- Hypertensive Disorders and Heart Disease
- Diseases of Respiratory System
- Diseases of Gastrointestinal Tract
- Diseases of Genitourinary System
- Endocrine Disorders During Pregnancy
- Dermatological Lesions During Pregnancy
- Disorders of Coagulation During Pregnancy
- Problems Related to Central Nervous System
- Autoimmune Diseases During Pregnancy
- Anti-malarials Drugs for the Pregnant
- Anti-toxoplasma Drugs for the Pregnant
- Some Typical Foetus-related Problems of Antenatal Period
- Night Cramps and Migraine During Pregnancy
- Oxytocics and Tocolytics
- Drugs for Ripening of Cervix
- Drugs for Labour Analgesia
- Some Typical Problems of Puerperium
- Scope and Safety of Some Commonly Prescribed Drug-Groups During Pregnancy and Lactation
- Recommendation for Immunisation During Pregnancy
- Drugs for Resuscitation of Newborn
- Safety Guidelines about use of Drugs During Pregnancy and Lactation
1.1 DRUGS FOR PREVENTION OF PRE-ECLAMPSIA
INSTANT PHARMACY
Aspirin, Calcium, Anti-oxidants—vitamin E and vitamin C (Restriction of sodium and fluid intake are not effective, Cunningham et al., 2010).
LOW-DOSE ASPIRIN (75 mg)
Loprin (Unichem); ASA (Zydus)
Dose: 1 tablet daily after food.
Basis: It is an anti-thromboxane therapy. Aspirin, by acting on platelet, suppresses the synthesis of thromboxane, which appears to play a significant role in the pathogenesis of pre-eclampsia.
Scope: It may be given from about 12th week of pregnancy—but only to those women who, from the past history and current clinical situation, are judged to be highly prone to develop pre-eclampsia. The aim here is to prevent development of hypertension-proteinuria syndrome.
Debatable position of low-dose Aspirin therapy: Collaborative Low-dose Aspirin Study in Pregnancy (CLASP) study (1994) and other studies have found this therapy ineffective or of marginal benefit (William Obstetrics, 2010).
Caution
It has been reported to increase the incidence of retroplacental bleed by seven fold (Hopkinson, 1997).
In any case, according to manufacturer's literature, aspirin is contraindicated in third trimester of pregnancy for fear of causing bleeding in both mother and foetus. The author has reported two cases of severe foetal bleed along with typical cardiotocography tracings (Debdas, 1998).1
Calcium Citrate Preparation: Methycal 1,000 mg (Indoco); Supracal XT 1,000 mg (Pharmed).
Usual dosage 1,000 mg daily but for mothers from low socioeconomic status up to 2 g daily may be prescribed.
Calcium supplementation in high dosage has been found by some worker to lower the incidence of pre-eclampsia in deficient subjects but others found it to be ineffective even in the dosage up to 2 g daily (Levine et al., 1997).
ANTI-OXIDANTS
Vitamin E
Evion (Merck); Natvie (Franco-Indian) 400 mg capsule.
Dose: 1 or 2 capsule daily.
Vitamin C
Celin (GSK); Chewcee (Wyeth) 500 mg tablet studies have not found to reduce the incidence of pre-eclampsia by these (Cunningham et al., 2010).
1.2 DRUGS TO BE USED FOR TREATMENT OF PRE-ECLAMPSIA
INSTANT PHARMACY
Labetalol, Nifedipine, Hydralazine, Magnesium sulphate, Phenytoin, Ringer lactate solution, continuous lumbar epidural.
Therapeutic approaches towards treatment of pre-eclampsia are as follows:
- Anti-irritation therapy
- Anti-hypertensive therapy
- Anti-convulsant therapy
- Anti-haemoconcentration therapy
(Restriction of sodium and fluid intake are no longer recommended, Williams Obstetrics, 2010).
ANTI-IRRITATION THERAPY
Sedatives and Tranquilizers
Routine use of these are no longer recommended (Williams Obstetrics, 2010). These are indicated only if the patient cannot sleep or is too upset and fearful about her raised BP.
It's possible consequences on her and her foetus are well-known. Because they are sedated, sometimes this itself calls for admission to hospital for looking after.
Alprax (Torrent); Zolam (Stadmed)
Dose: Just one tablet on the day of admission only as an exception. It is actually contraindicated in pregnancy.
However, more important than the drug is repeated counseling and assurance of both patient and her husband and family members.
Note: If there is sudden rise of BP or BP remains constantly high sedative is not the appropriate treatment. In such cases, antihypertensive, anticonvulsant, delivery of the patient, etc., should be considered.
ANTI-HYPERTENSIVE THERAPY FOR PRE-ECLAMPSIA (PROTEINURIC)
It varies with the severity of the disease.
- For mild to moderate pre-eclampsia (specially in premature gestation between 26 and 34 weeks where pregnancy must be continued)BP—> 140/90 but <160/110, Proteinuria—<2 g in 24 hours, normal platelet.There is no scope of anti-hypertensive therapy here. Because:
- It does not make any difference in perinatal mortality.
- It doubles the rate of intrauterine growth restriction (IUGR) (Williams Obstetrics, 2010).
The plan of treatment here would be, in addition to obstetric management, close monitoring of BP and proteinuria to ensure that the patient is not entering the severe stage of the disease in which event anti-hypertensive and anticonvulsive therapy would be instantly necessary as an emergency measure. - For severe pre-eclampsiaCriteria (Williams Obstetrics, 2010)BP—160/110, Proteinuria—2.0 g/24 hours, serum creatinine— 1.2 mg/dL or higher, Platelet—100,000 or less, increased lactate dehydrogenase (LDH), elevated liver enzymes—doubling of aspartate transaminase.Headache, epigastric pain, visual disturbanceTherapeutic approach
- Anti-hypertensive
- Anti-convulsant
- Anti-haemoconcentration.
ANTI-HYPERTENSIVES
These are must here as a part of crisis management until the appropriate treatment for the condition, i.e., prompt delivery of the patient can be arranged. The purpose of instantly bringing down the BP here are:
- To prevent cerebral haemorrhage
- To prevent abruption of placenta
- To cover the stress of labour if she is in labour
- To cover the stress of general anaesthesia—if it is required. (Safe maturity of foetus is also a concern here but a secondary one).
Choice of Anti-hypertensive Drugs
- Cut-off level of BP for starting the drug—105 diastolic
- Must be ‘rapidly acting’ (within 5–10 minutes)
- Choice of drug:
- First-line drugs
- Nifedipine
- Labetalol
- Hydralazine
- Second-line drugs: Indicated only the first-line drugs fail.
- Nitroglycerine
- Sodium nitroprusside
- Continuous lumbar epidural analgesia helps to control BP and is indicated for patients in labour and for those whose labour is being induced.
Nifedipine
- Depin (Zydus); Nifedipine (AHPL)
- Availability: 5 mg and 10 mg capsules
- Dose: 5–10–20 mg orally (not sublingually—risk of precipitous fall of BP) depending on the level of BP. Dose has to be titrated by BP response. The aim is to bring down the diastolic BP to between 90 and 100 mmHg but no lower because that would reduce placental perfusion and cause foetal distress (abnormal CTG). It has been found that Nifedipine gives comparable result as hydralazine.
- Mechanism of action: Calcium channel blocker.
Labetalol
(This is preferred because of its less side effects, Williams Obstetrics, 2018)
- Normadate (GSK) 50 mg and 100 mg tablet
- Labebet (Sun) (20 mg/4 mL and 100 mg/20 mL injection
- Dose: 20 mg slow IV bolus—wait for 10 minutes, if no response give 40 mg slow bolus—wait for 10 minutes—give 80 mg slow IV—if no response, may give up to total 220 mg per episode of treatment (NHBP, 2000; Williams Obstetrics, 2010). If still uncontrolled—80 mg every 10 minutes. If still uncontrolled, start Hydralazine (Williams Obstetrics, 2018). The target diastolic BP is 90–100 mm. Tablets are for chronic use (see topic 1.4 “Anti-hypertensives for Essential Hypertension During Pregnancy” later).
- Mechanism of action: It is an alpha-1 and non-selective beta blocker.
Hydralazine
Note: Intravenous preparation which is necessary for such hyper- tensive crisis is not easily available in India.
- Dosage and administration:
- Slow IV—5 mg diluted in 10 mL of normal saline slow IV at 15–20 minutes interval until diastolic BP comes down to between 90 and 100 mmHg (Williams Obstetrics, 2010) maximum cumulative dose is 30 mg per treatment cycle.
- IV infusion: It must be diluted only in normal saline or Ringer lactate solution. In 500 mL bottle—50 mg of the drug is to be added. Initially the rate of infusion should be 150–250 μg/minute (i.e. 30–50 drops/min). The maintenance dose is 50–150 μg/minute (10–30 drops/min).
- Oral (Hydralaze, Dahlia): This is meant for less urgent cases. Tablet of 25 mg may be given twice daily and if necessary may be increased to 50 mg BD (British National Formulary, 2012).
- Monitoring: Besides other things close monitoring of pulse is a must because this drug can cause troublesome tachycardia. It should not be given to patients who already has tachycardia.
- Mechanism of action: It causes direct relaxation of arteriolar muscle.
Nitroglycerin
- Onset of action: Very fast—0.5–5 minutes
- Dose: 5 μg/minute IV.
Sodium Nitroprusside
Dose: 0.25–5 μg/kg/minute IV
For such intractable cases needing second-line anti-hypertensive a physician or an intensivist should be around.
ANTI-CONVULSANT THERAPY
This is to be started.
This has been discussed separately in details in the next topic 1.3 “Drugs to be used for Controlling Eclamptic Fit”.
ANTI-HAEMOCONCENTRATION THERAPY
Blood volume expansion therapy: Since haemoconcentration is a part of pathology of pre-eclampsia-eclampsia syndrome, this approach is logical.
However, trails of this approach using both crystalloids and colloids have shown that the grave complication of pulmonary oedema takes place quite quickly in these cases on fluid overloading. So, the recommendation is, fluid should be infused 8in moderation only (see ‘Dose’) unless there is some exceptional fluid loss, e.g., by vomiting, etc., Ringer lactate solution in the fluid of choice (Williams Obstetrics, 2018).
Ringer Lactate: This is the fluid to be chosen.
Dose: 60–120 mL/hour at 15–30 drops/minutes. A total of 1,500–3,000 mL can be given 24 hours.
Note: Plasma volume expanders are ‘contraindicated’ in eclampsia and severe pre-eclampsia.
Plasma Exchange
This is under trial for persistent severe hypertension, fits hemolysis elevated liver-enzymes, low platelet count (HELLP) syndrome, etc., post-delivery (Williams Obstetrics, 2018).
1.3 DRUGS TO BE USED FOR CONTROLLING ECLAMPTIC FIT (ANTI-CONVULSANT THERAPY)
INSTANT PHARMACY
Magnesium sulphate, Phenytoin
MAGNESIUM SULPHATE REGIME
- Availability: As 50% solution—each (2 mL) ampoules contains 1.0 g (Vulcan Lab)Easy calculation—1 ampoules = 1 gSo, for 4 g dose—use 4 ampoules, for 5 g dose—use 5 ampoules
- Dose: The dose detailed here is that for eclampsia, i.e., for a patient who actually had a fit or many fits and also that for cases of severe pre-eclampsia (diastolic BP 110 or more plus proteinuria, etc. For details, see the topic 1.2 “Drugs to be Used for Treatment of Pre-eclampsia”).
- Mode of action:
- Reduces motor end-plate sensitivity to acetylcholine and thereby reduces neuromuscular irritability
- Blocks neuronal calcium influx
- Induces cerebral vasodilatation
- Dilates uterine artery
- Increases production of endothelial prostacyclin and inhibits platelet activation
- No neonatal depression
(Note: It is not a hypotensive drug) - Protocols: Two protocols
- Intramuscular protocol
- Intravenous protocol
Eclampsia Drug Tray
This must be ready in each labour room in which the following should be:
- Distilled water (10 mL vial)—3 numbers
- 20 mL syringe—4 numbers
- Long IM needle—4 numbers for deep IM injection (normal needle comes with the syringe)
- Lignocaine injection (2%)—one vial
- Tourniquet—one
- Spirit swab for cleaning the injection site—4 numbers
- Calcium gluconate (10%)—one ampoule of 10 mL = 1 g
Intramuscular Protocol
This regime is preferred by many for safety specially in domiciliary practice, in primary health centers (PHCs) and small hospitals because of their fear of administering the drug IV and also sometimes because patient's veins are difficult to get (generalized oedema). For this route 50% solution is ideal (not 25%) because volume to be injected will be less.
Instant Dose
Instant dose are in two parts: (1) intravenous and (2) intramuscular.
Intravenous Part
Even for IM protocol the initial dose has to be given in IV shot as follows in order to stop the fit and near fit instantly:
- Take 4 ampoules of Magnesium sulphate = 4 g of the medicine. The volume of the medicine will be (2 mL × 4) 8 mL. This is to be drawn in a 20 mL syringe. Then distilled water is to be drawn into the syringe (12 mL) to make the total volume of 20 mL. This is then is to be given IV slowly over 5 minutes at the rate of roughly 1 g/minute.
Intramuscular Part
Two lots of 5 g of 50% solution, i.e., 5 ampoules or (2 mL × 5) 10 mL of medicine is to be made ready in two 20 mL syringes. These are then to be injected deep IM into two buttocks with the help of a (ideally) 3 inches or 7 cm long 20-gauge needle in two separate shots of 10 mL each, i.e., since this injection is very painful one may add 1 mL of 1% Lignocaine to each injection dose.
Subsequent dose: 5 g of 50% solution (5 ampoules = 2 mL × 5 = 10 mL) to be given deep IM as usual in alternate buttocks every 4 hours guided by recurrence of fit and monitoring report. If fit recurs and it is not yet 4 hours after the last injection, another shot of magnesium sulphate 2 g have to be given IV right then.
Intravenous Protocol
Instant Dose
About 4 g (4 ampoules = 2 mL × 4 amp) or 8 mL of 50% solution to be drawn in a 20 mL syringe and diluted by drawing 12 mL of 10distilled water (as described above under IV part of IM protocol) is to be injected slowly IV over 5 minutes at the rate of 1 g/min. If convulsion persists even after this instant dose-another 2 g (2 ampoules = 4 mL) diluted with 6 mL of distilled water is to be given IV slowly as above.
Subsequent Dose
1–2 g hourly, diluted as above, depending on (a) the findings of the monitoring parameters as given below and (b) recurrence of fit. Alternatively, for subsequent IV dose 25 g of the drug may be added in a drip bottle (500 mL of 5% dextrose or normal saline) and using a micro or paediatric drip set or syringe pump—the drip rate is to be titrated as desired. In this mixture each 20 mL will contain 1 g of the medicine—so it has to be given very very slowly.
Criteria for Monitoring Magnesium Sulphate Toxicity
Clinical Criteria
These three criteria must be checked hourly and recorded.
- Respiratory rate: Must be more than 12/minute
- Patellar reflex: Must be present and must be of normal intensity. But hyper-reflexia is not an indication to increase the dose
- Urinary output: This must be more than 25 mL/hour. Since Magnesium sulphate is excreted solely through kidneys any oliguria would mean its accumulation.
Biochemical Criteria
- Magnesium level: It should be done every 2 hours and its level be kept between 4 and 7 mEq/L. However, this test is not a must. Strict clinical monitoring has been found to be good enough.
- Plasma creatinine: This should be done in all cases every 3–4 hourly and whenever it is 1.3 mg/dL or higher—the maintenance dose of Magnesium sulphate should be halved.
Duration of Magnesium Sulphate Therapy
It should be continued up to 24 hours after delivery.
Anti-dote to Magnesium Sulphate
Calcium gluconate 1 g (10 mL of 10% solution) is to be given IV over 2–3 minutes. This injection must be ready at bedside.
Efficacy of Magnesium Sulphate Therapy
According to the current reports, of the three alternatives namely Magnesium sulphate, Diazepam and Phenytoin, Magnesium sulphate would appear to give the best fit control and overall maternal and foetal results (Williams Obstetrics, 2010).
In the rare event of fits not getting controlled by Magnesium sulphate—Sodium Amobarbital 100–250 mg may be given IV very slowly. Alternatively, Thiopental may be given (Williams Obstetrics, 2010).
Place of Diuretics in the Treatment of Eclampsia
Diuretics have no role in the routine treatment of eclampsia specially because not only it does not help, but also it actually aggravates the haemoconcentration which is a significant part of the pathology of the disease. The only indication of its use is for treatment of ‘acute pulmonary oedema’ which sometimes occurs as a life-threatening complication of eclampsia. The diuretic of choice here is furosemide injection given IV.
Furosemide
Lasix, 10 mg/mL (Aventis). It comes in 2 mL ampoule and 15 mL vial.
Dose: 100–250 mg to be given IV depending upon the state of the patient and her lungs.
Dose may have to be repeated.
Status Eclampticus
- Patient having convulsion almost continuously.
- It is a life-threatening condition.
- Anaesthetist to be summoned urgently.
- Options:
- Thiopentone sodium: 0.5 g dissolved in 20 mL of 5% dextrose is to be given IV very slowly. If this fails:
- General anaesthesia with intubation and artificial ventilation and muscle relaxant is to be resorted to.
These patients almost invariably need termination of pregnancy and one should proceed for caesarean section when anaesthetist permit.
Half Dose Magnesium Sulphate
This is used in poor resource distant rural situation in lean patients. There is no randomised controlled trial (RCT) on this method.
Anti-hypertensive Treatment
These patients along with anti-convulsive therapy also need management of her hypertension. This has been given in topic 1.2 “Drugs to be Used for Treatment of Pre-eclampsia”.
This is the ultimate treatment. It will not only dependent on obstetrics factors like maturity, dilatation of os, presentation, state of foetal heart rate (FHR) but also duration since last fit and number of fits. In any case, as a general rule, not more than 6 hours should be allowed.
1.4 ANTI-HYPERTENSIVES FOR ESSENTIAL HYPERTENSION DURING PREGNANCY
INSTANT PHARMACY
Labetalol, Methyldopa
Scope of Anti-hypertensive
Blood pressure (BP) of 160 + systolic and 90 + diastolic (Williams Obstetrics, 2010).
Risk
Development of superimposed pregnancy-induced hypertension (PIH) which can occur in 4–40% cases. Occurrence of this can be predicted by uterine artery Doppler velocimetry at 16–20 weeks by increased impedance.
Aim of Therapy
To bring down and maintain the diastolic between 90 and 100 mmHg.
Choice of drug: Two choices
- First-line drug—Labetalol
- Second-line drug—Methyldopa
Methyldopa
Sembrina (Sanofi); Alphadopa (Merind) 250 mg tablet.
Dose: 250 mg BD, TD or QDS up to maximum 2 g daily titrated by BP.
Safety: Safe throughout the gestation. If a non-pregnant hypertensive woman is planning to conceive—she may be changed to Methyldopa beforehand.
Mechanism of action: Acts centrally and decreases the central nervous system (CNS) sympathetic outflow.
Caution: Avoid giving to depressives and postpartum, may cause depression.
Labetalol
Recently, this has been acknowledged as first-line therapy by Royal College of Obstetricians and Gynaecologists (RCOG) 13and The American College of Obstetricians and Gynaecologists (ACOG).
Normadate (GSK) 50, 100 mg tablet; Labebet (Sun) 100 mg tablet.
Dose: 50–100 mg BD or TD to be titrated according to BP.
Mechanism of action: It is both alpha and beta blocker.
Contraindication: Asthma
ANTI-HYPERTENSIVE DRUGS CONTRAINDICATED IN PREGNANCY
- Angiotensins-converting enzyme (ACE) inhibitors
- Oligohydramnios, poor foetal renal function and malformation
- Guanethidine
- Minoxidil
- Sodium nitroprusside
- Diltiazem
- Atenolol—may cause intrauterine growth restriction (IUGR) if given in first and second trimester.
Overall Results of Anti-hypertensive Therapy
It may cause IUGR but it is controversial. According to literature overall adverse outcome is not altered by the therapy. However, 11% of those not treated from early in pregnancy have been reported to develop severe hypertension in later pregnancy with all its complications. Those with end-organ disease must be treated right from the beginning (Williams Obstetrics, 2010).
1.5 DRUGS USED FOR HEART DISEASES DURING PREGNANCY
INSTANT PHARMACY
Beta blocker (Atenolol), Digoxin, Adenosine, Verapamil, Diuretic, Antibiotic, Anticoagulant.
The patient should be under care of Cardiologist.
Atenolol
Aten (Zydus); Betacard (Torrent) 25, 50 mg and 100 mg tablet.
Mechanism of action: It is a beta blocker
Dose: To be individualised.
Note: Its regular use is contraindicated in pregnancy because it can cause intrauterine growth restriction (IUGR).
Indication: Mitral stenosis, mitral valve prolapse, etc.
Tablet: Digox (Cadila); Lanoxin (GSK) 0.25 mg
Injection: Digoxin (GSK); Celoxin (Celon) 0.05 mg/2 mL
Indication: Congestive cardiac failure, arrhythmia, paroxysmal supraventricular tachycardia, atrial fibrillation and flutter, etc.
Dose: It has to be individualised depending on the gravity of indication and higher doses must be given in divided schedule.
Schedule:
- Rapid digitalisation by mouth—0.5–1.0 mg stat followed by 0.25 mg 6 hourly
- Slow digitalisation by mouth—for less urgent cases. 0.25 mg once or twice daily.
Safety: Digoxin is the drug of choice in pregnancy. No teratogenicity has been reported with this drug.
Caution: Pulse chart, intake-output chart and blood urea must be watched.
Note: Digoxin has been successfully used to control supraventricular tachycardia in the foetus.
Adenosine
Adenoz (Celon); Adenoject (Sun) 3 mg/mL
Dose: 6–12 mg rapid IV under cardiac monitoring.
Indication: Paroxysmal supraventricular tachycardia, cardioversion
Mode of action: Acts rapidly and specifically on AV nodal conduction on A1 and A2 Adenosine receptors.
Verapamil
Calaptin (AHPL); Celovera (Celon): Tablet—40 mg and 80 mg
Injection: 5 mg/2 mL injection
Dose: Oral 40–80 mg TDS
Intravenous: 5–10 mg over 2–3 minutes under electrocardiography (ECG) control
Indication: Fibrillation, arrhythmias
Note: Risk of potential foetal bradycardia.
Diuretic
See topic 18.6 “Diuretics Therapy in Obstetrics”.
Antibiotic
Indication
- Rheumatic heart prophylaxis—for this ‘long-term’ Penicillin is given. Benzathine Penicillin 1.2 million unit (PENIDURE LA-12, Wyeth) every 2 weeks throughout pregnancy and puerperium.
- 15Bacterial endocarditis prophylaxis—this involves giving a ‘short course’ of antibiotic after delivery specially after operative delivery, manual removal, history of ruptured membranes, suspicion of bacteraemia, etc. Given below is the current recommendation for the purpose (Williams Obstetrics, 2010):
- IV regime: Ampicillin 2 g or Cefazolin 1 g or Ceftriaxone 1 g Clindamycin 600 mg IV for those allergic to Penicillin.
- Oral regime: Amoxicillin 2 g or Vancomycin 0.5–2 g daily in 3–4 divided doses for 7–10 days (Vancomycin) if allergic to Penicillin.
Note: Blood culture aerobic and anaerobic should be done intermittently.
Anticoagulant
Mandatory anticoagulant therapy for certain thrombogenic heart diseases. Example:
- Pregnancy in women with artificial heart valve
- Mitral stenosis with atrial fibrillation
Anticoagulant of Choice
Paradoxically the drug of choice here is Warfarin though it is ‘contraindicated’ in pregnancy. This is because, it causes congenital malformation and foetal and retroplacental bleeding. However, this risky drug has to be chosen for the cases mentioned above because subcutaneous heparin does not give adequate anticoagulant protection here exposing the patient to the great risk of cerebral embolism. Patient and husband must be thoroughly counseled about both the aspects of the therapy and this communication is to be documented. The risk is greatest during first 3 months and last 3 weeks of pregnancy.
Dose and Plan
Dose of Warfarin and its monitoring has been described in detail in the topic 7.2 “Regime of Anti-coagulation for Postnatal Deep Venous Thrombosis”. However, Warfarin must be stopped at the end of 36 weeks when the patient must be admitted to hospital and switched over to subcutaneous heparin 10,000 units twice daily in the way as described in topic 7.1 “Regime of Anti-coagulation for Antenatal Deep Venous Thrombosis”.
DRUG SKETCH FOR MANAGEMENT OF MITRAL STENOSIS
This is being presented since this is the most common cardiac condition during pregnancy.
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