OBMidterms - Teratology, Medications Affecting the Fetus, And Immunization During Pregnancy

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AUFMED

Dr. Agnes Gaddi | August 10, 2015 | OBSTETRICS TERATOLOGY, MEDICATIONS AFFECTING THE FETUS, and IMMUNIZATION DURING PREGNANCY

OUTLINE 1. Teratogenicity - Criteria for Proof of Human Teratogenicity 2. Maternal Consumption of Drugs - Placental Transfer of Drugs - Physicochemical Factors Affecting Placental Transfer of Drugs - Placental and Fetal Circulation - Fetal Exposure to a Drug - Drug Effects to a Fetus - Staging of Fetal Development 3. USDA Five Risk Categories 4. Genetic and Physiological Susceptibility to Teratogens 5. Effects of Drug on Fetus 6. Immunization During Pregnancy TERATOGENICITY

Criteria for Proof of Human Teratogenicity 1. Careful delineation of clinical cases The defect must be completely characterized and therefore it should be repetitive and almost the same in many cases. Many genetic and environmental factors produce the same defect (phenocopies). To identify teratogenicity whenever a drug has been approved for use, there should be follow-up studies and case control surveillance after drug has been released and used by the population. Step 1: Drug is studied first in the laboratory. Step 2: Drug is then tested in animals. Step 3: Progresses to case trials where they are used in selected and willing individuals. Step 4: Surveillance after use of the drug.

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Teratology is the study of birth defects. Teratogen is defined as “any agent – chemicals, viruses, environmental agents, physical factors, and drugs that act during embryonic or fetal development to produce a permanent alteration in form or function Although several drugs are possible teratogens in human beings, at present only a few have been positively identified. The best-known teratogen is thalidomide. The discovery that thalidomide caused congenital malformations was possible because the drug was widely used in the 1950s and 1960s and induced dramatic and rare congenital defects and a high probability (an estimated 25-30%) It has been estimated that to establish that a given drug changes the naturally occurring frequency of a congenital deformity by 1% would require a sequential trial of 35,000 patients. In doses that it can cause analgesia to mother, it was proven to have major teratogenic effects such as phocomelia. Many drugs are released for any reason without testing it for teratogenic effects as it is unethical. If problems develop after drug is released, a study will then be conducted. It is unethical to conduct a prospective study regarding this, as the baby’s consent cannot be elicited Follow-up and case control surveillance are the two studies that can be done.

2. Rare environmental exposure associated with rare defect, with at least three reported cases – easiest if defect is severe. Cleft palate is widely known to be multifactorial. There is a long list of anomalies but many still are not in the literature. At least three instances of the effect is the criteria needed for investigation. 3. Proof that the agent acts on the embryo of the fetus directly or indirectly. The agent must cross the placenta. With few exceptions, all drugs cross the placenta, but it must be shown that the drug cross in: a. Sufficient amount to directly influence fetal development or b. Alter maternal or placental metabolism to exert an indirect fetal effect. There are chemical properties of the drug that allows them to cross the placental membranes. Often times, what happens is simple passive diffusion. There is large concentration of drug in the maternal circulation and little or none is in the fetal circulation. Thus, drug diffuses passively to the fetal circulation. 4. Consistent findings of two (2) or more epidemiological studies of high quality: The initial evaluation of teratogen exposure is usually retrospective and therefore, it can be tampered by bias, inadequate reporting and

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incomplete assessment of the exposed population. Investigation is often confounded by a variety of factors. There should be: a. Control of confounding factors b. Sufficient numbers c. Exclusion of positive and negative bias factors d. Prospective studies, if possible e. Relative risk of three or more (necessary to support hypothesis) Many good drugs in the market have been put out because of litigation cases against manufacturers. Even if proven wrong, the negative publicity gives manufacturers no choice but retract drug.

6. The association must be biologically plausible. It is always possible that an exposure and defect are not causally related. A 1:1 anomaly wherein one exposure and one defect results do not usually happen. 7. Teratogenicity in experimental animals has been proven, especially primates. Human teratogenicity is more likely, if the agent produces adverse effects in many different species especially subhuman primates. If the teratogen causes defects in many species, then it might be also teratogenic in humans, especially so if it becomes positive in some human primates (e.g. monkeys, gorillas, etc.)

5. Proven exposure to agent at critical time/s in prenatal development. Pre-Implantation Period - First 2 weeks from fertilization to implantation is the “all or none period” o Implantation – 8 to 9 weeks - Division from one-cell to the 6th cell to the 8th cell morula - If insult happens to this particular stage, there will be a decrease in the number of cells. If there is a decrease in the number of cells in the 6 cell stage, there will be death.

MATERNAL CONSUMPTION OF DRUGS 1. Drugs are administered for symptomatic relief of benign problems in the mother (like pain, vomiting, dizziness especially in the 1st trimester) with little or no consideration to the unintended recipient. o

Embryonic Period - 2nd to 8th week - Organogenesis happens - The most crucial period for structural abnormalities - Insults that may happen in this particular stage may allow life but there can be major congenital anomalies that may also not allow line extrauterine. Fetal Period - After 8 weeks (fetopathy, in contrast with 2 to 8 weeks, embryopathy) - Certain organs remain vulnerable An important aspect of teratology is that teratogenic medications administered after vulnerable period usually will not cause structural malformations. Timing of Exposure to Drug:  2nd to 6th week – CNS, heart, extremities, eyes, palate, etc.  From 6th week – genitalia  First 2 weeks – cleavage occurs; if an insult occurs, there would be death of the zygote; failure of implantation  2nd to 8th week – if catastrophic, structural defects occur; sometimes incompatible with life; occasionally, it may be compatible with life but there would be growth restriction and transplacental carcinogenesis may occur

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3rd to 9th month – CNS development is affected and also abnormalities of the heart (minor and compatible with life)

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Many are not educated, they do not know that whatever they take in will also be passed to the fetus. Average number of prescribed drugs taken during pregnancy = 4. If self-prescribed are included, this number increases to 10.

2. Many pregnant women have conditions for which specific drug therapy is indicated o o o o

Many patients will have prescriptions to medications. Most drugs (with few notable exceptions) prescribed for common medical or surgical diseases can be used with relative safety. E.G. antihypertensive drugs, diabetics Moreover, if untreated disease may pose more risk to the mother and fetus, it is more beneficial to take the drug. DM, if untreated may cause multiple effects to the mother and fetus.

Placental Transfer of Drugs Placental transfer depends on: o Maternal metabolism o Specific characteristics of the drug o Molecular size/weight o Storage o Protein-binding o Electrical charge or degree of ionization

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Lipid solubility  Placental maturation and metabolism of drugs  Placental and fetal circulation

Physicochemical Properties Affecting Placental Transfer of Drugs o Molecular Weight (Daltons)  250 – 500 daltons = easily crosses  500 – 1000 daltons = more difficult  1000 dalton = + very poorly Exceptions to the size rule are maternal antibody globulins and some polypeptides (peptide hormones – AVP, ACTH, etc.) Heparin is large, so it does not cross the placenta. It is the treatment of choice for patients who need coagulation during pregnancy. Warfarin crosses the placenta, and thus can cause adverse effects to the fetus. o

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Lipid Solubility  Lipophilic drugs tend to diffuse readily  Highly ionized drugs tend to cross slowly.  If the maternal-fetal concentration gradient is high enough, polar compounds will cross the placenta  There is, most of the time, passive diffusion but some substances can transfer by active or facilitated transfer. Placental Maturation  As the placenta develops, its physiology changes including transport of drugs and enzymes that can continuously degrade or metabolize drugs.there are new enzymes as the placenta grows and develops .  Sometimes if the primary compound of the drug is not teratogenic, it is the by-products of the drug’s degradation that may cause teratogenic effects.

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The primary mode of drug transfer is passive non-ionic diffusion  There are many amino acid, peptide, ion, sugar nucleotide transporters in the brushborder membrane of the syncytiotrophoblast cells.

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Metabolism of Drugs  The metabolic activity of the placenta may lead to creation of toxic metabolites  The metabolites of some drugs are more active than the parent compounds and may affect the fetus more strongly than the parent compound.

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Placental and Fetal Circulation o Drugs that cross the placenta enter the fetal circulation via the umbilical vein 40-60% of umbilical blood flow enters the fetal liver and the remainder bypasses the liver and goes to the general fetal circulation. o During pregnancy, we know that the placenta grows by the number of its cotyledons, by the size and by the size of its cotyledons and by the number of blood vessels crossing. o The thinnest surface area increases from 3-4 to 12.6 mm during pregnancy. Fetal Exposure to a Drug - The extent of fetal exposure to a drug administered to the mother will depend on: o The above physicochemical properties that determine placental transfer o Dose of the drug o Duration of treatment o Rate of drug maternal drug elimination and it will mimic the exposure of the mother to the fetus. High dose in the mother  slow elimination  what the mother gets, the fetus get A drug that is proton bound is diffused more slowly. However, accumulation of drug may accumulate if multiple doses are given. Higher concentration and multiple doses causes higher concentration in fetal compartment. Effect of Drugs on the Fetus Currently, the fetus is only a passive recipient of drugs, and consequently any drug effects are undesirable unless proven otherwise. Antipyretic on the mother  also relieves fever of the fetus IgG given to the mother may pass in the placenta and lodge to the baby and it is beneficial as it joins the pool of antibodies on the fetus. Effects on the fetus may vary from: o Reversible effects like transient behavioral changes, transient changes in clotting time or fetal breathing movements. o Irreversible consequence like fetal death, IUGR, structural malformations and mental retardation Staging of Fetal Development Timing of Drug Exposure -

Period of Zygote: first week after conception when cleavage occurs. Most common effect is miscarriage. May lead to decreased cell number in the blastocyst.

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Embryonic Period: second to eight weeks when organogenesis occurs. Catastrophic structural defects (thalidomide), fetal wastage, fetal growth restriction and transplacental carcinogenesis (DES) may result. Fetal Period: third to ninth month. CNS development, behavioral teratogenic effect.

Fetal brain is susceptible to insults even at birth, which is only 80% developed at birth and continues to develop until adult life. USDA- FIVE RISK CATEGORIES Category A - Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester Category B - Either animal studies have not shown fetal risk but no controlled studies in pregnant women have been reported, or animal studies have shown an adverse effect that was not shown in woman in the first trimester, e.g. Ampicillin. Category C - Either animal studies have revealed an adverse effect on the fetus but no controlled studies in women have been reported, or studies in animals or women are not available, - E.g., AZT. Category D - Positive evidence of human fetal risk exists, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., drug required for a life-threatening illness) - E.g., Dilantin Category X - Studies in animals or humans have demonstrated fetal abnormalities, or evidence exists of fetal risk based upon human experience, or both, and the risk clearly outweigh any possible benefit. The drug is contraindicated in women who are at risk of becoming pregnant. - E.g., Accutane Additional information found on Table 12-3, Appendix A. GENETIC AND PHYSIOLOGICAL SUSCEPTIBILITY TO TERATOGENS A. Fetal Genome Genetic composition has been linked to susceptibility to teratogenic effects of specific medications. Ex. Fetuses exposed to hydantoin are more likely to develop anomies if homozygous for a gene mutation that results in abnomally low levels of epoxide hydrolase.

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B. Homeobox gene teratogenicity Homeobox genes are regulatory and encode proteins that act as transcription factors. Any drug that obstructs function in the production of these proteins can cause structural abnormalities. Ex. 1. Retinoic acid – abnormalities in the hindbrain and limb buds 2. Valproic acid – prevent normal closure of the posterior neuropore (neural tube defects) C. Disruption of Folic Acid Metabolism Fetuses who were exposed during embryogenesis to folic acid antagonists (anticonvulsants), had a 3x risk of oral clefts, cardiac defects and urinary tract abnormalities D. Paternal Exposures Proposed mechanisms include induction of a gene mutation or chromosomal abnormality in sperm. Because of the 64 days in which male germ cells mature into functional spermatogonia, drug exposure during the 2 months before conception could cause gene mutations. (ex. Ethyl alcohol, cyclophosphamide, lead, opiates). That is why doctors planning to conceive are not advised to go the operating room when general anesthesia is being inducted. Another possibility is that during intercourse, the developing embryo is exposed to a teratogenic agent in seminal fluid.

EFFECTS OF DRUG ON FETUS Teratogens likely act by disturbing specific physiological processes which leads to cell death, altered tissue growth or abnormal cellular differentiation - May vary from reversible effects like transient behavioral changes, transient changes in clotting time, transient changes in the fetal breathing movements. Irreversible effects also occur like fetal death, IUGR, structural malformations, and mental retardation. - The effects of drugs on the fetus are highly dependent on individual drugs. - Within same group of drugs, each individual drug can cause the same type of malformation.  E.g. anticonvulsants  Three or four drugs that are considered anticonvulsants may produce the same effect - In another class, each individual drug differ greatly in their teratogenic potential  E.g., sedatives-hypnotics

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I. Angiotensin Converting Enzymes (ACE inhibitors) - An anti-hypertensive agent which has good effect among hypertensive patients because of improved renal function and cardiac-sparing effects. - Disrupt the fetal renin-angiotensin systems - Out of 209 fetus exposed to ACE inhibitors, 8% had major congenital anomalies (compared to 2.9% in the general population) - Causes fetal hypotension, renal hypoperfusion with subsequent ischemia and anuria - Reduced perfusion causes fetal-growth restriction and calvarium maldevelopment. - Fetal anuria and problems with fetal swallowing (fetus does not swallow) causes oligohydramnios resulting to pulmonary hypoplasia and limb contractures. II. Antifungals - Fluconazole is associated with skull abnormalities, cleft palate, humeral-radial fusion - Local brands include difloccan - Pregnant patients are prone to fungal infections such as candidiasis. Pregnant patients are usually given local acting vaginal cream as the oral antifungals are contraindicated. - Fluconazole is the only known antifungal agent with teratogenic effects. - 400-800 mg/day in first trimester for severe fungal infections - 150 mg single dose for patients with vulvovaginal candidiasis (as suppositories) III. NSAIDS - Most are safe in pregnant women except for indomethacin - Examples of NSAIDS: aspirin and ibuprofen - Function is to inhibit prostaglandin production - Low dose aspirin (80 mg) – used among patients with history of MI and also given among pregnant patients with high risk for developing preeclampsia (though controversial) a. Indomethacin - In the 3rd trimester, cause constriction of the fetal ductus  pulmonary hypertension - Intraventricula hemorrhage, bronchopulmonary dysplasia and necrotizing enterocolitis b. Leflunomide - Pyrimidine synthesis inhibitor used to treat rheumatoid arthritis. - Embryo death, hydrocephalus, eye anomalies, skull abnormalities (in multiple animal species) IV. Antimicrobials - Aminoglycosides causes auditory/ocular nerve damage - Sulfonamides pose conflicting reports on teratogenicity (It causes decrease in lecithin-

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sphingomyelin ratio as well as increases risk for convulsion) Tetracycline causes staining of dentition

V. Antimalarials - Quinidine causes deafness - Mefloquine causes stillbirths - Chloroquine (Fansidar) safe for pregnancy VI. Antivirals - Ribavirin inhalation given intranasally is highly teratogenic in multiple species (skull, palate, eye, limb and GI abnormalities) VII. Hormonals a. Androgens (at 7-12 weeks) - Full masculinization – does not progress after bith - Reversed after birth b. -

Norethindrone Progestin found in the pills It causes masculinization in 1% of exposure Other progestins (e.g. medroxyprogesterone acetate) given to women with AUB are not found to be teratogenic

c. DES - Found to have structural abnormalities in the cervix, vulva and vagina, adenosis and some cancers especially clear cell CA in female fetuses - Epididymal cysts, microphallus, cryptorchidism, testicular hypoplasia - Majorities are adenosis in the cervix, vulva and vagina. Many of these adenosis may become the jumping point for malignancy - 1940 – 1971 – about 2 million women in U.S. were given DES (synthetic estrogen) and it was found to have caused genital tract abnormalities in 30 to 35%. VIII. Antineoplastic agents - Cyclophosphamide may cause missing and hypoplastic digits. It is usually given among patients with GI and blood cancers. Methotrexate and Aminopterin may cause MAS – IUGR, failure of calvarial ossification, craniosynostosis, hypoplastic supraorbital ridges, small posteriorly rotated ears, micrognathia, and severe limb abnormalities. IX. Immunosuppressives o Corticosteroids - Cleft palate - High doses over a long period of time but short doses of corticosteroids, like what we give for preterm babies in whom we want to increase surfactant, they are given over a 48 hour period. 46 doses of Betamethasone or hydrocortisone. These are found safe and are given in the third trimester

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Mycophenolate Mofetil - Ear and Auditory Canal Anomalies Radioactive Iodine (crosses the placenta) - Fetal Thyroid Ablation (irreversible fetal hypothyroidism)

X. Psychiatric Medications o Lithium - Ebstein anomaly, hypothyroidism, diabetes insipidus, cardiomegaly, ECG abnormalities, cyanosis, hypotonia o SSRIs o Paroxetine - Cardiovascular malformations - 2-3x increased risk for omphalocoele, craniosynostosis and anencephaly, neonatal behavioral syndrome (jitteriness, irritability or agitation, increased muscle tone, feeding or digestive disturbances) - Many of which are irreversible XI. Retinoids (Vit A derivative) o Isotretinoin, Acitretin, Bexarotene given orally Cranial- neural crest defects (retinoic acid embryopathy) o Retinol - cranial-neural crest defects - It is a preformed vitamin A. it’s a natural vitamin A - Beta carotene –non teratogenic - It is naturally occurring in fruits and vegetables. They are safe. o Topical Retinoids - No evidence of teratogenicity - Popular among women, it counteracts the effects of the sun at the same time, it is anti acne. If applied in large quantities over a huge surface area, it is almost the same as taking it orally. There may be an accumulation or systemic absorption. Discourage patient from using topical retinoids. XII. Thalidomide - There is a relationship between timing of exposure to the type of structural abnormality. - Exposure days  27-30 = upper phocomelia  30-33 = lower limb phocomelia  42-43 = gall bladder aplasia  40-47 = duodenal atresia - Exposure days are days after menstruation. Meaning, if you have fertilization at day 14, your phocomelia can happen at 2 weeks of age from fertilization. XIII. Other Drugs: Warfarin (6th-9th weeks) o Vit. K antagonist o Low molecular weight, so it readily crosses the placenta o Stippling of the vertebrae and femoral epiphysis, nasal hypoplasia, choanal atresia o Beyond the first trimester= hemorrhage into the fetal structures abnormal growth in the brain especially in the optic nerve (agenesis of the corpus callosum, micropthalmia, optic atrophy

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Illicit Drugs Cocaine - Vascular disruption in the fetus  skull defects, ileal atresia, porencephaly, cardiac anomalies, visceral infarcts o Drug with multi-system effect Opiates Heroin - IUGR, perinatal complications, death, developmental delay, behavioral disturbances o Withdrawal symptoms: irritability, sneezing, fever, diarrhea, seizures (later trimester) Methadone - withdrawal symptoms Examples of Known and Suspected Teratogens: NonTherapeutic Agents 1. Alcohol - Chronic intake is associated with the fetal alcohol syndrome (US prevalence = 0.6 to 3/1000 births) - Most frequent documented cause of mental retardation in the western world - Birth defects and neuro-behavioral disorders related to it is 9/1000 live births - Alcohol effect on the fetus is dose-related  Average of 8 ounces intake per day  23% frontal cortex below the 10th percentile  16% premature births  28% small for dates  32% congenital malformations  Binge drinking – linked to increased risk of stillbirths  16% major malformations 2. Smoking - Results in small for date infants - Associated with increased hyperactivity and low achievement - Increases risk for placenta previa, abruption placenta, prematurity and respiratory disease and abortion - In utero – decrease fetal breathing movements and increased fetal heart rate - All of these related to decreased uterine blood flow because of the hardened small caliber arteries due to smoking 3. Environmental Chemicals Lead - Causes fetal growth abnormalities and developmental delays Methylmercury - Developmental delays, microcephaly, severe brain damage CONCLUSIONS - Medications should only be used if expected benefits to mother or fetus outweigh risks. - Avoid use in the first trimester if at all possible/  Only folic is required in first trimester

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Use extensively tested in pregnancy drugs rather than “new”/untried meds. Use minimum dose that would be beneficial to mother The list of proven teratogens is short but by no means complete. More will be added as data become available.  Discussion focuses on chemicals proven not to have teratogenic effects  Many effects when studied are proven later not to have a relationship with the effect that they are suspected to cause Absence of data does not imply safety. Obtain accurate details of exposure:  Especially gestation age at which drugs are taken  Check for confounding family or medical history  Get up-to-date info on published risks of the specific drug in humans  Emphasize background risks in counseling  Be clear about what is known but do not assume absence of data means no risk. IMMUNIZATION DURING PREGNANCY

General Considerations for Vaccination based on the 2011 CPG on Immunization for Filipino Women: 1. Never administer vaccines on the buttocks. 2. Confirm completion (or more recent) primary vaccine series for measles, mumps, and rubella (MMR); and Tetanus-Diptheria (Td) before initiating adult recommended vaccine schedules. 3. Maintain vaccine administration record in patient chart, including the [DR ManuLotS] date, route of administration, manufacturer, lot number, and site of administration. 4. Knowing the route of vaccine administration, needle size, and vaccine storage and handling are critical components of a quality, office-based vaccine program. 5. Simultaneous use contraindicated.

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6. Antibiotic therapy or breastfeeding are not contraindications to vaccination. Likewise, in the presence of a pregnant woman or immunosuppressed person in the household is not a reason to withhold an indicated vaccine to a family member. 7. Generally, vaccines that contain (inactivated) viruses can be given

killed during

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pregnancy. Vaccines that contain live viruses are not recommended for pregnant women. General Contraindications to Vaccination based on the 2011 CPG on Immunization for Filipino Women: 1. Severe allergy to vaccine components. 2. Pregnancy (or if planning pregnancy within 4 WEEKS) for live attenuated vaccines. 3. Severe immune attenuation (for live attenuated vaccines only) – consultation with infectious disease specialist is advised. 4. Moderate or severe acute illness. 5. If a live attenuated vaccine is given simultaneously with another vaccine, a 4 WEEK separation interval should be used between vaccinations. TETANUS-DIPTHERIA (Td) & TETANUS-DIPTHERIAPERTUSISS (Tdap) INDICATION RECOMMENDATION 1. Pregnant women with no previous tetanus immunization (or with an unknown immunization history)  3 doses Td vaccine given one month apart starting the 2nd or 3rd trimester. Third dose may be given post partum. 2. Pregnant women whose last Td/Tdap vaccination was more than 10 years ago  Td booster in the 2nd and 3rd trimester. DOSE REGIMEN  Primary vaccination series: 3 Td injections IM  First 2 doses given 1 month apart  Last dose given 6-12 months after 2nd dose. CONTRAINDICATION: Severe allergic reaction after previous dose or to a vaccine component. PRECAUTION: History of Arthus-type hypersensitivity reaction following a TT-containing vaccine – Defer vaccination at least 10 years since last TT-containing vaccine. ADVERSE REACTIONS:  Mild: (noticeable reactions but does not interfere with daily activities) o Pain o Redness and/or swelling o Mild fever o Headache or tiredness  Moderate: (interferes with activities but does not require medical attention) o Fever over 102ᵒF (38.9ᵒC) o Extensive swelling on vac site.

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Severe: (unable to perform usual activities; requires medical attention) o Severe swelling, pain, and redness of the entire arm

CAUTION  Gullain-Barre Syndrome within 6 weeks of previous dose of influenza vaccine  Moderate or severe acute illness with or without fever

PNEUMOCOCCAL BACTERIA IMMUNIZATION RECOMMENDED to pregnant and breast-feeding women who are high risk for developing disease. Preferably administered during the 2nd or 3rd trimester of pregnancy, or before becoming pregnant. HIGH RISK WOMEN:  Chronic Cardiovascular diseases (Congestive Heart Failure, Valvular Heart disease)  Chronic Pulmonary Disease (Asthma, COPD, PTB)  Sickle Cell Disease  DM / GDM  Chronic Liver Disease  Immunocompromised person o HIV/AIDS o Leukemias and other neoplasias o Severe Renal Pathologies o Transplant patients DOSE REGIMEN: Single, 0.5mL IM/SQ CONTRAINDICATIONS:  Hypersensitivity  Severely compromised Cardiovascular or Pulmonary function  Children