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Drug use in pregnancy
This document discusses drug use and management of common medical conditions during pregnancy. It covers gastrointestinal issues, gestational diabetes, hypertensive disorders, thyroid abnormalities, thromboembolism, urinary tract infections, sexually transmitted infections, headache, malaria, tuberculosis, asthma, allergic rhinitis, diabetes, epilepsy, HIV, preterm labor, and antibiotics used during pregnancy. For each condition, it provides recommendations for first-line and alternative drug treatments as well as contraindicated medications. References for the information are also included.
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Drug use in pregnancy
- 1. Drug use inPregnancy (II) Capt. Htet Wai Moe 06/05/17
- 2. Pregnancy-influenced issues • GItract – constipation, GERD, hemorrhoids, nausea, vomiting • Gestational diabetes • Hypertensive disorders of Pregnancy • Thyroid abnormalities • Thromboembolism
- 3. GI Tract Constipation 25%- 50% of pregnant women • First-line treatments – Bulk-forming agents(Psyllium, methylcellulose) – Osmotic laxatives (Polyethylene glycol, lactulose, sorbitol) • Second-line treatment – Stimulant laxatives (Senna, bisacodyl) • Contraindication – Castor oil (stimulate uterine contraction) – Mineral oil (impairment of maternal fat-soluble vitamin absorption)
- 4. GI Tract Hemorrhoids • First-linemanagement – Laxatives, stool softeners – Topical anesthetics, skin protectants, astringents for irritation and pain – Hydrocortisone cream to reduce inflammation and pruritus
- 5. GI Tract GERD 40-80%of pregnant women • First-line – Antacids (aluminium, calcium, magnesium prepartions) • Second-line – H2 blockers (ranitidine and cimetidine) • Reserve – Famotidine and nizatidine – Proton pump inhibitors
- 6. GI Tract Nausea andvomiting 90% of pregnancy • First-line management – Pyridoxine, Doxylamine • Alternatives – Phenothiazines, Metoclopramide (risk of sedation and extrapyramidal effects) – Ondansetron – Corticosteroids (for hyperemesis gravidarum)
- 7. Gestational diabetes • Prevalence– 1-14% • First-line treatment – Insulin • Alternatives – Glyburide and metformin • Intravenous drip insulin should be used during labor
- 8. Hypertension • Approximately 10%of pregnancies • SBP > 140 mmHg or DBP > 90 mmHg (two or more measurements at least 4 hours apart) • Preeclampsia – hypertension + proteinuria (>300 mg/24 hr)/ thrombocytopenia/ serum creatinine > 1.1 mg/dL / elevated liver tansminases – Low dose aspirin – prevent preeclampsia in high-risk patient – Calcium supplement – prevent preeclampsia
- 9. Hypertension • Eclampsia –occurrence of seizures superimposed on preeclampsia • Magnesium sulfate – recommended to prevent and treat eclampsia – 4-6 g IV over 15-20 min followed by 2 g/hr continuous infusion for 24 hrs
- 10. Nonsevere hypertension Drug DosageComments First choices Methyldopa 250-500 mg orally 2-4 x daily May cause orthostatic hypotension, drowsiness, depression, hemolytic anemia Labetalol 100-400 mg orally 2-4 x daily Maternal adverse reactions – headache, flushing, dizziness, transient hypotension, pulmonary edema Hydralazine 5 mg IV or IM: could be repeated every 30 min (total 30 mg) May cause tachycardia, headaches, hypotension Second choices Clonidine 0.05-0.2 mg orally (max: 0.8 mg daily) May cause hypotension, drowsiness
- 11. Severe hypertension Drug DosageComments First choices Labetalol 10-20 mg IV over 2 min: could be repeated every 15-30 min (total 30 mg) Not for asthmatic women May cause fetal bradycardia Nifedipine (short acting) 5-10 mg orally: could be repeated after 30 min Maternal adverse reactions – headache, flushing, dizziness, transient hypotension, pulmonary edema Hydralazine 5 mg IV or IM: could be repeated every 30 min (total 30 mg) May cause tachycardia, headaches, hypotension Second choices Clonidine 0.05-0.2 mg orally (max: 0.8 mg daily) May cause hypotension, drowsiness
- 12. Thyroid Abnormalities • 0.4-1.7%- hyperthyroidism – Associated with fetal death, low birth weight, IUGR, preeclampsia • 2-3% - hypothyroidism – Untreated hypothyroidism increases risk of pre- eclampsia, premature birth, miscarriage
- 13. Thyroid Abnormalities Hyperthyroid • Propylthiouracil– first trimester • Methimazole – second and third trimesters • Contraindication – Iodine131 – risk of thyroid damage in fetus Hypothyroid • Thyroid replacement therapy – Levothyroxine (0.1 mg/day)
- 14. Thromboembolism • Risk increasesfive- to tenfold over nonpregnant women • First-line management – LMWH throughout pregnancy and for 6 wk after delivery • To avoid – Warfarin (between 6 and 12 wk) – Unfractionated heparin – Injectable direct thrombin inhibitors
- 15. Acute care issuesin Pregnancy • Urinary tract infection • Sexually transmitted infections • Headache
- 16. Urinary tract infections •Associated with higher risks of hypertension, low birth weight, and preterm delivery Asymptomatic bacteriuria and cystitis acute pyelonephritis Septic shock and acute respiratory distress syndrome
- 17. Urinary tract infections •Antimicrobial therapy should target Escherichia coli infection • Empirical therapy – Beta-lactamase inhibitor – Cephalosporins – Nitrofurantoin • Second-line choices – Sulfonamides – Ampicillin – Amoxicillin
- 18. Urinary tract infections •Nitrofurantoin – contraindicated in pyelonephritis • Trimethoprim-sulfamethoxazole – During organogenesis (congenital malformation) – Near term (risk of neonatal jaundice) • Quinolones – Reserved for resistant infections (concerns of arthropathy)
- 19. Sexually transmitted infections •Bacterial vaginosis • Chancroid • Trichomoniasis • Chlamydia • Gonorrhea • Syphilis
- 20. Bacterial vaginosis Recommended Metronidazole 500 mgorally two times daily x 7 days 250 mg orally three times daily x 7 days Clindamycin 300 mg orally two times daily x 7 days Recommended Azithromycin 1 g orally x 1 dose Ceftriaxone 250 mg IM x 1 dose Erythromycin 500 mg orally three times daily x 7 days Chancroid Recommended Metronidazole 2 g orally x 1 dose Trichomoniasis
- 21. Chlamydia Recommended Azithromycin 1 g orallyx 1 dose Amoxicillin 500 mg orally x 7 days Recommended Azithromycin 1 g orally x 1 dose Ceftriaxone 250 mg IM x 1 dose Alternative Cefixime + Azithromycin 400 mg orally x 1 dose 1 g orally x 1 dose Gonorrhea Alternatives Erythromycin 500 mg orally three times daily x 7 days
- 22. Syphilis Recommended Benzathine penicillinG 2.4 millions unit IM x 1 dose Recommended Benzathine penicillin G 2.4 millions units IM x 3 doses weekly Tertiary, late latent Primary, secondary, early latent Recommended Aqueous penicillin G 3-4 millions unit IV every 4 hr or continuous IV x 10-14 days Alternative Procaine penicillin + Probenecid 2.4 millions unit IM daily x 10-14 days 500 mg orally four times daily x 10-14 days Neurosyphilis
- 23. Headache Tension headache • Paracetamol •Ibuprofen (Other NSAIDS are contraindicated in third trimester) Migrainous headache First choice • Paracetamol, Ibuprofen
- 24. Headache Unresponsive patients • Sumatriptan(little safety information of other triptans) Contraindication • Ergotamine and dihydroergotamine Migraine-associated nausea • Promethazine, Prochlorperazine, metocloperamide
- 25. Headache Prevention of severemigrainous headache • Agent of choice – Propranolol (lowest effective dose) • Alternatives – Tricyclic antidepressants (amitriptyline, nortriptyline)
- 26. Malaria Prophylaxis andtreatment in pregnancy • Safe drugs – Quinine, Chloroquine, Proguanil, Clindamycin • Uncomplicated malaria – First trimester - Quinine plus clindamycin – Second and third trimester – Artemisinin derivatives
- 27. Malaria Prophylaxis andtreatment in pregnancy • Reserve medications – Amodiaquine, atovaquone, dapsone, lumefantrine, mefloquine, piperaquine, pyrimethamine plus sulfadoxine • Caution and contraindication – Halofantrine and primaquine – Doxycycline
- 28. Specific antimalarial drugs •Artemisinin derivatives – Relatively safe in second and third trimester • Mefloquine – Throughout the pregnancy for prophylaxis and treatment • Proguanil – Throughout the pregnancy for prophylaxis and treatment
- 29. Specific antimalarial drugs •Quinine – Drug of choice for chloroquine-resistant malaria • Lumifantrine, Amodiaquine, Atovaquone – Reserve medication
- 30. Tuberculosis in pregnancy First-linedrugs • Isoniazid • Rifampicin • Ethambutol • Pyrazinamide Contraindicated • Streptomycin
- 31. Asthma • Common chronicillnesses in pregnancy • Diagnosis and staging of asthma is same as in nonpregnant women • Risks of medication use are lower than the risks of untreated asthma
- 32. Asthma • Intermittent -Short acting β2 agonist (albuterol is preferred) • Persistent – step-appropriate doses (low, medium, high) of inhaled corticosteroids (Budesonide is preferred)
- 33. Asthma • Long actingβ2 agonist –considered safe • Cromolyn – less effective • Leukotriene receptor antagonists – less experience in clinical trials • Theophylline – more potential toxicity • Systemic corticosteroids – for the most severe asthma
- 34. Allergic rhinitis • Approximately20% of pregnancy are impacted • Vascular engorgement in nasal passages and hormonal effects on mucus secretion – nasal congestion • Treatment strategies – similar to those used in nonpregnant women
- 35. Allergic rhinitis • First-linemedications – Intranasal corticosteroids – Nasal cromolyn – Fist generation antihistamines (chlorpheniramine, hydroxyzine)
- 36. Diabetes • Poorly controlleddiabetes can cause fetal malformations, fetal loss and maternal morbidity • Women with diabetes should use effective contraception until optimal glycemic control is achieved before attempting pregnancy • Target organ problems may become worsen during pregnancy
- 37. Diabetes • Insulin isdrug treatment of choice • Women receiving insulin glargine or detemir should be switched to NPH insulin • Glyburide and metformin may be alternatives, but not recommended by the American Diabetes Association
- 38. Epilepsy • Seizures maybecome frequent because of changes in maternal hormones, sleep deprivation, and medication adherence problems • Changes in free serum concentrations of antiepileptic drugs
- 39. Epilepsy • Carbamazepine andlamortigine – safest • Valporic acid – risk of neural tube defects, facial clefts, and cognitive teratogenicity • Phenobaribital – cardiac malformation • Polytherapy – greater rate of major malformations than monotherapy
- 40. Epilepsy • If drugwithdrawal is planned, it should be attempted at least 6 months before attempting to conceive • Folic acid supplementation – all women taking antiepileptic drugs
- 41. HIV • Generally, pregnantwomen should be treated as nonpregnant women, with some exceptions • Efavirenz – avoid during first trimester • Drugs that cross placental barrier – Abacavir, Emtricitabine, Lamivudine, Tenofovir, Zidovudine
- 42. HIV • Lopinavir-ritonavir – Recommendedin pregnant women • Prevention of mother-to-child transmission – Zidovudine with single dose of nevirapine
- 43. HIV • Women currentlyreceiving ARV treatment should be continued on their regimen • For ARV-naïve women, use of three-drug combination regimen – Two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) with high transplacental passage (preferred: Zidovudine, Lamivudine: alternatives: emtricitabine, tenofovir, abacavir) – A protease inhibitor (preferred: Atazanavir plus low- dose ritonavir, lopinavir/ritonavir; alternative: Darunavir or saquinavir, both with low-dose ritonavir)
- 44. HIV • NNRTI (Nevirapine) –Alternative to protease inhibitor – Risk of severe rash and life-threatening or fatal hepatotoxicity • After discussion of risks and benefits, ARV may be delayed until after first trimester to avoid potential teratogenic complications
- 45. HIV • Caesarean sectionbefore the onset of labor is recommended to reduce the risk of perinatal HIV transmission • IV Zidovudine should be initiated with a 1- hour loading dose followed by a continuous infusion for 2 hours (cesarean) or until delivery (for vaginal delivery) • IV Zidovudine should still be administered in the presence of resistance to oral Zidovudine
- 46. Preterm labor • Pretermbirth especially before 32 weeks of pregnancy • Major cause of short- and long-term neonatal mortality and morbidity
- 47. Preterm labor Antenatal corticosteroids •Single course of corticosteroids – between 24 and 34 weeks gestation to women at risk of preterm delivery within 7 days • To decrease incidence and severity of neonatal respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and death
- 48. Tocolytic agents • Usedto buy time to complete a course of corticosteroids • To delay delivery to allow transfer of the patient to a center with neonatal intensive care unit facilities • No clear first-line tocolytic drugs – based on maternal status and potential adverse drug reaction Preterm labor
- 49. Tocolytic agents • Magnesiumsulfate, terbutaline, indomethacin, nifedipine • Magnesium sulfate – Prevent neonatal risk of cerebral palsy • Indomethacin – Prolongs pregnancy, particularly beneficial in women with hydramnios Preterm labor
- 50. Tocolytic agents • Terbutaline –Risk of serious side effects (increased heart rate, transient hyperglycemia, hypokalemia, cardiac arrhythmias, pulmonary edema, myocardial ischemia) • Nifedipine – Best benefit to risk ratio Preterm labor
- 51. Antibiotics • Parenteral/ Oralampicillin or amoxicillin and erythromycin – In PROM (before 34 wk gestation) – Delay in delivery and reduce maternal and neonatal morbidity Preterm labor
- 52. Progesterone • To preventpreterm birth in women with previous preterm delivery • Also useful in women with sonographic short cervix Preterm labor
- 53. References • Christof Schaefer,Paul Peters, Richard K Miller. Drugs during pregnancy and lactation. 3rd edition. Elsevier; 2015. • Joseph T DiPiro et al., Pharmacotherapy, A pathophysiologic approach. 10th edition. McGraw Hill; 2017. • Katzung B G, Masters S B, Trevor A J. Basic and clinical pharmacology. 13th edition. McGraw Hill; 2015.
- 54.
Editor's Notes
- #4 Bulk-forming agents (eg, psyllium, methylcellulose, and polycarbophil) are safe for long-term use because they are not absorbed. Osmotic laxatives (eg, polyethylene glycol, lactulose, and sorbitol) and stimulant laxatives (eg, senna and bisacodyl) can also be used. Use of magnesium and sodium salts may cause electrolyte imbalance. CLASSIFICATION 1. Bulk forming Dietary fibre: Bran, Psyllium (Plantago) Ispaghula, Methylcellulose 2. Stool softener Docusates (DOSS), Liquid paraffin 3. Stimulant purgatives (a) Diphenylmethanes Phenolphthalein, Bisacodyl, Sodium picosulfate (b) Anthraquinones (Emodins) Senna, Cascara sagrada (c) 5-HT 4 agonist Prucalopride (d) Fixed oil Castor oil 4. Osmotic purgatives Magnesium salts: sulfate, hydroxide Sodium salts: sulfate, phosphate Sod. pot. tartrate Lactulose
- #5 Conservative treatment (ie, high dietary fiber intake, adequate oral fluid intake, and use of sitz baths) should betried first. Laxatives and stool softeners can be used if conservative management is inadequate for preventing or treating constipation. Topical anesthetics, skin protectants, and astringents (eg, witch hazel) can be used for anal irritation and pain. Hydrocortisone may reduce inflammation and pruritis.
- #6 Lifestyle and dietary modifications (eg, small, frequent meals; alcohol and tobacco avoidance; food avoidance before bedtime; elevation of the head of the bed). Antacids (eg, aluminum, calcium, or magnesium preparations) or sucralfate are acceptable; however, sodium bicarbonate and magnesium trisilicate should be avoided. The use of proton pump inhibitors (PPIs) during pregnancy does not appear to increase the risk of major birth defects; most data comes from use of omeprazole. Since more data and clinical experience are available for H2 antagonists, use of PPIs should be reserved for women with inadequate response to H2 antagonists.
- #7 NVP usually begins between weeks 4 and 6 of gestation and usually resolves by weeks 16 to 20; peak symptoms occur between weeks 8 and 12. Hyperemesis gravidarum (HG; ie, unrelenting vomiting causing weight loss of more than 5% prepregnancy weight, dehydration, electrolyte imbalance, and ketonuria) occurs in 0.5% to 2% of women. CLASSIFICATION 1. Anticholinergics Hyoscine, Dicyclomine 2. H 1 antihistaminics Promethazine, Diphenhydramine, Dimenhydrinate,Doxylamine,Meclozine (Meclizine),Cinnarizine. Neuroleptics Chlorpromazine,(D2 blockers) Triflupromazine,Prochlorperazine,Haloperidol, etc. Prokinetic drugs Metoclopramide,Domperidone,Cisapride, Mosapride,Itopride 5-HT 3 antagonists Ondansetron,Granisetron, Palonosetron,Ramosetron 6. NK 1 receptor antagonists Aprepitant,Fosaprepitant 7. Adjuvant antiemetics Dexamethasone, Benzodiazepines, Dronabinol, Nabilone
- #8 Gestational diabetes mellitus (GDM) is diabetes diagnosed in the second or third trimester that is not overt diabetes. KDT 259 Risks of GDM are many and include fetal loss, increased risk of major malformations, and fetal macrosomia. Overt diabetes occurs if the A1C is greater than or equal to 6.5% (0.065; 48 mmol/mol Hgb), fasting plasma glucose (FPG) is greater than or equal to 126 mg/dL (7.0 mmol/L), or 2-hour plasma glucose 200 mg/dL (11.1 mmol/L) or greater during an oral glucose tolerance test (OGTT), or if random plasma glucose (RPG) is greater than or equal to 200 mg/dL (11.1 mmol/L) in a patient with hyperglycemic crisis or classic hyperglycemic symptoms.
- #10 Signs of more severe preeclampsia include: persistent severe headache, vomiting; hyperreflexia, chest pain or dyspnea, and HELLP (hemolysis, elevated liver enzymes, low platelets). Treatment of hypertension in women with preeclampsia depends upon the blood pressure measurement and follows the same principles discussed under Chronic Illnesses in Pregnancy.
- #13 During pregnancy, stimulation of the thyroid gland may occur because of hCG’s structural similarity to thyroid-stimulating hormone (TSH; thyrotropin). In some women, gestational transient thyrotoxicosis (GTT) may result. Occurrence of GTT is often associated with HG. By 20 weeks of gestation, GTT usually resolves as production of hCG declines. Treatment with antithyroid medicationis not usually needed. Nausea and vomiting can be treated as for patients without this pseudohyperthyroid state. Causes of hypothyroidism include autoimmune diseases (eg, Hashimoto’s thyroiditis), iodine deficiency (uncommon in the United States), and thyroid dysfunction following surgery or ablative therapy for previous hyperthyroidism.
- #15 Treatment should be continued throughout pregnancy and for 6 weeks after delivery; the minimum total duration of therapy should not be less than 3 months. Fondaparinux and injectable direct thrombin inhibitors (eg, lepirudin and bivalirudin) should be avoided unless a severe allergy to heparin (eg, heparin-induced thrombocytopenia) is present. The novel oral anticoagulants (eg, dabigatran, rivaroxaban, and apixaban) are not recommended. Warfarin is not used because it causes nasal hypoplasia, stippled epiphyses, limb hypoplasia, and eye abnormalities; the risk period appears to be between 6 and 12 weeks of gestation. CNS anomalies are associated with second- and third-trimester exposure.
- #21 Bacterial vaginosis adverse pregnancy outcomes – PROM, chorioamnionitis, preterm birth, postpartum endometritis Tx is recommeded in all symptomatic women and in asympatomatic women at high risk of preterm delivery Trichomoniasis is caused by the protozoa, Trichomonas vaginalis. Infection with T. vaginalis is associated with an increased risk of premature rupture of the membranes, preterm delivery, and low birth weight. Treatment may prevent respiratory or genital infection in the neonate.
- #22 Cmplications of C. trachomatis include pelvic inflammatory disease (PID), ectopic pregnancy, and infertility. C. trachomatis infects the newborn through exposure to the infected cervix during delivery. Perinatal infection most commonly causes conjunctivitis that develops 5 to 12 days postpartum. A subacute, afebrile pneumonia with an onset at ages 1 to 3 months may occur. Gonorrheal infection can cause PID, a known risk for infertility. Perinatal gonococcal infection results from exposure to the infected cervix during birth. Symptoms usually manifest within 2 to 5 days after delivery. Milder manifestations include rhinitis, vaginitis, and urethritis. More severe presentations include ophthalmia neonatorum and sepsis.50 Identification and treatment of the infection in neonates is crucial, as permanent sequelae such as blindness can occur.
- #23 Syphilis is caused by Treponema pallidum; complications are many (eg, mucocutaneous lesions, altered mental status, visual and auditory abnormalities, gumma, cranial nerve palsies). If a penicillin allergy is present, women with IgE-mediated hypersensitivity can undergo desensitization. Penicillin effectively prevents transmission to the fetus and treats the fetus, if already infected. Treatment during the second half of pregnancy may increase the risk for preterm labor and fetal distress because a Jarisch-Herxheimer reaction may occur; however, treatment should not be withheld or delayed.
- #24 Migraine headaches are associated with estrogen fluctuations in women of childbearing age. Between 60% and 70% of pregnant women with a history of migraine headaches experience symptom improvement during pregnancy; 20% experience complete cessation. Improvement is more likely in women who have migraine without aura and in women with a history of menstrual migraine. All NSAIDs are contraindicated in the third trimester because of the potential for premature closure of the ductus arteriosus. Aspirin should be avoided in the third trimester because, in addition to its effects on the ductus arteriosis, it can cause maternal and fetal bleeding as well as decreased uterine contractility (hence, prolonged labor). Opioids are rarely used.
- #25 For migraines that are not responsive to other treatments, triptans may be used; sumatriptan is the triptan of choice because for other triptans, there is relatively little information about use in pregnancy. Ergotamine and dihydroergotamine are contraindicated because of effects on uterine tone.
- #31 Streptomycin – ototoxic to fetus
- #32 Health consequences of untreated or poorly treated asthma include preterm labor, preeclampsia, intrauterine growth restriction, premature birth, low birth weight, and stillbirth; therefore, the treatment goal is to achieve and maintain control of asthma symptoms. Asthma is controlled when there are no daytime symptoms, limitations of activities, nocturnal symptoms, short-acting β2-agonist use, or exacerbations, and there is normal pulmonary function.
- #36 Intranasal corticosteroids are most effective Rx, low risk of systemic effect (Beclomethasone, Budesonide are most widely studied) Second gen Antihistamines do not appear to increase fetal risk but are less extensively studied than first generation products.
- #37 Diabetic retinopathy may worsen, hypertension may develop, renal function may deteriorate. Diabetes in pregnancy includes pregestational and gestational diabetes. Women with pregestational diabetes should be counseled about Increase risk of complications such as miscarriage, fetal/neonatal death, malformations, macrosomia, preeclampsia, need for cesarean section. Euglycemia at conception and during pregnancy is the best approach in preventing poor pregnancy outcomes. Women with type 2 DM may be started with insulin therapy before pregnancy if they do not achieve optimal control of DM. Gestational DM is associated with neonatal macrosomia, PE, cesarean section but not with major fetal malformations.
- #38 Diabetic retinopathy may worsen, hypertension may develop, renal function may deteriorate. Intravenous drip insulin should be used during labor.
- #39 Increase maternal volume of distribution, decrease protein binding from hypoalbuminaemia, increase hepatic metabolism, increased renal drug clearance – changes in free serum concentrations of antiepileptic drugs. A woman’s clinical condition and her free serum concentrations of antiepileptic drug should be the basis for dose adjustments.
- #48 Only single course. Current guidelines do not support the use of repeated courses of corticosteriods.