradient causing increased placental transport)
3. Compounds that alter blood flow also alter maternal drug disposition and consequently affect placental transfer
4. Placental metabolism (i.e. dealkylation, hydroxylation and demethylation) also influence drug transport through the placenta, although these effects are relatively minor compared to metabolism via the maternal and fetal liver
5. Fetal metabolism may also play a part, but these effects may change during pregnancy 5
.
Fetal pharmacokinetics also plays a role in determining the net effect of drugs on the fetus (i.e. teratogenicity):
1. Maternal blood flow through the placenta gradually increases during gestation (from 50mL/min at 10 weeks of pregnancy to a peak of 600mL/min at 38 weeks AOG), thereby increasing the fetal drug exposure as pregnancy progresses.
2. The protein binding capacity of fetal plasma is significantly lower than that of maternal circulation (fetal plasma albumin concentration may be 15% greater than maternal, but this is offset by the lower levels (37%) of alpha1-acid glycoprotein and the lower affinity for binding of fetal plasma proteins) leading to a greater free fraction for drugs that enter the fetal circulation (especially basic drugs such as propranolol and lidocaine and drugs with poor affinity to fetal proteins such as ampicillin and benzylpenicillin) and consequently, a greater risk for toxicity.
3. The fetal plasma and amniotic fluid are slightly more acidic than maternal blood, favoring the ionization and subsequent ion-trapping of basic drugs in the fetal compartment after transplacental passage. This apparent accumulation in the fetal plasma further predisposes to toxicity.
4. The fetal liver also expresses drug-metabolizing enzymes such as cytochrome oxidases, but the metabolizing capacity is much less than that of the mother. Drugs that pass through the placenta may thereby undergo first-pass metabolism through the fetal liver before reaching systemic circulation, though this effect is modulated by the ductus venosus shunt and may vary by 30-70%.
5. The fetal kidney is immature and glomerular filtration is markedly reduced. Glomerular filtration rate increases with gestational age, but peaks to only 2-4mL/min at term, primarily because the fetal kidney receives only 3% of cardiac output, compared to 25% in the adult. Cation secretion (e.g. cimetidine) is efficient, but the renal excretion of anionic drugs (e.g. penicillin) is very low.
6. Fetal urine enters amniotic fluid, which may be subsequently swallowed by the fetus, and renally excreted drugs and metabolites may subsequently be reabsorbed.2,3,
In general, drugs that exist as large, highly protein bound and/or ionized molecules in maternal plasma and are poorly absorbed into the maternal bloodstream rarely cross the placental membrane and are usually confined to the maternal circulation in therapeutic doses, thus exhibiting minimal effects to the fetus.
Because of decreased protein binding, ion-trapping and poor metabolism and excretion, drugs that do pass to the fetal circulation exhibit a greater potential for toxicity than they do for the mother.
PRINCIPLES OF TERATOGENESIS
By far the greatest concern for both patient and physician in drug therapy during pregnancy are the possible teratogenic effects of drugs on the fetus. Teratogens (from the Greek teratos meaning “monster”) refer to any agent that acts during the embryonic or fetal period and produces a permanent alteration in form or function. These alterations include birth defects, or visible deformities that are congenital in origin, but may occur as metabolic derangements that may be more subtle at birth.
Environmental factors (e.g. maternal conditions, infectious agents, mechanical problems, chemicals, drugs, radiation, hyperthermia, etc.) account for about 10% of all abnormal outcomes in pregnancy. Evaluation of the teratogenic effect of agents depends on the following criteria: 1) proven exposure to agent at critical times in prenatal development, 2) consistent epidemiologic evidence, 3) clearly characterized clinical effects (i.e. syndromes), 4) frequency of clinical syndromes reflecting actual frequency of exposure in the population and 5) the ability of the agent to cross the placenta or sufficiently alter maternal or fetal metabolism to cause significant effects. Other useful but non-essential criteria for evaluating teratogenicity are experimental animal models that mimic the human malformation at clinically comparable exposures and that the mechanisms of teratogenesis are understood and/or results are biologically plausible.1,3, , 7
The timing of exposure to a suspected teratogen plays a crucial role in its effect on fetal development (figure 3). Periods of susceptibility in embryogenesis are characterized by rapid cell division and differentiation.
Fig 3. Sequence of events in normal embryogenesis. (Figure taken from Human Pharmacology: Molecular to Clinical, 2nd ed.)
Fig 4. Outcomes associated with exposure at different stages of reproduction
During the preimplantation or the so called “all or none” period (<15 days from fertilization to implantation), the zygote undergoes rapid cleavage and organization into an outer and inner cell mass (blastocyst formation). Development during this stage can be considered “all or none”, that is, injurious stimuli are either sufficient enough to cause the death of the embryo, or compensation by the uninjured cells are enough to continue normal development (figure 4).
The embryonic period (from the 2nd to the 8th weeks AOG) is the most crucial stage in teratogenesis. Fetal susceptibility to teratogens is greatest at this stage, and is central to the pathogenesis of most structural malformations
The fetal period (from 9 weeks up to term) is characterized by the maturation of fetal organs important to functional development. The fetus remains vulnerable to insult, and exposure to teratogens may still result to defects in function and minor anomalies. An example is the pulmonary hypoplasia caused by any agent that causes a reduction in amniotic fluid volume from 20-25 weeks.
MECHANISMS OF TERATOGENESIS
Some proposed mechanisms of teratogenicity include:
1. Cell death beyond recuperative capacity of the embryo/fetus
2. Mitotic delay; increase in the length of the cell cycle
3. Retarded differentiation
4. Physical constraint and vascular insufficiency
5. Interference with histogenesis by cell depletion, necrosis, calcification, etc
6. Inhibited cell migration and cell communication 6
Other agents have more established physiologic and genetic mechanisms. For example, agents may disrupt the metabolism of folic acid. Folic acid plays an important role in the synthesis of DNA and RNA bases. Drugs that either prevent the absorption of folate or acts as antagonists (e.g. anti-seizure medications: valproic acid, phenobarbital, carbamazepine and phenytoin) predispose to a variety of congenital malformations, the most common of which are neural tube defects.4, 6
Other drugs exert their effects by the production of oxygen free radicals and other oxidative intermediates. Free radicals are often rendered innocuous by cytoplasmic epoxide hydroxylase. This enzyme system, however, is immature in the fetus, leading to the accumulation of these free radicals in fetal tissues, and subsequent carcinogenic and mutagenic effects. Specific examples include phenobarbital, phenytoin and carbamazepine, which are metabolized by hepatic microsomes into epozides and arene oxides.6
The maternal condition itself may play a role in fetal malformations, and provide a synergistic effect with the drug in question. Alcoholism in pregnant women, for instance, is often associated with concomitant use of other recreational drugs and smoking, as well as nutritional deficiencies. Fetuses born to alcoholic mothers, thus, exhibit greater tendencies for congenital defects than would otherwise be explained by exposure to alcohol alone. Likewise, epileptic mothers, even without therapy, carry a greater risk for congenital malformations.
Genetic factors of the fetus also contribute to the teratogenic mechanism of toxins. Previous mutations that alter the functions of certain enzymes, especially those crucial to the removal of toxic agents, may increase the susceptibility of a particular teratogen (e.g. risk of malformation after exposure to phenytoin is increased in fetuses with low activities of epoxide hydroxylase). This interplay of both environmental and genetic factors probably account for most anomalies that are “multifactorial” in origin.1,6,8
Other agents act by the direct alteration of key genetic sequences in embryogenesis. A key example is a group of genetic sequences that direct the future position of numerous structures in the body. These homeobox genes are arranged in a fixed order along the length of the chromosome. This position, in turn corresponds to a particular body region: the 3’ end corresponds to the caudal region, and the 5’ end directs the development of the caudad region. Agents that predispose to a particular homeobox gene (e.g. valproic acid exhibits a predilection to the 5’ end) thus preferentially cause malformations to the corresponding body region (caudally in the case of valproic acid). 4,6,8,9
Finally, paternal factors can also exert effects on malformations on the fetus. Agents that cause germline mutations and genetic maldevelopment of sperm cells can destine the fetus to become malformed even before implantation takes place. Also, drugs or agents taken by the paternal spouse can gain access to the developing fetus during sexual intercourse in pregnancy.4,6,7, 8, 9
The great majority of agents, however, have poorly understood mechanisms of teratogenesis. The difficulties in analyzing the mechanisms of teratogenicity include the following:
1. Normal development is an extremely complex process that even now is not completely understood.
2. Environmental toxicants include a wide range of chemical, physical and biological agents that initiate a wide variety of mechanisms, and exposure to specific toxicants are rarely encountered alone in the clinical setting.
3. Some toxicants may affect only a fraction of individuals in the population, while sparing others from their teratogenic effects.
4. A mechanistic understanding of developmental toxicity involves understanding at several levels of biologic organization 1,2,3,9
FDA PREGNANCY CATEGORIES
As a guide to physicians, the Food and Drug Administration utilizes a lettered classification system with regards to their safety for use in pregnancy. The FDA recommendations are based on the best available clinical evidence, and assigns lettered categories to drugs from “A”, or drugs that have been categorically demonstrated to have no teratogenic effects in humans, to “D” and “X”, or drugs that have been directly linked to congenital malformations in humans. The “X” classification is used for drugs that are absolutely contraindicated in pregnancy, while “D” is usually applied to drugs that are positively teratogenic, but for which no other useful alternatives are presently available.
Table II. Drug FDA categories
FDA Category Interpretation Examples
A Controlled studies in humans show no risk. Adequate, well-controlled studies in pregnant women have failed to demonstrate risk to the fetus. Multivitamins or prenatal supplements
B No evidence of risk in humans. Either animal findings show risk, but human findings do not; or, if no adequate human studies have been done, animal findings are negative. Penicillins
C Risk cannot be ruled out. Human studies are lacking, and animal studies are either positive for fetal risk, or lacking as well. However, potential benefits may justify the potential risk.
D Positive evidence of risk. Investigational or post-marketing data show risk to the fetus. Nevertheless, potential benefits may outweigh the potential risk. Carbamazepine, phenytoin
X Contraindicated in pregnancy. Studies in animals or hmans, investigational or post-marketing reports have shown fetal risk which clearly outweighs any possible benefit to the patient. Isotretinoin, Thalidomide, Diethylsilbestrol
The next table (Table 3) lists drugs that are proven human teratogens. Most drugs in this list are either Category D or X, but some are listed as Category C. When viewing this list, it is important to note that some medications may commonly cause malformations, while others rarely cause them, even when a positive relationship does exist. Also, because drugs are only used when a disease already exists, it is often hard to show whether the birth defects are caused by the agent itself and not the clinical condition. Careful clinical judgment is then necessary to weigh the possible risk and benefits from the use of a particular agent.
Table III. Human Teratogens 7,8,10
• ACE inhibitors (eg, captopril, enalapril) - D • Acetohydroxamic acid (AHA) - X
• Aminocaproic acid - D • Androgens (eg, Danazol) - X
• Angiotensin II receptor antagonists (eg, losartan, valsartan) - D • Antineoplastics (alkylating agents) - D
• Antineoplastics (antimetabolites) - X o 5-Fluorouracil
o Methotrexate o Methylaminopterin
o Cytarabine o Busulfan
o Chlorambucil o Azathioprine
o Cyclophosphamide o Mechlorethamine
o Cisplatin o Bleomycin
• Aminoglycosides (eg, gentamicin, streptomycin) - D • Aspirin - D
• Atenolol - D • Benzodiazepines - D and X
• Flurazepam (X) o Temazepam (X)
o Triazolam (X) • Bromides - D
• Carbamazepine - D • Colchicine – D
• Corticosteroids - C • Danazol - X
• Diethylstilbestrol - Not on market • Ergotamine - X
• Finasteride - X • Fluconazole - C
• Folic acid antagonists o Phenytoin - D
o Methotrexate – X • Lithium - D
• Methimazole - D • Methylene blue - C
• Mifepristone, RU-486 - D • Minoxidil - C
• Misoprostol - X • Mysoline - D
• Penicillamine - D • Phenobarbital or methylphenobarbital - D
• Potassium iodine and medications that effect iodine levels (diatrizoate) - D • Progestins - X (except megestrol and norethindrone - D)
• Raloxifene (Evista) - X • Retinoic acid, isotretinoin (Accutane), acitretin (Soriatane), etretinate, topical tazarotene - X
• Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) - X • Tamoxifen – D
• Tetracycline - D • Thalidomide - X
• Valproic acid - D • Warfarin - X
REPRESENTATIVE HUMAN DEVELOPMENTAL TOXICANTS
The deleterious effects of medications vary depending on the critical periods of development when exposed to said agents. Different organs have different critical periods, although the period from gestation day 15 to day 60 is critical for many organs. The brain and skeleton are always sensitive, from the beginning of the third week to the end of pregnancy and the neonatal period. The heart is most sensitive during the third and fourth weeks of gestation while the external genitalia are most sensitive during the eighth and ninth weeks.1,2,3,4,6,810
One must also consider that genetic mutations and medications may cause similar abnormalities and syndromes. Axial malformations in mice can result from mutations in certain HOX genes or exposure to retinoids in cases of treatment of dermatologic disorders in unsuspected pregnant women. Maternal ingestion of warfarin can result in defective bone mineralization, telebrachydactyly, and facial dysmorphism with nasal hypoplasia. Human X-linked dominant chondrodysplasia punctata (CDPX2), or Happle syndrome, is associated with mutations in the human emopamil-binding protein, a delta-delta-sterol isomerase involved in cholesterol biosynthesis. Happle syndrome is a genetic disease of bone and cartilage whose phenotype is quite similar to the dysmorphism caused by warfarin ingestion. 10
The following table (table 4) lists some representative human developmental and their associated clinical syndromes:
Table IV. Representative human teratogens.
AGENT USE ADVERSE EFFECTS
13-cis retinoic acid Tx of cystic acne Craniofacial, CVS and mental deficits
Aminopterin Folate antagonist Abortion, CNS, craniofacial, growth defects
ACE inhibitors Antihypertensive Skull defects and kidney hemorrhage
Cigarette smoke Stimulant Growth retardation, facial defect
DES Synthetic estrogen Reproductive tract defects and vaginal cancer
Diphenylhydantoin Anticonvulsant Craniofacial, mental defects, fetal loss, growth retardation
Etretinate Psoriasis Limb, ear, cardiac, thymic defects
Lead Environmental contaminant Abortion, growth retardation, CNS defects
Penicillamine Chelator Connective tissue defects
Polychlorinated biphenyls Environmental contaminant Growth retardation, hyperpigmentation, neurobehavioral deficits
Thalidomide Antiemetic Reduction defects in limb and ears
Valproic acid Anticonvulsant Neural tube closure defects
Lithium Bipolar disorders Cardiac defects
GUIDELINES FOR PRECRIBING AND COUNSELING IN PREGNANCY
As a rule of thumb, drug intake in the pregnant patient is generally avoided, especially in the first trimester, when the fetus exhibits the greatest risk for congenital malformations. It is important to consider, then, whether non-pharmacologic treatments are available and equally as effective for the condition (i.e. pain management).
When drug therapy is absolutely necessary, preference must be given to drugs that have a proven safety profile (Category A and B), as opposed to newer agents for which data is lacking or equivocal. Monotherapy is preferred and in instances where drug combinations is the treatment of choice, agents must be introduced one at a time. Exposure of the fetus to the agent must be kept to a minimum: lowest possible dose and shortest possible effective treatment duration. When other routes are available, systemic administration should be avoided (inhalational and topical versus oral and intravenous). And most importantly, the benefits of the use of any drug should clearly outweigh any risks posed to both the fetus and mother.
But because most exposure to drugs in pregnant women occurs even before the pregnancy is known, the physician will often find himself in the position of counseling the patient of the teratogenic risk after exposure. Obstetricians, general practitioners, pediatricians and geneticists as well as other health professionals such as pharmacists, midwives and nurses are frequently asked by concerned pregnant women about the risk of drug intake, other medicinal products and exposure to other substances for the unborn child. In providing such counsel to patients, the physician must always make sure that he has the most current, best evidence about the drug in question. It must always be emphasized that a baseline 3% risk for congenital malformations exists for all pregnancies even without any known exposure to any agent. 1,2,3,7,9,10
It should also be emphasized that except for some important exceptions, most commonly prescribed and over-the-counter medications are relatively safe in pregnancy, and even for those with proven teratogenic potential, the issue of relative risk (an increase in probability versus an all-or-none phenomenon) should always be explained. Also, equal emphasis should be put on the possible risks for malformations associated with the condition for which the drug therapy was indicated (e.g. epileptics have a baseline 5% risk for malformations as opposed to 3% in uncomplicated pregnancies).2,3,7 ,11,12 And lastly, the dilemma of weighing risk versus benefit should also be touched, because some conditions (e.g. fever) carry a greater risk of producing malformations than any theoretical risk associated with the drug therapy in question (e.g. paracetamol).
Table 5 lists some common conditions in pregnancy and the important agents to consider for each:
Table V. Common conditions in pregnancy and associated drugs and interventions. Letters in parentheses indicate FDA categories. , , , ,11,12
CONDITION DRUGS/INTERVENTION
Bacterial Infections Penicillins (B) - preferred agents and probably the safest antimicrobial in pregnancy
Eryhtromycin (B) - for penicillin allergic patients
Use with caution: Cephalosporins (B), Chloramphenicol (B), Metronidazole (C)
Tuberculosis Rifampicin, Isoniazid, Ethambutol - have shown no increased risk for congenital malformation; use with caution
Colds, Coughs Always aim for symptomatic relief with fluids and rest.
Antihistamines with relative safety: Chlorpheniramine (B), Triprolidine (C), and Diphenhydramine (C) (more rapid onset of rebound congestion in pregnancy; use for no longer than 2-4 days)
Pseudoepehdrine (C) - generally considered safe in pregnancy
Cough Suppressants: Guaifenesin (C) or Dextromethorphan (C) (avoid preparations with alcohol and iodine)
Nausea and Vomiting Should always be treated conservatively when effective (rest, small, frequent meals, and acupressure)
Pyridoxine - Vit B6 (A); Pyridoxine in combination with Doxylamine (B); or Emetrol - first-line
Use with caution: Promethazine (C), Metaclopramide (C)
Pain Relief Paracetamol (B) - pain reliever and antipyretic of choice
Ibuprofen (B), Naproxen (B), Aspirin (D) - use with caution
For Severe Pain: Narcotics (Codeine, Demerol, Morphine) may be considered, but addictive potential for both mother and fetus should be recognized (risk for respiratory depression)
Local Anesthetics (Xylocaine) may be used safely, but combinations with Epinephrine are generally avoided
Diarrhea Kaolin and Pectin (B) - anti-diarrheal of choice, not absorbed systemically
Loperamide (B) - most probably safe
Asthma Treatment is the same as with the non-pregnant patient
Theophylline (B), Salbutamol via aerosol (B), Steroids (B) and Leukotrienes (B) are all safe in pregnancy
Epilepsy Always emphasize the increase in risk for malformations (5% in epileptics vs 3% in others) with or without therapy. Avoid drug combinations whenever possible and use therapeutic drug monitoring when necessary
Therapy is ideally maximized before pregnancy and one may consider slowly withdrawing therapy if patient has been seizure free for 2-3 years.
There is absolutely no justification for shifting from a drug with teratogenic risk (e.g. carbamazepine) to one about which even less is known.
Phenobarbital (D) - no increased frequency in minor or major birth defects
Carbamazepine (D) - traditionally the drug of choice in pregnancy, but present data on its teratogenic potential is unclear
Phenytoin (D) - teratogenic potential influenced by genetics (epoxide hydroxylase levels)
Valproic Acid (D) - 1-2% risk of spina bifida, also associated with minor cranio-facial abnormalities
Hypertension Methyldopa (C) - most widely used, unparalleled safety record in pregnancy
Beta-blockers (except Atenolol (D)) - not teratogenic, but may cause growth restriction
Hydralazine - no adverse fetal effects, used for the 2nd-3rd trimesters
Sodium Nitroprusside - readily crosses placenta and in theory, may cause accumulation of cyanide in the fetus; no adequate clinical data
Hyperthyroidism Propylthiouracil - used more often than carbamazepine. Is less lipid-soluble and more protein-bound, thus transported less well to the fetus and breastmilk.
IMMUNIZATION IN PREGNANCY
Vaccination in pregnancy, similar to drug use, is a special scenario in that both the effects on the mother and fetus must be considered together in its administration. Vaccines that generate an immune response in the maternal serum may also become protective to the fetus when maternal antibodies pass through the placenta. This phenomenon, however, may be detrimental when a sufficient amount of maternal antibodies are transmitted as to interfere with the development of natural antibodies in the fetus. Maternal reactions to vaccination, such as fever and hypersensitivity may also adversely affect fetal support and development.
These risks, however, are primarily theoretical. At present, there is no available clinical evidence that vaccination either with inactivated bacteria or viruses or toxoids carries any risk to the fetus. Live vaccines, however, carry a greater theoretical risk of causing fetal disease and are generally avoided in pregnancy. Altogether, the benefits of vaccination in pregnancy generally outweigh the risks of fetal disease, especially when the risk of developing the disease is relatively high (post-exposure prophylaxis) and when the vaccine is unlikely to cause any harm.
Live-viruses (measles, mumps, rubella) are generally contraindicated in pregnancy because of the probable risk of vertical transmission. When a live-virus vaccine is inadvertently given to a pregnant woman, or when a vaccinated woman subsequently becomes pregnant within 4 weeks of the vaccine, counseling about the possible effects on the fetus is indicated. Regardless of whether a live attenuated or killed vaccine is administered, risk versus benefit assessment is still the rule of thumb.1,13,14
Table 6 summarizes the relative safety of common vaccines in pregnancy:
Table VI. Vaccination in pregnancy
VACCINE SAFE IN PREGNANCY? COMMENTS
Tetanus-Diphtheria (Td) Yes Pregnant patients should receive Tetanus toxoid as a booster if there has been no prior administration within the last 10 years. Previously unvaccinated patients should receive a complete series of 3 vaccinations. The preferred schedule is after the second trimester, with each dose given 4 weeks apart. This is the only vaccine routinely indicated for all susceptible pregnant patients
Hepatitis A Not established Because vaccine is a killed vaccine, theoretical risk is low, but safety in pregnancy has not been determined. May be indicated for high risk patients.
Hepatitis B Yes Pregnancy is not a contraindication, and patients at high risk (e.g. >1 sex partner in the last 6 months, concurrent STD, IV drug use, or an HBsAg-positive partner) should be vaccinated. Current vaccines are noninfectious and no data has shown detrimental effects to the fetus.
Human Papillomavirus (HPV) Not recommended Vaccine has been related to some adverse outcomes in pregnancy, but data is limited.
Influenza (Inactivated) Yes Recommended during influenza season, as pregnant patients who become infected are at increased risk for severe complications. No adverse fetal outcomes reported.
Measles, Mumps and Rubella No Risk to fetus of live vaccines cannot be excluded and should not be administered in pregnant patients. Vaccinated women should be advised not to become pregnant for 28 days after administration.
All Rubella containing vaccines are contraindicated because of the risk of developing Congenital rubella syndrome (CRS) in the fetus. But to date, no documented cases of post-vaccination CRS have been reported.
Pneumococcal Not established Safety in pregnancy has not been evaluated, although no adverse effects have been reported.
Polio (IPV) Yes, but avoided No adverse effects reported, but generally avoided due to theoretical risks. High risk patients, however, may be considered for vaccination
Tetanus-Diphtheria- Pertussis (DPT) Yes Pregnancy is not a contraindication to DPT. Maternal Pertussis antibodies may be protective to the infant in early life, and so many practitioners prefer this vaccine over Tetanus toxoid alone.
Varicella No Because effects on the fetus are unknown, Varicella should be avoided entirely in pregnancy. But because of its lower virulence, the risk of transmission (if any) should even be lower than the wild type. VZIG should be strongly considered, however, for pregnant patients exposed to varicella.
BCG Not recommended No harmful effects reported
Typhoid Not established No available data
Rabies Yes, as post-exposure prophylaxis Because the consequences of rabies far outweigh the risk of vaccination, pregnancy is not a contraindication for post-exposure prophylaxis
Sunday, September 7, 2008
Isang Awit
I
Di ko naman hinanap
Di ko naman ginusto
Ngunit sadyang ang tadhana
Ay lubhang mapagbiro
II
Nagkita, nawalay
Nagkita na muli
Sa una’y walang tama
Ng yumao’y tumindi
KORO:
Di ko na kaya
Sa yo ay mawalay
Bawat pintig
Bawat hininga
Sa yo ay aking alay
III
Mga taon na ang nagdaan
Ang sidhi’y di nagbago
Sulyap mo’y dulot pa rin
Tibok nitong aking puso
IV.
Bawat hibla ng hininga
Bawat galaw ng aking laman
Habang ako ay nabubuhay
Ito’y sayo lamang
Di ko naman hinanap
Di ko naman ginusto
Ngunit sadyang ang tadhana
Ay lubhang mapagbiro
II
Nagkita, nawalay
Nagkita na muli
Sa una’y walang tama
Ng yumao’y tumindi
KORO:
Di ko na kaya
Sa yo ay mawalay
Bawat pintig
Bawat hininga
Sa yo ay aking alay
III
Mga taon na ang nagdaan
Ang sidhi’y di nagbago
Sulyap mo’y dulot pa rin
Tibok nitong aking puso
IV.
Bawat hibla ng hininga
Bawat galaw ng aking laman
Habang ako ay nabubuhay
Ito’y sayo lamang
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