notes/DC Dutta Obstetrics 10th Edition_15.txt

Abdominal wall

terine wall

1                                             2                  4                  8 2                                         4                  8                  16 8                                         16                32                64


Ta bl e 34.3:The convenient regime.,'-<.:' 't,,,. , •,, ,-- .1 '""" • ,,; *,;.;,,.,,;;,.,
Solution  Escalating drop rate at Dose· of oxytocin	used	intervals of20-30 minutes
.,    ·  , .... ,	:·,.    _,   .·.« /,'·   ·   -c··•
w
·
j
1
,    -•
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 	<',.,\ C	c;  <          ,  '/,, ',.CC'fttl       ,-2,,"
To start with 1 unit	500 ml	15-30-60 Ringer solution
If no response-2 units             -do-                         -do-If still no response-8 units       -do-                         -do-

High-dose  oxytocin  begins  with  4  mIU/min  and increased 4  mIU/min at eve,y 20-30 min interval. It is mainly used for augmentation of labor and in active management of labor. Risks of uterine hyperstimulation and  fetal heart  irregularities  are  more  with high-dose regime.
In  majority  of  cases,  a  dose  of 4  to  8  mill/min (2  units in 500  mL  Ringer solution  with  drop  rate of  20-30/min)  is  enough  to  achieve  the  objective. Conditions  where  fluid  overload  is  to  be  avoided, infusion with high concentration and reduced drop rate is preferred (Tables 34.2 and 34.3). Use of infusion pump with variable speed can avoid excess volume infusion.
For augmentation of labor
Oxytocin infusion is used during labor in uterine inertia
or for augmentation of labor or in the active management of labor for details, p. 489. The procedure consists of low rupture of the membranes followed by oxytocin infusion when the liquor is clear. Fetopelvic disproportion must be ruled out beforehand.
Observation during oxytocin infusion
11    Rate of flow of infusion by counting the drops  per minute or monitoring the pump.
■   Uterine contractions-number of contractions per 10 min duration and period of relaxation are noted. 'Fingertip' palpation for the ton us of the  uterus in between contractions (Fig. 34.I) may be done where gadgets are not available.
■   Peak intrauterine pressure of 50-60 mm Hg with a resting tone 10-15 mm Hg is optimum when intrauter­ ine pressure monitoring is used (Fig. 25.2).
11    FHR monitoring is done by auscultation at every 15 minutes interval or by continuous EFM.
■   Assessment of progress of labor (descent of the head and rate of cervical dilatation).




Fig. 34.1: To note the uterine tonus.

Indications ofstopping the infusion
1.  Nature of uterine contractions-(a) Abnormal uterine contractions occurring  frequently  (every 2 minutes
or less) or lasting more than 60 sec ( tachysystole). (b) Increased tonus in between contractions.
2.  Evidences of fetal distress.
3.  Appearance of untoward maternal symptoms.
Carbetocin is a longer acting oxytocin derivative.  It is effective to control atonic PPHfollowing cesarean delive,y. It is given slow IV per dose.
Pharmacological properties of carbetocin are similar to myt.ocin. It has a longer biological half-life (40 minutes). Its onset of action is 2 minutes. after IV or IM administration. It causes sustained uterine contraction and is  stable at room temperature. It is given IV, slowly over 1 minute. Each mL of vial contains carbetocin 100 ftg.
Contraindication  of  use:  Pregnancy,  labor  before delivery of the baby, induction/augmentation of labor, renal, hepatic, cardiovascular disorders, epilepsy and drug hypersensitivity.

I._Q _ GNOSTIC USE OF OXYTOCIN ♦   Contraction Stress Test ( CST)
♦    Oxytocin Sensitivity Test ( OST)

CONTRACTION STRESS TEST (CST) (Syn: Oxytocin challenge test)
It is an invasive method to assess the fetal wellbeing during pregnancy. When there is alteration in FHR in response to uterine contractions, induced by oxytocin, it suggests fetal hypoxia. This test is not commonly done these days (Box 34.1).
Principles: The test is based on determination of the respirato,y function of the fetoplacental unit during induced contractions when the blood flow through the unit is curtailed. The objective is to detect the degree of fetal compromise so that a suitable time can be selected to terminate the pregnancy.
Candidates for CST: (1) Intrauterine Growth Restriction, (2)  Postmaturity, (3) Hypertensive disorders of pregnancy, ( 4) Diabetes.
Chapter 34: Pharmacotherapeutics in Obstetrics

Table 34.4: Composition of different Ergot preparations.

■  Positive: Persistent late deceleration of FHR with 50% ormore of uterine contractions.
■  Negative: No late or significant variable deceleration. ■  Suspicious: Intermittent late or variable decelerations.
11      Unsatisfactory: <3 contractions per 1 Ominutes or an unpredictable tracing.
■   Tachysysto/e: Decelerations with contractions lasting >90 seconds or occurringmore frequently than every 2minutes.


Preparations
Ergometrine (ergonovine)
Methergine (methylergonovine)
Syntometrine (Sandoz)


Ampoules 0.25-0.5mg

0.125-0.250 mg

0.5 mg-ergometrine +
5 units-syntocinon

Tablet 0.5-1mg

0.125-0.5mg



Contraindications: (i) Compromised fetus, (ii) Previous history of cesarean section, (iii) Complications likely to produce preterm labor, (iv) APH, (v) multiple pregnancy.
Procedure: The oxytocin infusion is started in the same manner as mentioned earlier. The initial rate of infusion is 1 mIU/minute which is stepped up at intervals of20 minutes until the effective uterine contractions are established. The alteration of the FHR during contractions is recorded by electronic monitoring. Alternatively, clinical monitoring can effectively be performed using hand to palpate the hardening of the uterus during contraction and auscultation of FHR during contraction and for 1 minute thereafter. It takes at least 1-2 hours to perform the test.
Importance: A negative test is associated with good fetal outcome. Whereas a positive CST is associated with increased incidence of IUD, fetal distress in labor and low Apgar score. But there is 50% chance of false-positive results and as such positive test cases are subjected to other methods of evaluation [biophysical profile and Doppler studies for the wellbeing of the fetus. Suspicious CST should have a repeat test in 24 hours.
I ERGOT DERIVATIVES
Out of many  ergot derivatives,  two are used extensively as oxytocics. These are:
♦   Ergometrine (Ergonovine in USA)
♦   Methergine (Methyl-ergonovine in USA)
CHEMISTRY:  Ergometrine  is  an  alkaloid isolated by  Dudley and Moir in  1935  from  Ergot,  a  fungus  Claviceps  purpurea that develops commonly  in  cereals  like  1ye,  wheat,  etc.  The alkaloids are detoxified in the liver and eliminated in the urine. Methergine is a semisynthetic product derived from lysergic acid (Table 34.4).

MODE OF ACTION: Ergometrine acts directly on the myometrium. It excites uterine contractions which come so frequently one after the other with increasing intensity that the uterus passes into a state of spasm without any relaxation in between.
EFFECTIVENESS: Keeping the physiological functions in mind, it should not be used in the induction of abortion or labor. On the contra1y, it is highly effective in hemostasis-to stop bleeding from the uterine sinuses, either following delivery or abortion. Methergine is somewhat slower in producing uterine response taking 96 seconds in contrast to 55 seconds by ergometrine when administered intravenously (Table 34.5).
MODE OF ADMINISTRATION: Ergometrine and methergine can be used parenterally or orally. As it produces tetanic uterine contractions,  the preparation should  only be used either in the late second stage of labor ( after the


delivery of the anterior shoulder) or following delivery of the baby. Syntometrine should always be administered intramuscularly.
SIDE EFFECTS AND HAZARDS
1. Common side effects are nausea and vomiting.
2.  Because  of  its  vasoconstrictive  action,   it  may precipitate  rise  of  blood  pressure,   myocardial infarction, stroke and bronchospasm.
3. Repeated use may lead to gangrene of the toes due to its vasoconstrictive effect.
4.  Repeated  use  in  puerperium  may  interfere  with lactation by lowering prolactin level.
CONTRAINDICATIONS: Table 34.6.
USES OF ERGOMETRINE/METHERGINE
CAUTIONS: Ergometrine should not be used during preg­ nancy, first stage of labor, second stage prior to crowning of the head (Table 34.6).
COMMENTS:  As  a  hemostatic  in  uterine  hemorrhage following expulsion of the fetus irrespective of duration of pregnancy, ergometrine or methergine is the drug of choice (Table 34.7). On the contrary, oxytocin is predominantly used  to initiate uterine contractions  (induction)  and to accelerate uterine contractions in labor (augmentation). I PROSTAGLANDINS (PGs)
Prostaglandins are the derivatives of prostanoic acid from which they derive their names. They have the property of acting as "local hormones''. They were first described and named by Von Euler in 1935.
Chemistry: Prostaglandins are 20-carbon carboxylic acids with a cyclopentane ring which are formed from pol  unsaturated fatty acids. Ofthe many varieties ofprostaglandins (Table 34.8)
y

Table.34:5: Comparative stucly ·oi"onset'ana ,i:luratidn°of action' of
i
 d fMrent:oxytocics. :,; > -     '   ,',.     "           ,,_-,.     '.'     ,., '·,
1
:
,
:i'    - :
Syntocinon on puerperal
Routes  Ergometrine  Methergine   Syntometrine   uterus
Onset of action
IV	45-60 sec	l½ min	Not to be used  30 sec
IM	6-7min	?min	21h min	2½min Oral	10min	10min	-	-
Duration of action
3 hr	3 hr	3 hr	8 min
Chapter 34: Pharmacotherapeutics in Obstetrics     il Table 34.6: Place of ergometrine/methergine in Obstetrics.
Indications	Contraindications
A.    Prophylactic	1. Suspected multiple pregnancy: If given accidentally following the delivery of the first baby, the Active management of third        second baby is compromised by the tetanic contractions of the uterus.
stage of labor as prophylaxis    2. Organic cardiac diseases: Results in sudden squeezing of blood from the uterine circulation into the
to excess bleeding following	systemic circulation causing overload of the right heart and failure.
3. Severe pre-eclampsia and eclampsia: Sudden rise of blood pressure or development of fits (eclampsia). 1---------------1 4. Rh-negative mother: More risk of fetomaternal microtransfusion.
delivery
B.    Therapeutic	5. Heart disease (cardiac failure).
To  stop  the  atonic uterine    6. Severe hypertensive disorders: Because of its vasoconstrictive effect, it may cause transient bleeding; following delivery,	hypertension or cardiac failure. Oxytocin is a better alternative in such cases.
abortion   or   expulsion   of    7. Presence of sepsis.
hydatidiform mole	8. Labor induction or during the course of labor (first and second stage).
9. Vascular disease.


Table 34.7: Comparati'.e study of Ergot d rivatives a'n :oxytocin. :  . ,


Mode of action

Onset of action Duration Clinical uses



Hazards


Contraindication

Ergot derivatives
Acts directly on the myometrium producing tetanic contraction with complete loss of polarity.
Comparatively slower. Long sustained.
■   To stop hemorrhage following delivery, abortion or
expulsion of H mole.
•  Prophylactic use in third stage to hasten separation of placenta and to minimize blood loss.
• Nausea and vomiting,
• Rise in blood pressure, stroke. Rarely gangrene of the toe,
•
See above

Oxytocin
Acts on the physiological uterine contractile system. Law of polarity is maintained.
Faster in action.
Short lived.
• In the induction of labor.
■  To augment uterine contraction during labor.
■  To stop postpartum or postabortal hemorrhage
along with ergometrine or in isolation. • Uterine hyperstimulation.
■   Antidiuretic effect, uterine rupture. ■   Anginal pain or rarely hypotension.
Table 34.1



Table 34.8: Pharmacoki,netic properties of PGE1  and routes of use.'-Routes         Onset of action (min)   Peak(min)    Duration (min)
Oral	8 (fastest to act)	60	 120 (shortest duration)
Sublingual    11                                        60                     180 Vaginal          20                                        120                   240
Rectal	100	120-180	240 (longest action)


PGEJI PGE2 and PGF2a are exclusively used in clinical practice.
The subscript numeral after the letter indicates the degree of unsaturation. Inactivation is done in lungs and liver.
Source: Prostaglandins are synthesized from one of the ess­ ential fatty acids; arachidonic acid, which is widely distributed throughout the body. In the female, these are identified in men­ strual fluid, endometrium, decidua and amniotic membrane.
Prostaglandins  (PGs)  in  obstetrics:  Increased biosynthesis of PGs of E and F series in the uterus is a prerequisite for labor in both term and preterm. PGs are paracrine/autocrine hormones as they act on locally at their site of production. Their half-life in the peripheral circulation is about 1-2 minutes.  Decidua is the main
source of PGF2a,  fetal membranes (amnion) produce PGE2   and  the  myometrium  mainly  produce  PGI2.

In vivo, PGF20  promotes myometrial contractility. PGE2
induces labor with cervical effacement and dilatation. It shortens induction to delivery interval. PGs promote myometrial contraction irrespective of the duration of gestation,  whereas oxytocin acts predominantly on the uterus at term or in labor. This has helped the widespread use of PGs to effect first trimester medical termination of pregnancy and also for induction of labor at term. Side effects of PGs are less when  used vaginally.  Local
application of PGE2 gel is the gold standard for cervical
ripening (Table 34.9).



10



Prostanoic acid
USE IN OBSTETRICS
■   Induction of abortion (MTP and missed abortion. ■   Termination of molar pregnancy.
■   Induction of labor.
■   Cervical ripening prior to induction of abortion or labor.
Chapter 34: Pharmacotherapeutics in Obstetrics


Table 34.9: Prostaglandins in Obstetrics. Advantages
■   Powerful oxytocic effect, irrespective of duration of gestation.
■ ·  Induction of labor (PGE1, PGEJ In cases with-(a) low pre-induction score; (b) IUFD.
■   Used in induction of abortion (PGE1)  with success ■   It has got no antidiuretic effect (cf oxytocin).
■   PGE1  (misoprostol) can be used for augmentation of labor.


Disadvantages and side effects
■   It is costly compared to oxytocin.
■   Nausea, vomiting, diarrhea, pyrexia, bronchospasm, tachycardia and chills.
■   Cervical laceration may occur (PGF al when used as an abortifacient. ■   Tachysystole (hyperstimulation) of the uterus, may occur during
2
induction and may continue for a variable period.
■   Risk of uterine rupture in cases with previous scar.



■   Augmentation (acceleration) of labor.
■   Management of atonic postpartum hemorrhage. ■  Medical management of tubal ectopic pregnancy.
CONTRAINDICATIONS
♦   Hypersensitivity to the compound. ♦   Uterine scar.
♦   Active cardiac, pulmonary, renal or hepatic disease;
hypotension (PGE2).
♦   Bronchial asthma (PGF20).
MECHANISM OF ACTION: Both PGE2  and PGF20 have got
an oxytocic effect on the pregnant uterus when used in appropriate dose. The probable mechanism of action is change in myometrial cell membrane permeability and/ or alteration of membrane-bound Ca++. PGs also sensitize
the myometrium to oxytocin. PGE2 is at least 5 times more potent than PGF2a.  PGF2a acts predominantly on
the myometrium, while PGE2 acts mainly on the cervix
due to its collagenolytic property. PGE2 causes dissolu­
tion of collagen bundles and increases submucosal water content of the cervix.
Preparations
Prostaglandin E2 is widely used because it is less toxic and
more effective than PGF2a. It is, however, more costly.
Vaginal tablet: Contains 3 mg dinoprostone (Prostin E2).
Instilled in the posterior fornix followed by 3 mg after 6-8 hours maximum dose of 6 mg.
Vaginal pessary ( with retrieval device process) releasing dino­ prostone approximately 10 mg over 24 hours. It is removed when cervical ripening is adequate. Dose not to be repeated.
Prostin E2  (Dinoprostone) gel-500 pg into the cervical canal,
below the level of internal os or 1-2 mg in the posterior fornix
(Fig. 34.2); may be repeated after 6 hours. Prostin E2 gel and tablet
are not bioequivalent.










Fig. 34.2:  Dinoprostone  gel in disposable syringe with catheter.


Parenteral: (a) PGE2  (IV)-Prostin E2 containing 1 mg/mL,
(b} PGF2a-Prostin F2a (Dinoprost tromethamine) containing 5 mg/mL, (c) Methyl analogue of PGF2a (Carboprost containing
250 pg/mL).
PGE2 is effective for induction of labor causing cervical effacement and dilatation. It reduces the need of oxytocin
use and cesarean delivery. PGE2  preparations are rela­ tively expensive and require refrigeration as it is unstable
at room temperature.
Methyl  ester  of PGE1   (misoprostol}:  It  is rapidly
absorbed  and  is  more  effective   than  oxytocin  or dinoprostone for induction oflabor.
Misoprostol (PGE1}   (Table 34.8)  has been used for
cervical ripening. Primarily it has been used for peptic ulcer disease. Transvaginal misoprostol is used for induction of labor. Oral misoprostol can be used as it is convenient to the patient. It is given 25-50 µg eve1y 3-6 hours by oral or
vaginal route. Low doses of oral PGE1  ( dissolving 200 µg
tablet in 200 mL tap water) 2-25 µg in solution is safe. It is to be repeated at interval of 2 hours. Buccal or sublingual misoprostol is also used for induction of labor and vaginal delive1y.  Oxytocin when needed may be  added  after 4 hours. Misoprostol has been found to be as effective as
PGE2 for cervical ripening and induction of labor. To date,
no evidence of teratogenic or carcinogenic effects has been
observed. PGE1  is effective in the management of AMTSL
and in the management of atonic PPH.
Advantages of PGE1 over PGE2: Misoprostol is cheap,
stable at room temperature, long shelf-life, easily admin­ istered ( oral, vaginal or rectal) (Table 34.8) and has less side effects. Induction delive1y interval is short. Need of oxytocin augmentation is less. Failure of induction is less.
Risks: Incidence of tachysystole (hyperstimulation), fetal heart rate changes and meconium passage are high. Rupture of uterus, though rare, has also been observed. It should not be used for cases with previous cesarean birth because the risk of rupture is high. Misoprostol is not yet approved for use in pregnancy by FDA. Use of misoprostol for induction of abortion has been discussed on p. 166.
Tachysystole: Contractions more than 5 in 10 minutes time averaged over a 30 minutes window. It may occur in spontaneously or stimulated labor. FHR changes may or may not be present.
Contraindications: Pre-eclampsia, eclampsia, epilepsy.
Chapter 34: Pharmacotherapeutics in Obstetrics      -   .


SELECTION OF OXYTOCICS IN OBSTETRICS: All the oxy­ tocics have got their place.
♦    To arrest hemorrhage  following  delivery (PPH)  or abortion, ergot preparation (methergine, ergometrine) is the life-saving drug.  In refractory cases of atonic
PPH, PGF2a (IM/intramyometrial) or PGE1  (misopro­
stol) 1,000  1g (rectal) is an effective choice.
♦    PGE1  is used in the active management of third stage of
labor.
♦    For induction  of  labor-either  prostaglandins  or oxytocin can be used. With favorable pre-induction cervical score, there is ve1y little to choose between

oxytocin and prostaglandin, but when the score is unfavorable as in IUD, shorter period of gestation or in elderly primigravida, prostaglandins have got a distinct advantage over oxytocin. Misoprostol has
certain advantages over PGE2•
♦    In augmentation or acceleration of labor, oxytocin
is still the drug of choice although prostaglandins are equally effective.
♦    For induction of abortion-prostaglandins (misopros­
tol-PGE1) has got a distinct advantage over oxytocin.
Oxytocin may supplement the effects of PGs in the pro­ cess.





►   Oxytocics are the drugs used to stimulate uterine contractions.
►   Oxytocin can be used in pregnancy, labor and puerperium. Contraindications and dangers of oxytocin use must be carefully assessed.
►   Oxytocin is given by controlled intravenous infusion. During infusion, the woman must be monitored carefully. Oxytocin must be preserved between 2°C and 8°C to be effective.
►   Methergine (ergot derivative) can  be used  orally or parenterally.  It differs with  oxytocin  in its  action (Table 34.5). Indications, contraindications and hazards of ergot derivatives must be assessed.
►   Prostaglandins are widely used in Obstetrics. They have many advantages. Of the different preparations, PGE2, PGF 20, and PGE1 are commonly used. Prostaglandins (PGE2, PGE1) have some advantages over oxytocin in medical induction of labor.
►   Carbetocin is used to prevent PPH due to uterine atony after cesarean delivery.


ANTIHYPERTENSIVE THERAPY

Antihypertensive drugs are essential for women with severe preeclampsia (BP  160/110 mm Hg) to protect the  mother  from  eclampsia,  cerebral  hemorrhage, cardiac failure and placental abruption (Table 34.10). Aim is to  reduce  BP to a mean less than  125  mm  Hg. Their benefit in mild or moderate hypertension is not yet known.  If there is any risk of target organ damage (kidney) antihypertensives are given to maintain BP :;140 mm Hg. systolic. The following are the drugs with their pharmacological property and clinical use (Table 34.10). ■  In  pre-eclampsia and eclampsia  (Tables 34.10  and
34.11).
■  Chronic hypertension.

DIURETICS
The diuretics are used in the following conditions during pregnancy:
♦   Pregnancy-induced hypertension with pathological edema. ♦   Eclampsia with pulmonary edema.
♦   Severe anemia in pregnancy with heart failure. ♦   Prior to blood transfusion in severe anemia.
♦   As  an  adjunct  to  certain  antihypertensive  drugs  such  as hydralazine or diazoxide.
COMMON   PREPARATIONS  USED:   Frusemide  (loop  diuretic)­ dose-40 mg tablet daily following breakfast for 5 days a week. In acute conditions, the drug is administered parenterally in doses of 40-120 mg daily. Mode of action: It directly prevents reabsorption of sodium and potassium mainly from the loop of Henle.

Hazards-(a) Maternal complications include-weakness, fatigue, muscle cramps, hypokalemia and postural hypoten­ sion. These can be corrected by potassium supplement during therapy. (b) Fetal-in pre-eclampsia, its routine use should be restricted, as it is likely to cause further reduction of maternal plasma volume, which is already lowered. This may result in diminished placental perfusion leading to fetal compromise. Other hazards include thrombocytopenia and hyponatremia.
Thiazide diuretic is often used in conjunction with other antihypertensives. It is safe in pregnancy.
Dose: 12.5 mg twice daily maximum up to 50 mg daily may be used. Side effects are: Maternal and fetal hyponatremia, acute pancreatitis, rise in uric acid levels, and neonatal thrombocyto­ penia. In a diabetic patient, it may cause hype1glycemia.
Spironolactone potentiates thiazide or loop diuretics by antagonizing aldosterone. It is a potassium-sparing diuretic. It is contraindicated in hyperkalemia. Drospirenone is an analog of spironolactone. It has antiandrogenic and antimineralocorticoid properties. The dose used in COCs is usually not associated with hyperkalemia.

TOCOLYTIC AGENTS

Preterm labor and delivery can be delayed  by drugs in order to improve the perinatal outcome. Short-term delay of 48 hours allows the use of corticosteroids that can reduce the perinatal mortality and serious morbidity signi­ ficantly. The commonly used drugs are: Betamimetics, prostaglandin synthetase inhibitors, magnesium sulfate, calcium channel blockers, oxytocin receptor antagonists, nitric oxide donors and progesterone.
&I Chapter 34: Pharmacotherapeutics in Obstetrics Table 34.1 0: Anti hypertensive drugs.
Contraindications

Drugs Labetalol






Nifedipine


Mechanism of action
Combined a and p adrenergic blocking agent.





Direct arteriolar vasodilatation by inhibition


Doses
■   Orally-100 mg tid may be increased up to 2,400 mg daily
■   IV infusion (hypertensive crisis) 20-40 mg IV every 10-15 min until desired effect, maximum up to 220mg.
Orally-5-1 O mg tid maximum dose


Side effects
■   Tremors, headache, asthma, congestive cardiac failure. May cause neonatal bradycardia.
•




Flushing, hypotension, headache, tachycardia,


and precautions
•  Hepatic disorders.
■   Asthma, congestive cardiac failure.





Simultaneous use of magnesium sulfate could be




Hydralazine






Methyl dopa





Sodium nitro-prusside

of slow inward calcium	60-120 mg/day. channels in vascular
smooth muscle.
Acts by peripheral	■   Orally-100 mg/day in vasodilatation as it relaxes            four divided doses
•
the arterial smooth muscle.	IV 5-1O mg every 20 min Orally, it is weak and should	maximum 20 mg.
be combined with meth-yldopa or p blockers. It increases the cardiac out-put and renal blood flow.
Central and peripheral	■   Orally-250 mg bid-antiadrenergic action.                     may be increased to 1 g Effective and safe for both             qid depending upon the the mother and the fetus.              response.



Direct vasodilator (arterial	IV infusion-0.25-8 µg/ and venous).	kg/min.


inhibition of labor.	hazardous due to synergistic effect.
• Maternal-hypotension,	Because of variable sodium tachycardia, arrhythmia,	retention, diuretics should be palpitation, lupus-like	used. To control arrhythmias,
syndrome, fluid retention.	propranolol may be
■   Fetal-reasonably safe.	administered intravenously. ■   Neonatal
thrombocytopenia.
•  Maternal-postural	• Hepatic disorders, psychic hypotension, hemolytic                  patients, congestive
anemia, sodium retention,	cardiac failure. excessive sedation.	Postpartum (risk of Coombs'   test    may    be	depression). positive.
•
•
Fetal-intestinal ileus .
• Maternal-nausea,	Drug of last resort for acute vomiting, severe	hypertension. Should be hypotension.	used in critical care unit for Fetal toxicity due to	very short time (10minutes). metabolites-cyanide and
•
thiocyanate.



Nitroglycerin	 Relaxes mainly the venous but also arterial smooth muscle (vasodilatory effect).


Given as IV infusion-5 µg/ min to be increased at every 3- 5 min up to 100 µg/min.


Tachycardia, headache, methemoglobinemia.


Used in hypertensive crisis for short time only. Contraindicated in hypertensive encephalopathy as it increases blood flow and intracranial pressure.



ACE inhibitors/ angiotensin-11 receptor blockers (AARB)


ACE inhibitors: Inhibit formation of angiotensin-11 from angiotensin-1.
ARB-block angiotensin-11 receptors.

■   Captopril orally-6.25 mg bid.
■   Telmisartan-orally 20-40 mg a day.


■   Maternal-hypotension, headache, asthenia, arrhythmias.
•
Fetal-oligohydramnios, IUGR, fetal renal tubular dysgenesis, neonatal renal failure, pulmonary hypoplasia.


Should be avoided in pregnancy.
Suitable for chronic hypertension in nonpregnant state or post pa rtu m.




DRUGS: The commonly used drugs are given in Table 34.12.

ANTICONVULSANTS

Convulsion in pregnancy is largely due to eclampsia.  Other common causes are-epilepsy,  meningitis,  cerebral malaria and cerebral tumors, and metabolic causes. Eclampsia should be considered first unless proved otherwise by history,
examination and investigations.


The commonly used drugs are given in the tabulated form (Table 34.13).

ANTICOAGULANTS
Anticoagulants  are  used  in  pregnancy  to  prevent thromboembolic  problems.  Cardiac disease,  venous thrombosis and antiphospholipid syndrome are some of the indications. The commonly used drugs are discussed here  (Table 34.14). Venous Thromboembolism  (VTE)


Table 34.11: Drugs to treat Hypertensive emergencies in pregnancy (Table 34.9).
Treatment of severe hypertension
as emergency	Side effects/precautions
Labetalol IV: 10-20 mg over 2 min;     Asthma, CCF, heart disease. 20-80 mg every 20-30 min.
Hydralazine: IV 5 mg over 2 min.	■  Tachycardia Headaches
•
Nifedipine: 10 mg PO, repeat in 30      •  Tachycardia min.                                                                    Palpitations
•
Long-term treatment of hypertension:
•
•
•
Labetalol 100 mg BID PO	Nifedipine 10 mg BID PO Hydralazine 10 mg BID PO                 ■  Thiazide 12 .5 mg BD PO
Other drugs Vasodilators:	■   Nitroglycerin
•   Sodium nitroprusside ACE inhibitors (postpartum)	Captopril.
Seizure prophylaxis: MgSO4; 4 g IV loading dose, followed by 2 g IV
per hour infusion.

Chapter 34: Pharmacotherapeutics in Obstetrics

encompasses  Deep   Vein   Thrombosis  (DVT}  and Pulmonaty Embolism (PE}. Pregnant women are 4-5 times more likely to suffer VTE than the nonpregnant women. Pregnancy is  a hypercoagulable state.  The high-risk factors for VTE are: hypertension, diabetes, obesity, lupus, prolonged immobilization and thrombophilias. Commonly used LMWH in pregnancy are-enoxaparin,  tinzaparin and deltaparin {Table 34.14).

MATERNAL DRUG INTAKE AND BREASTFEEDING
Maternal drug intake during nursing may have adverse effect not only on lactation but also on the baby through the ingested breast milk. Any drug ingested by a nursing mother  may be  present  in her  breast  milk,  but  its concentrations are usually low compared to blood levels in the mother. Usually such low levels are not of any clinical significance to the infant (Boxes 34.2 to 34.4 and Tables 34.12 to 34.16).


Table 34.12: Tocolytic agents.

Drugs
Calcium channel blockers:
■   Nifedipine ■   Nicardipine ■  Verapamil
Magnesium sulfate for PTL: <32 weeks. Neuroprotection against cerebral palsy



lndomethacin: Cyclo-oxygenase inhibitor (Sulindac another
NSAID is also used as it has less placental transfer)


Mechanism of action
Nifedipine blocks the entry of calcium inside the cell. It is equally effective to MgSO4


It acts by competitive inhibition to calcium ion at the motor end plate reducing calcium influx
+ Increased cerebral perfusion


Reduces synthesis of PGs, thereby reduces intracellular free ca++, activation of MLCK and uterine contractions. (PGs cause    in free intracellular ca++ and activation of MLCK)
t


Doses
Oral (not sublingual)
10-20 mg every 3-6 hours



Loading dose 4-6 g IV
(10-20% solution) over 20-30 min followed by an infusion of 1-2 g/hr ➔ to continue tocolysis for 12 hours after the contractions have stopped.

Loading dose 50 mg PO or PR followed by 25 mg every
6 hours for 48 hours


Side effects and precautions
■  Maternal: Nausea, headache, flushing hypotension and tachycardia.
Combined therapy with p mimetics or MgSO4
should be avoided.
■   Fetal/neonatal:Tachycardia.
MgS04 is relatively safe.
■   Common maternal side effects are flushing, perspiration, headache and muscle weakness.
■   Fetal side effects: Decrease in FHR variability ■   Dose monitoring.
Contraindications: Myasthenia gravis and impaired renal function.
Maternal:Heartburn, asthma, GI bleeding, thrombo­ cytopenia, renal injury, platelet dysfunction. Contraindications: Hepatic disease, active peptic ulcer, coagulation disorders.
Fetal and neonatal side effects:
(i) Constriction of the ductus arteriosus (due to
inhibition of synthesis of PGl2 and PGEil, (ii) Oligohydramnios.
(iii) Neonatal pulmonary hypertension; (iv) IUGR.



Betamimetics: ■  Terbutaline •   Ritodrine
■   lsoxsuprine (effective for 48 hours to allow time for steroids and antibiotics to work)


Activation of the intracellular    Ritodrine   is   given   by   IV enzymes  (adenylate  cyclase,    infusion,  50   µg/min  and  is cAMP, protein kinase), reduces    increased  by 50  µg  every  10 intracellular free calcium (Ca++       min until contractions cease. ,.,.)  and  inhibits  activation  of    Infusion is continued for about MLCK (,.,.J ➔	12  hours after the contractions Reduced     interaction     of    cease.
actin  and  myosin ➔  smooth    Terbutaline  has  longer  half­
muscle relaxation.  P2  receptor    life and has fewer side effects. stimulation  causes   smooth    Subcutaneous injection of0.25
muscle relaxation	mg every 3-4 hours is given.


Side effects of p mimetics are more when used parenterally,
Maternal: Headache, palpitation, tachycardia, pulmonary edema, hypotension, cardiac failure, hyperglycemia, ARDS, hyperinsulinemia, lactic acidemia, hypokalemia and even death. Fetal:Tachycardia, heart failure, IUFD. Neonatal: Hypoglycemia and intraventricular hemorrhage.
Contraindications: maternal cardiac disease, diabetes.



Oxytocin antagonists: Atosiban (between:
24 and 32 weeks)


Oxytocin analogue (antagonist) that blocks myometrial oxytocin receptors. It inhibits intracellular calcium release, release of PGS and thereby inhibits myometrial contractions.


IV infusion 300  1g/min	Nausea, vomiting, chest pain (rarely). Initial bolus may be needed.




Contd...
ZI Chapter 34: Pharmacotherapeutics in Obstetrics


Contd... Drugs
Nitric Oxide (NO) Donors: Glyceryl Trinitrate (GTN)


Mechanism of action
Smooth muscle relaxant


Doses
Patches


Side effects and precautions
• May cause cervical ripening . Headache.
•
•
Hypotension .



Table 34.13: Ahticonvulsants.
Drugs	Mode of actions	Doses	Side effects

Magnesium   It decreases the	Repeat injections are given only if knee jerks are sulfate	acetylcholine	present, urine output >30 ml/hr and respiration rate (also)	release from the         > 16/min. Therapeutic level of serum Mg is 4-7 mEq/L.
nerve endings and reduces the motor end plate sensitivity to acetylcholine.


Mg5O4   is relatively  safe  and  is  the  drug  of
choice.  Muscular  paresis  (diminished  knee jerks), respiratory failure. Renal function is to be monitored. It does not affect the duration of labor. Antidote: Calcium Gluconate.
Fetal effects are usually absent. It is contraindi-cated in patients with myasthenia gravis.



Diazepam




Phenytoin


Central muscle relaxant and anticonvulsant.


Centrally acting anticonvulsant (for other anticonvul-sant drugs.


Initially, 20-40 mg IV slowly to be followed by an infusion  ■  Mother: Hypotension, apnea, cardiac arrest. containing 500 ml of dextrose with 40 mg of diazepam,  ■   Fetus: Respiratory depressant effect which the drip rate being 30 drops/min or adjusted as per need.	may last for even 3 weeks after delivery. Status epilepticus: 10-20 mg IV slowly, may be followed	Hypotonia, hypothermia in newborn.
by IV infusion to a maximum of 3 mg/kg over 24 hours.
Epilepsy: 300-400 mg daily orally in divided doses.	Maternal: Hypotension, cardiac arrhythmias, and Status epilepticus: 18  mg/kg  slow IV (SO mg/min);  phlebitis at the injection site.
maintenance dose of about 100 mg is given at an interval  Fetal hydantoin syndrome (when used in first of 6-8 hours. BP and ECG monitoring should be done.      trimester) is observed in 5-10% offspring. This may be due to the disease itself due to drug
metabolism and deficient folate level. For the abnormalities.



Table 34.14: Anticoagulants.	'·
Drugs	Mode of action	Doses (weight adjusted dose)	Side effects
Heparin	Inhibits factor Xa	5,000-10,000 IU to be administered parenterally.   Maternal: Hemorrhage, urticaria with long-
•
Unfractionated    and thrombin.	DVT and Pulmonary Embolism: Loading dose     term use thrombocytopenia, osteopenia, Heparin (UFH)     Increases factor	5,000 units IV followed by continuous infusion	hyperkalemia.
Antidote: Prat-	Xa inhibitor	of 18 units/kg/hr	Protamine sulfate reverses the action of UFH. amine sulfate                                                 Pregnancy: 5,000-10,000 SC every	Fetal:  It does  not  cross  the  placenta  and  not
12 hours (with monitoring).	secreted in the breast milk. It is not teratogenic.
• Low-Molecular-Weight Heparin (LMWH) are as effective and safe as Unfractionated Heparin. It has longer half-life and once daily dose is convenient. Standard doses need not require monitoring. It has higher activity against factor Xa. LMWH heparins have better bioavailability. Commonly used LMWH in pregnancy are: Enoxaparin, Tinzaparin and Deltaparin. Heparin-induced thrombocytopenia and osteoporosis are less. Dose of Enoxaparin: 1 mg/kg twice daily SC.
■  Contraindications of Heparins are: (1) Known bleeding disorders (hemophilias); (2) APH, PPH; (3) Thrombocytopenia (<75 x 109/L);
(4) Severe renal (creatinine clearence <30 ml per min.) and liver disorders (PT above normal); (5) Uncontrolled hypertension BP >200 min Hg or> 120 mm Hg diastolic; (6) Recent stroke.

Warfarin	 Interferes with synthesis of vitamin K dependent factors (II, VII, IX,X)


5-10 mg orally daily for initial 2 days then 3-9 mg daily (taken at the same time each day) depending upon the prothrombin time and INR.
(INR-2.0-3.0)


Maternal: Hemorrhage
Fetal: Warfarin embryopathy (5%) nasal, mid-face hypoplasia, bone stipplings, optic atrophy, mental retardation,  microcephaly,  chondrodysplasia punctata. Women with mechanical heart valves, warfarin is preferred. To avoid in first trimester.

(Read more Dutta's Clinics in Obstetrics, Ch. 31)

.  .
■   Chemical properties of the drug.
•  Molecular weight.
■   Degree of protein binding. ■   Degree of ionic dissociation.




■   Lipid solubility. ■  Tissue pH.
■   Drug concentration in maternal blood.
■   Duration of exposure time.




+   Benefits of medication must outweigh the risks.
+   Select drugs that are most widely tested and with short half-life. +  Monitor the infant during the course of therapy.
Nonionized, low molecular weight, lipid-soluble compounds are usually excreted through breast milk.



■   Cytotoxic drugs (cyclosporine, doxorubicin, cyclophosphamide): Might cause immune suppression.
■   Drugs of abuse: Cocaine, heroin, marijuana.
■   Radioactive compounds: 1311, Technetium - 99 m.
■   Drugs, whose effects on nursing infants are unknown but may be of concern: Amiodarone (hypothyroidism), Sertraline. Benefits of breastfeeding are to be weighed against the negative effects.
Medical complications during pregnancy and lactation are best managed without any drug whenever possible. Risk and benefit ratio of any drug is to be weighted before a drug is to be used. Therapy may be deferred whenever possible till the first trimester is over.



■   Codeine phosphate.
■   Nitrofurantoin in babies with G6PD deficiency or <8 days old.
■   ACE ls other than enalapril. ■   Diuretics.
■   Angiotensin receptor blockers. ■    Phenobarbital, primidone.
■   Sertraline. ■   Fluoxetine.


Table 34.15: Effects of various medications on  Lactation and Neonates.
Maternal medications	Effects on lactation and the neonate
Oral pill (combined)	Suppression of lactation. Bromocriptine                                        -do-
Ergot	Vomiting, diarrhea, convulsions in infants Progesterone-only pill      It is ideal for breastfeeding mother.
Metronidazole (single-	No adverse effects have been reported dose regimen)	Temporary cessation of lactation
(12-24 hours) is advised.
Antithyroid drugs (PTU)   Can continue with supervision of infant.
Warfarin:	 Safe in therapeutic doses. Prophylactic vitamin K to the infant
ACE inhibitors, 13 blockers   Generally no adverse effects.
Cytotoxic agents	 Risk of immune suppression. Risks may outweigh the benefits depending on individual drug.
Lithium	Lethargy, hypotonia, poor feeding.
Narcotics, sedatives and   Generally no adverse effects. anticonvulsants
Tetracycline	Tooth staining, delayed bone growth.


However,  milk  concentrations  of  some  drugs  (e.g., iodides) may  exceed those in the maternal plasma so that therapeutic doses in the mother may cause toxicity
to the infant (Table 34.13). Common side effects from maternal medication on breastfed infants are: diarrhea (antibiotics),  irritability (antihistaminics), drowsiness (sedatives, antidepressants, antiepileptics).
Benefits of breastfeeding are well known. The risk of drug exposure to the neonate must be weighed against these benefits. If the drug amount is 1-2% of the mother, usually no adverse effects are noted. Short-term effects

Chapter 34: Pharmacotherapeutics in Obstetrics

of most drugs on breastfed infants are little. Benefits of breastfeeding must be weighed against the theoretical effects of small amount of drug.

FETAL HAZARDS OF MATERNAL MEDICATION DURING PREGNANCY
I TERATOLOGY AND PRESCRIBING IN PREGNANCY Fetotoxic  agents or the known teratogens  are:  (A)
Viruses (Rubella, CMV); (B) Environmental (Radiation); (C) Chemicals (alcohol,  mercury);  (D) Drugs (warfarin, isotretinoin). Depending on the timing of exposure,  the felotoxic effect may cause-(A) miscarriage, (B) structural malformations,  (C)  fetal  demise,  growth restriction or neurobehavioral abnormalities.
Approximately, 25% of human development defects are genetic in origin, 2-3% are due to drug exposure and about 65% are either unknown orfom combination of genetic and environmental factors.
r
Mechanism of teratogenicity: The actual mechanism is unknown. Teratogens may affect through the following ways: 1.  Folic  acid  deficiency  leads  to  deficient  methionine production and RNA, DNA synthesis. Folic acid is essential for normal  meiosis  and  mitosis. Periconceptional  folate
deficiency leads to neural tube defects, cleft lips and palate.
2.  Epoxides or arena oxides are the oxidative inter-metabolites of many drugs like hydantoin and carbamazepine. These intermediaty metabolites have carcinogenic and teratogenic effects unless they are detoxified by fetal epoxide hydrolase.
3.  Environment    and   genes:   Abnormalities   that   are multifactorial depend on the ultimate interaction between the environment and fetal gene mutation. Genotype of the embryo and their susceptibility to teratogens (valproic acid) are the important  determinants.  FDA has categorized the drugs and medications according to the risks (Table 34.17). Embtyonic period (2nd to 8th weeks) is most vulnerable. Homozygous  gene  mutations  are  associated  with  more anomalies.
4.   Maternal disease and drugs (epilepsy and anticonvulsants) have an increased risk of fetal anomalies (Table 34.13). Pater­ nal exposure to drugs or mutagens (polycyclic hydrocarbons) can cause gene mutation and chromosomal abnormality in sperm. FDA has categorized the drugs and medications according to the risks in human fetus (Table 34.15).
5.   Homeobox  genes  are  groups  of  regulatory  genes  that control the expression of other genes involved in the normal development of growth and differentiation. Teratogens like retinoic acid can dysregulate these genes to cause abnormal gene expression.
TIMING OF TERATOGEN EXPOSURE AND THE HAZARDS
■  Before D 31: Teratogen produces an all or none effect. The conceptus either does not survive or survives without anomalies. In early conception, only few cells are there. So any damage at that phase is irreparable and is lethal.
■  D 31-D 71 is the critical period for organ formation. Effects of teratogen depend on the following factors: {i) Amount of the drug reaching the fetus, (ii) Gestational age at the time of exposure, (iii) Duration of exposure.
,ll Chapter 34: Pharmacotherapeutics in Obstetrics
Table 34.16: Fetal or neonatal affections caused by various maternal medications.

Maternal medications Cytotoxic drugs

Medroxy progesterone acetate Lithium

Anticonvulsants ■  Phenytoin
■  Valproate

■  Carbamazepine Aspirin


Cocaine Antimalarials Corticosteroids

Aminoglycosides Anxiolytics Quinolones
Methotrexate, antimetabolities Nitrofurantoin
Metronidazole
Cimetidine, omeprazole, ranitidine Retinoids (isotretinoin)
Efavirenz Acyclovir
ACE inhibitors Vitamin A (large dose) All live viral vaccines Narcotics
Smoking (nicotine, CO, and other polycyclic hydrocarbons)

Fetal or neonatal affection and comment
First trimester:Teratogenic major malformation, single agent 10-17% and combination agent up to 25%; abortion; 2nd and 3rd trimester: FGR, IUFD, myelosuppression.
Hypospadias, masculinization of the female offspring.
Cardiovascular (Ebstein's) anomalies, fetal diabetes insipidus, polyhydramnios, neonatal goiter, hypotonia and cyanosis, prenatal diagnosis with echocardiography needed.

■  Benefits of treatment outweigh the risks to the fetus. Polytherapy should be avoided.
■  Fetal hydantoin syndrome. It includes-microcephaly, IUGR, mental retardation, craniofacial abnormalities, hypertelorism, hypoplasia of the nails and distal phalanges.
•
Increased risk of neural tube defects, ASD, cleft palate, polydactyly, hypospadias, craniosynostosis.
High doses in the last few weeks cause premature closure of ductus arteriosus, persistent pulmonary hypertension and kernicterus in newborn. Risk of prolonged pregnancy and maternal bleeding due to platelet dysfunction is there.
Congenital anomalies (cardiac, CNS), miscarriage, placental abruption, microcephaly.
Chloroquine, quinine-no evidence of fetal toxicity in therapeutic doses; benefits outweigh the risk.
High doses  (>10  mg  prednisolone  daily)  may produce  fetal and  neonatal  adrenal suppression. Prolonged systemic use may cause IUGR.
Nephrotoxicity, ototoxicity in preterm infants.
Neonatal withdrawal, hypotonia, cyanosis, floppy infant syndrome. Arthropathy in animal studies. No malformation was noted. Craniofascial, axial skeletal, gastrointestinal malformation.
Hemolysis in newborn with G6PD deficiency, if used at term. No congenital defects noted. No evidence of teratogenic risk. High-dose regimens should not be used.
No known teratogenic risk.
Severe CNS, CVS, endocrine dysfunction, mental retardation. Thought to be teratogenic, risks of NTD.
No increased risk of malformation.
1st trimester: CVS/CNS malformation; others. May be teratogenic.
Potentially dangerous to the fetus.
Maternal: Miscarriage, FGR. Fetal: Depression of CNS-apnea, bradycardia and hypothermia.
Placental abruption, placenta previa, prematurity and IUGR increased.

Selective serotonin reuptake inhibitors (SSRIS):
Sertaline: Omphalocele, atrial, ventricular septal defects. Paroxetine: 1' Congenital cardiac malformation, anencephaly, omphalocele.
Anticoagulants (p. 474), antihypertensives (p. 473), antithyroids (p. 273) diuretics (p. 473). Antiemetics (p. 152),  -mimetics (p. 475) and oral contraceptives (p. 477) are mentioned earlier.

Table 34.17: FDA risk categories for drugs and medications: FDA drug bulletin (1994).

Category A B

C

D

X

Definitions
Adequate and Well-controlled Studies (AWS) in pregnant women have failed to demonstrate a fetal risk in all trimesters.
No evidence of risk in humans: AWS in pregnant women have not shown any increased risk of fetal malformation despite adverse findings in animals. The chance of fetal harm is remote but remains a possibility.
Risk cannot be ruled out. Adequate, well-controlled human studies are lacking. Animal studies have shown a risk to the fetus or are lacking as well. Potential benefit may outweigh the risk.
Positive evidence of risk: Studies in humans have demonstrated fetal risk. Potential benefits from the use of the drug (life-threatening situation) may outweigh the potential risk.
Contraindicated in pregnancy: Proven fetal risks clearly outweigh any possible benefit. Drugs in this group are: Alcohol, ACE inhibitors, lithium, methotrexate, valproic acid, mifepristone, danazol, isotretinoin, radioactive iodine and others.

Teratogen information databases: Organization ofTeratology Information Services (OTIS): http:## www.otispregnancy.org./www.fda.gov.
Chapter 34: Pharmacotherapeutics in Obstetrics	IDL


Last menstrual period	Conception (14 days)
to parturition
(280 days)	Heart, central
/	nervous system
(31 days) /




Brain
growth	Palate, ear
(71 days)



Fig. 34.3: Gestational age and teratogenicity.

■  After D 71 development of other organs continues. Diethyl­ stilbestrol  (DES)-related  uterine  anomalies  occur  with exposure around 20 weeks (Fig. 34.3).
Brain continues to develop throughout pregnancy and neo­ natal period. Fetal alcohol syndrome occurs in late pregnancy.
Placental transfer of drugs: Most drugs cross the placental barrier by simple difusion. The factors responsible for transfer are-(i) Molecular weight (molecular weight >1,000 Da do not cross the placenta), (ii) Protein binding, (iii) Concentration of free drug, (iv) Lipid solubility, (v) Degree of ionization and tissue pH, {vi) Uteroplacental blood flow, and {vii) Placental surface area. The rate of drug transfer across the placenta is increased in late pregnancy.


This is due to:  (i) Increased unbound drug available for transfer, (ii) Increased uteroplacental blood flow, {iii) Increased placental surface area, {iv) Decreased thickness of the placental membranes.
Keeping these  in  mind,  the  following  guidelines  are formulated:
■   If  the  benefit  outweighs  the  potential  risks,  only  then can the particular drug be used with prior counseling.
■   Only well-tested and reputed drugs are to be prescribed and, that too, using the minimum therapeutic dosage for the shortest possible duration.
ALCOHOL: Heavy drinkers ('.3 oz) have major risk to the fetus (6%). Fetal Alcohol Syndrome {FAS) is defined as the presence of at least one characteristic from each of the following three categories:
1.  Growth restriction before and/or after birth.
2.  Facial  anomalies:  Small  palpebral  fissures,  indistinct  or absent  philtrum,  epicanthic  folds,  flattened  nasal  bridge, short length of nose, thin upper lip, low set and unparallel ears and retarded midfacial development.
3.  CNS   dysfunction:    Microcephaly,   mental   retardation, abnormal neurobehavioral  development  (attention  deficit with hyperactivity).

PATERNALLY MEDICATED DRUGS AFFECTING HUMAN PROGENY: Adverse effects on human progeny has been observed in the form of miscarriage, congenital malformations, low birth weight and increased perinatal loss when the father has been exposed to lead, anesthetic agents, smoking or caffeine ingestion. These agents probably alter the morphology of the spermatozoa or cause some changes in the composition of the semen.



ANALGESIA AND ANESTHESIA IN OBSTETRICS


Relief of pain during labor and delivery is an essential part in good obstetric care. Choice of anesthesia depends upon the patient's conditions and the associate disorders. Anesthetic complications may cause death. Anesthesia following full meal may cause death due to vomiting and aspiration of gastric contents. Maternal risk factors for anesthesia are: Short stature, short neck, marked obesity, severe pre-eclampsia, bleeding disorders, placenta previa, medical disorders, like cardiac, respiratory and neurological diseases.

ANATOMICAL AND PHYSIOLOGICAL CONSIDERATIONS

NERVE SUPPLY OF THE GENITAL TRACT: Uterus is under both nervous  and  hormonal  control.  Hypothalamus  controls  the uterine activity through the reticular formation which balances the effects of the two autonomic divisions.
Motor nerve supply: The uterus receives both sympathetic and parasympathetic nerve fibers. The sympathetic nerve fibers arise from lower thoracic and upper lumbar segments of the spinal cord. The parasympathetic fibers arise from sacral 2, 3 and 4 segments of the spinal cord {Fig. 34.4).
The preganglionic fibers of the sympathetic nerves arising from the spinal cord pass through the ganglia of the sympath­ etic trunk to aorticorenal plexus where they synapse. The aorticorenal plexus continues as the superior hypogastric plexus or

presacral nerve and passes over the bifurcation of aorta and divides into right and left hypogastric nerves. Each hypogastric nerve joins the pelvic parasympathetic nerve of the corresponding side and forms the pelvic plexus (right and left) or inferior hypogastric plexus. The pelvic plexus then continues along the course of the uterine artery as paracervical plexus on each side of the cervix.
Sensory pathway: Sensory stimuli from the uterine body are transmitted through the pelvic, superior hypogastric and aorticorenal plexus to the 10th,  11th and 12th dorsal and the first lumbar segments of the spinal cord. Sensory stimuli from cervix pass through the pelvic plexus along the pelvic parasympathetic nerves to sacral segments 2, 3 and 4 of the spinal cord. Sensory stimuli from upper vagina pass to 2, 3 and 4 sacral parasympathetic segments and from lower vagina pass through the pudenda! nerve. The perineum receives both motor and sensory innervation from sacral roots 2, 3 and 4 through the pudenda! nerve. The branches of ilioinguinal and genital branch of genitofemoral nerves supply the labia majora and also carry the impulses from the perineum.
NERVOUS  CONTROL  OF  UTERINE ACTIVITY: Regarding motor innervation of the uterus, the sympathetic nerves rather than the parasympathetic have the influences over the uterine activity.
HORMONAL CONTROL: It is generally agreed that intact nerve supply is not essential for the initiation and progress of labor. Total spinal block does not inhibit uterine activity, provided
·· ~"!J Chapter 34: Pharmacotherapeutics in Obstetrics Pain pathways in labor
[
 
I


1st stag, {


Lumbar
epidural block



2od stag,{



Caudal epidural block


Paarffaesryemntpfaibtheerstic


Pudenda! block	Paracervical block

Fig. 34.4: Diagrammatic representation of the pain pathways during labor and the methods of their interruption.
-c

Flowchart 34.1: Stress of labor and body response.
•

Physical (pain of surgery, trauma)
 .   Stress		J--. Hypothalamus • Psychological
 


I+ P1tu1tary  --+ [ tGH, tTSH, 1'endorph1n, tprolactin
-+_. + Adrenal	 Cortex	Medulla	' tcortisol	tNorepinephrine
tADH, 1'ACTH
L
tAldosterone	 tEpinephrine tGlucagon

• Hyperventilation
• Respiratory alkalosis	FETAL
r
• tGlucose	Acidosis
---+ • tFFA	t-----+  Hypoxia
• Metabolic acidosis
• I-Placental flow





blood  pressure  is  not  allowed  to  fall,  and  normal  vaginal delivery can  occur  in  the paraplegic  patient.  It  is  believed that some hormones are essential for the control of uterine activity. Oxytocin, a hormone derived from posterior pituitaty, maintains  the  uterine  activity during  labor.  Progesterone  is the pregnancy-stabilizing hormone. Labor commences when it  is  withdrawn.  Adrenaline  with  its  beta  activity inhibits the contraction of uterus, while its alpha activity excites it {Flowchart 34.1).
I ANALGESIA DURING LABOR AND DELIVERY
Pain during labor results from a combination of uterine contractions and cervical dilatation. During cesarean delivery incision is usually made around the Tl 2 dermatome and anesthesia is requiredfrom the level ofT4 to block the peritoneal discomfort. Labor pain is experienced by most women with satisfaction at the end of a successful labor. Antenatal (mothercraft) classes, sympathetic care and encouraging environment during labor can reduce the need of analgesia. Drugs have an important part to play in the relief of labor pain but it must not be supposed that they are of greater importance than proper preparation and training for childbirth. The intensity of labor pain depends on the intensity and duration of uterine contractions, degree of dilatation of cervix, distension of perinea! tissue, parity and the pain threshold of the subject. The most distressing time during
the whole labor is just prior to full dilatation of the cervix.


■  The ideal procedure should produce efficient relief of pain but should neither depress the respiration of the fetus nor depress the uterine activity causing prolonged labor.
■  The drug must be nontoxic and safe for both mother and fetus.  But it is regretted that no such agent is available at present that fulfills all these conditions. Every case of labor does not require analgesia and only sympathetic  explanation  may be  all that is required (Table 34.18).

PSYCHOPROPHYLAXIS   (Syn:   Natural   childbirth):   It   is psychological  method  of  antenatal  preparation  designed  to prevent or at least to minimize pain and dificulty during labor. For most women,  labor  is a  time of apprehension,  fear and agony. As a result of suitable antenatal preparation, majority of women have labor that is easy and painless.
Relaxation and motivation can reduce the fear and appre­ hension to a great extent. Patient is taught about the physiology of pregnancy and labor in antenatal (mothercraft) classes. Relaxation exercises are practiced. Husband or the partner is also involved in the management. His presence in labor would encourage the bearing down efforts. Need of analgesia would be less.
TRANSCUTANEOUS ELECTRIC NERVE STIMULATION (TENS): It is a noninvasive procedure and is preferred by many women
Chapter 34: Pharmacotherapeutics in Obstetrics    ml Table 34.18: Analgesia during Labor and Delivery.

Methods of pain relief
Nonpharmacologic analgesics • Psychoprophylaxis.
•
•  Continuous support (Doula). • Acupuncture.
• Transcutaneous (TENS).
•
Sedatives, analgesics and anesthetics • Patient-Controlled Analgesia (PCA).
• Neuroaxial analgesic and anesthetic. • Inhalation agent.
• General anesthesia.

Commonly used sedatives and analgesics in labor
Drugs	Usual doses	Frequency
Pethidine	50-100 mg IM	4 hours Fentanyl	50-100 µg IV	1 hour Nalbuphine	10 mg (IV/IM)	3 hours Morphine	5-l0mg IM	4 hours Meperidine	25-50mg (IV/IM)	4 hours
Remifentanil	0.15-0.5  tg/kg used for PCA    2-3minutes


Neonatal half-life (approx)
13-20 hours 5 hours
4 hours
7 hours



during labor.  Electrodes are placed over  the  level of Tl0-Ll and S2-4. Current strength can be adjusted according to pain. It works by inhibiting transmitter release through interneuron level.  However,  no change in pain score was observed when TENS was switched on.
I SEDATIVES AND ANALGESICS
The following factors are important to control the dose of sedatives and analgesics:
1.  Pain threshold: The threshold of pain varies from patient to patient. Some patients experience severe pain though the uterine contractions are relatively weak. In such cases, it is preferable to control the pain adequately.
2.  Parity: The multiparous women need less analgesia due to added relaxation of the birth canal and rapid delivery.
3.  Maturity of the fetus: Minimal doses of drugs are indicated while the fetus is thought to be premature to avoid neonatal asphyxia.
For the purpose of selecting a general analgesic drug, labor has been divided arbitrarily into two phases. The first phase corresponds up to 8 cm dilatation of the cervix in primigravidae and 6 cm in case of multipara. The second phase corresponds to dilatation of the cervix beyond the above limits up to delivery. The first phase is controlled by sedatives and analgesics, and the second phase is controlled by inhalation agents. The idea is to avoid the risk of delive1y of a depressed baby.
OPIOID ANALGESICS-Pethidine: For a long time, pethidine has been used as an analgesic in labor. It has got strong sedative, eupharic but less analgesic efficacy. It is generally used in the early first stage of labor and indicated when the discomfort of labor merges into regular, frequent and painful contractions. The initial dose is 100 mg (1.5 mg/kg body weight) IM and repeated as the effect of the first dose begins to wane, without waiting for the re-establishment of labor pain.
The  side effects of pethidine to the mother are nausea, vomiting, delayed gastric emptying.  Ranitidine should be
given to inhibit gastric acid production, and emetic effect is counteracted by metoclopramide (10 mg IM). Pethidine crosses the placenta and accumulates in fetal tissues. It reduces baseline variability, depresses respiration and suckling of the newborn when administered before delivery.
Meperidine: Compared to morphine, analgesic effect is one- tenth. It is used 25-50 mg (1-3 mg/kg IM) or a PCA pump 15 mg every 10 minutes. Repeated use or PCA in labor, infants may need naloxone at delivery. Maximum placental transfer and neonatal depression occur 2-3 hours of use. It is not used for

peripartum analgesia. There is reduced or loss ofFHR variability or neonatal respiratory depression. Side effects: Tachycardia, delayed gastric emptying.
Fentanyl is a fast onset short-acting synthetic opioid and is equipotent to pethidine. It has less neonatal effects and less maternal nausea and vomiting. It needs frequent dosing. It can be used as PCA.
Remifentanil: It is an ultrashort-acting synthetic opioid. It is metabolized by plasma esterase. Metabolites are not active. It is used as PCA. Sedation and hypoventilation with oxygen desaturations may occur. Respiratory monitoring is needed. Placental transfer occurs. It is rapidly metabolized in neonates. Patients may be given supplemental oxygen. Side effects: Nausea, vomiting, decreasedFHR variability, respiratory, depression.
Benzodiazepines (diazepam): Sedatives like phenothiazines and benzodiazepines have no analgesic property. Benzodiazepines cause maternal amnesia, reduced baseline fetal heat variability and neonatal hypothermia.
Combination of narcotics and antiemetics: Narcotics may be used in combination with promethazine, metoclopramide or ondansetron. The advantages claimed that the combination potentiates the action of narcotic, produces less respiratory depression and prevents vomiting.
Nalbuphin and butorphanol are mixed agonist and antagonist. Therefore with an equianalgesic dose, respiratory depression is less.
Narcotic antagonists are used to reverse the respiratory depression induced by opioid narcotics. Naloxone is given to mother 0.4 mg IV in labor. It may have to be repeated. It is given to the newborn 10 µg/kg IM or IV and is repeated if necessary when the infant is born with narcotic depression. Naloxone is given to a newborn born of a narcotic addicted mother, with proper ventilation arrangement only otherwise withdrawal symptoms are precipitated.
I INHALATION METHODS
Premixed nitrous oxide and oxygen: Cylinders contain 50% nitrous oxide and 50% oxygen mixture. Entonox apparatus has been approved for use by midwives. This agent is used in the second phase (from 8 cm dilatation of cervix to delivery). It can be self-administered using a mask. Entonox is most commonly used inhalation agent during labor in the UK. Hyperventilation, dizziness and hypocapnia are the side effects. The woman is to take slow and deep breaths before the onset of contractions
and to stop when the contractions are over. Inhaled N20 is safe for the mother and the fetus. It is also used for repair of
ID Chapter 34: Pharmacotherapeutics in Obstetrics
Table 34.19: Commonly used Local Anesthetic agents in Obstetrics.

Drugs Lignocaine Bupivacaine
Ropivacaine


Usual doses	Onset 7 mg/kg	Rapid 3 mg/kg	Slow
15 mg/kg	Slow


Duration 60-90min 90-150min
90-150min


Use in obstetrics
Local or pudenda! block for instrumental delivery. Epidural or spinal for cesarean delivery.
Continuous epidural infusion for labor pain.

Toxicity-central nervous system: Depression, dizziness, tinnitus, metallic taste, numbness of tongue, slurred speech, muscle fasciculation. Rarely generalized convulsions and loss of consciousness.
Cardiovascular toxicity: Hypotension, cardiac arrhythmias and fetal distress due to impaired placental circulation.


short painful procedures as perinea! tear or manual removal of placenta. The woman should be monitored with pulse oximetry (Table 34.19).
I REGIONAL (NEURAXIAL) ANESTHESIA
When complete relief of pain is needed throughout labor, neuroaxial anesthesia is the safest and simplest method for procuring it.
Continuous lumbar epidural analgesia: A lumbar puncture
is made between L2  and L3  with the epidural needle (Tuohy needle). When the epidural space is ensured, a plastic catheter
is passed through the epidural needle for continuous epidural analgesia. A local anesthetic agent (0.5% bupivacaine) is injected into the epidural space. Full dose is given after a test dose when there is no toxicity. For complete analgesia, a block from TIO to the S5 dermatomes is needed. For cesarean delivery, a block from T4 to Sl is needed. Repeated doses (top ups) of 4-5 mL of 0.5% bupivacaine or  1 % Jignocaine are used to maintain analgesia. Maternal hydration should be adequate with normal saline or Ringer's solution (crystalloid) infusion prior  to commencing the blockade. The patient's hydration blood pressure, pulse and the fetal heart rate should be recorded at 15 minutes interval. The  woman  is  kept in semilateral position to avoid aortocaval compression.
Neuroaxial analgesia and anesthesia (Table 34.20) [epidural, spinal or a Combination of Spinal Epidural (CSE)]: It provides the most adequate analgesia to control pain during labor as well as anesthesia during delivery either for vaginal or cesarean section.
Blockade of sympathetic fibers improve the labor pain. The sensation of pressure, motor function of the perineum and the lower extremities are spared. Patient is able to move about in bed and feel the pressure of the presenting part on the perineum.
For maintenance of epidural analgesia, dilute local anesthetic is combined with an opioid (fentanyl). Patient-Controlled Epidural Analgesia (PCEA), may be adjusted according to the need of analgesia and anesthesia. A small gauge pencil point spinal needle is passed through the epidural needle before the catheter is passed.


This Combined Spinal-Epidural ( CSE) method, can provide more rapid onset of analgesia administering a small dose of opioid or a local anesthetic. CSE has better pain scores during first stage of labor. Parturients can ambulate during labor ( walking epidural) as there is no blockade with motor function. Drug dose used in spinal is smaller compared to epidural analgesia. Risks of high spinal block are avoided. FHR monitoring should be continued for any women in labor with either epidural or in the spinal or combined spinal epidural analgesia (CSE).
Epidural analgesia is especially beneficial in cases like pregnancy-induced hypertension, breech presentation, twin pregnancy and pretenn labor. It is commonly used to relieve pain in all cases of-(a) spontaneous vaginal delivery, {b) outlet forceps delivery, (c) low operative vaginal delivery (forceps/ ventouse). Previous cesarean section is not a contraindication (Box 34.5). Epidural analgesia when used, there is no change in duration ofirst stage of labo,: But second stage of labor appears to be prolonged by 15-30 minutes. This might lead to fequent need of instrumental delivery like forceps or ventouse (Box 34.5).
r
Paracervical nerve block was used earlier for relief of pain in the first stage of labor. Considering the potential adverse fetal effects, use of paracervical block is contraindicated. It is no longer considered safe in obstetrics.
Pudendal nerve block: It is a safe and simple method of analgesia during delive1y. Pudenda/ nerve block does not relieve the pain of labor but affords perinea/ analgesia and relaxation. Pudendal nerve block is mostly used for forceps and vaginal breech delivery. Simultaneous perinea/ and vulva/ infiltration is needed to block the perinea/ branch of the posterior cutaneous nerve of the thigh and the labial branches of the ilioinguinal and genitofemoral nerves (vide supra). This method of analgesia is associated with Jess danger, both for mother and baby than general anesthesia (Fig. 34.5).
Pudenda] nerve (S2-S4)  covers most part of the perineum. Other cutaneous nerves to be infiltrated are: inferior rectal nerve,
posterior femoral cutaneous nerve (S1-S3) covering anterior to the fourchette bilaterally. This nerve must be blocked separately.
Other two nerves are: ilioinguinal nerve (L1) and genital branch
of genitofemoral nerve (L1 and L2) (Fig. 34.6).



Table 34.20: Neuraxial Anesthesia. Advantages
■  No difficulties of intubation.
■  Most effective mode of pain relief. ■  No risk of aspiration.
■  Analgesia during labor and anesthesia for delivery (vaginal/cesarean) and postoperative period.
■  Reduced catecholamine release and decreased systemic response to surgery. ■  Allows mother newborn contact soon following delivery.
■  The patient is awake and can enjoy the birth time.


Side effects/disadvantages
■  Women may not prefer to be awake during operation. ■  Inadequate analgesia due to poor block.
■  Hypotension may occur. ■  Neurologic injury.
■  Postdural puncture, headache. ■  High neuraxial block.
■  Local anesthetic toxicity. ■  Infection, meningitis.
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Contraindications of Epidural Analgesia	Complications of Epidural Analgesia
•
•
•
•
•
Maternal coagulopathy or anticoagulant therapy.	♦  Hypotension due to sympathetic blockade (vasodilatation). Parturient Supine hypotension.                                                                                 should be well hydrated with (IL) crystalloid solution beforehand (left Hypovolemia                                                                                             lateral change or vasopressure, phenylephrine, may be used).
Neurological diseases.	♦  Pain at the insertion site. Back pain.
Spinal deformity or chronic low back pain.	♦  Postspinal headache due to leakage of cerebrospinal fluid through
the needle hole in the dura.
CoPatient hemodynamically unstable (APH, placenta accreta) .	♦  Total spinalidue to inadvertent administration of the drug in the
ntraindications to Neuraxial Anesthesia
•
•
•
•
•
subarachno d space.
Patient with sepsis.	♦  Injury to nerves, convulsions, pyrexia. Increased intracranial pressure, space-occupying brain lesion .	♦  Ineffective analgesia.
Cardiac disease.	♦  Infection (meningitis).
Acute deterioration of fetal condition.
For a healthy patient, choice primarily rests on the anesthetist (Boxes 34.6 and 34.7). Most consider spinal block is the easier, quicker to perform and also safe. After spinal or epidural catheter removal, start thromboprophylaxis after 4 hours.

Genitofemoral



---    ---- Sacrospinous
ligament

'----'L. lschial spine

Pudenda!
nerve

,,
,	•
llioinguinal	 --- ,•·-,," ··
.
nerve
Branches of pudenda!
nerve
lschial
tube rosily


>Ii'" 	•         '
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lschial spine


Fig. 34.5: Method of transvaginal pudenda! block anesthesia. Note the relation of the pudenda I nerve to the ischial spine in the inset.

Technique: The pudenda! nerve may be blocked by either the transvaginal or the transperineal route.
Transvaginal route: Transvaginal route is commonly preferred. A 20 mL syringe, one 15 cm (6") 22-gauge spinal needle and about 20 mL of 1 % lignocaine hydrochloride are required. The index and middle fingers of one hand are introduced into the vagina, the fingertips are placed on the tip of the ischial spine of one side. The needle is passed along the groove of the fingers and guided to pierce the vaginal wall on the apex of ischial spine and thereafter to push a little to pierce the sacrospinous ligament just above the ischial spine tip. After aspirating to exclude blood, about 10 mL of the solution is injected. The similar procedure is adopted to block the nerve of the other side by changing the hands (Fig. 34.6).
Complications: Hematoma formation, infection and rarely intravascular injection or allergic reaction. Toxicity may affect: (A)   CNS: Excitation, ringing in the ears and convulsions. (B) Cardiovascular: Tachycardia, hypotension, arrhythmias, convulsions, even cardiac arrest.
Spinal anesthesia: Spinal anesthesia is obtained by injection of local anesthetic agent into the subarachnoid space. It has less
procedure time and high success rate. Spinal anesthesia can be employed to alleviate the pain of delive,y and during the third stage of labor. For normal delivery or for outlet forceps with episiotomy,

Fig. 34.6: Methods of pudenda! and labial-perinea! block for episiotomy during outlet forceps/ventouse application.

ventouse delivery, block should extend from TIO (umbilicus) to SI. For cesarean delivery, level of sensory block should be up to T4 dermatome. Hyperbaric bupivacaine (5-10 mg) or lignocaine (25-50 mg) is used. Addition of fentanyl (to enhance the onset of block) or morphine (to improve pain control) may be done. Brief or minimal spinal anesthesia is far safer than prolonged spinal anesthesia Box 34.6. The advantages of spinal anesthesia are: (a) less fetalhypoxia unless there is hypotension, and (b) minimal blood loss. The technique is not difficult and no inhalation anesthesia is required. Postspinal headache occurs in 5-10% of patients.

Postdural headache.
■   Puncture of the dura occurs in 0.5-2.5% of epidurals.
■   If accidental dural puncture occurs, there is a 70-80% chance of a postdural puncture headache.
■   The headache is usually in the fronto-occipital regions and radiates to the neck. It is worse on standing and develops 24-48 hours post-puncture.
■   Conservative management includes hydration and simple analgesics.
■   Untreated, the headache typically lasts for 7-10 days but can last up to 6 weeks.
■   Epidural blood patch has a 60-90% cure rate.
Chapter 34: Pharmacotherapeutics in Obstetrics



+  Hypotension due to blocking of sympathetic fibers leading to vasodilatation and low cardiac output.
+  Respiratory depression may occur due to paralysis of respiratory
-q.
muscles (high spinal) including diaphragm (C3
+  Failed block, chemical meningitis, epidural abscess.
+  Total spinal-due to excessive dose or improper positioning.
+  Postspinal headache-due to low or high CSF pressure and leakage of CSF.
+  Infection-meningitis, maternal fever. +  Transient or permanent paralysis.
+  Toxic reaction of local anesthetic drugs. +  Paralysis and nerve injury.
+  Nausea and vomiting are not uncommon. +  Urinary retention (bladder dysfunction).
+  Nonrassuring fetal status-bradycardia.
+  Increased rates of forceps/ventouse delivery.


■   Maternal cardiac disease: Congenital, valvular, cardiomyopathy, PAH.
■  Neuromuscular disease: CNS disease, spinal surgery. ■   Obesity.
■   Obstructive sleep apnea.
■   Hematologic disease: Immune thrombocytopenia.
■   Obstetric complications: Placenta previa, accreta (PAS).

Spinal anesthesia can be obtained by injecting the drug into the subarachnoid space of the third or fourth lumbar interspace with the patient lying on her side with a slight head up-tilt. The blood pressure and respiratory rate should be recorded every 3 minutes for the first 10 minutes and every 5 minutes thereafter. Oxygen should be given for respiratory depression and hypotension. Sometimes, vasopressor drugs may be required if a marked fall in blood pressure occurs. It is used during vaginal delivery, forceps, ventouse and cesarean delivery.
High (total) spinal: The level of anesthesia rises danger­ ously high up to the cervical level of C3-C5. This may be due to the miscalculated dose of the drug or inadvertent sub arachnoid injection of an epidural block. Management needs quick assessment of the true level  of anesthesia. If diaphragm  is paralyzed assisted ventilation and endotracheal intubation is necessary. Intralipid (lipid solution) IV is very effective therapy to combat the cardiotoxic effects. Postdural headache is often due to puncture of the dura with a large bore needle. It is more severe in upright than in supine position. It usually subsides with analgesics as caffeine (cerebral vasoconstrictor). Epidural blood patch is very effective.
Combined Spinal-Epidural Analgesia (CSE): An introducer needle is first placed in the epidural space. A small gauge spinal needle is introduced through the epidural needle into the subarachnoid space (needle through needle technique). A single bolus of 1 mL 0.25% bupivacaine with 25 µg fentanyl is injected into the subarachnoid space. The spinal needle is then withdrawn. An epidural catheter is thus sited for repeated doses of anesthetic drug. The method gives rapid and effective analgesia during labor and cesarean delivery. Continuous Spinal Epidural (CSE) Analgesia can provide more rapid onset analgesia with a small dose of opioid or a local anesthetic or a combination. CSE can

Table 34.21: General Anesthesia for Cesarean delivery. Advantages	Disadvantages
Patient is not aware of the                    Intubation causes hyper-operation.                                              tension and tachycardia.
Total pain relief	 Intubation at times is difficult or impossible
No apprehension or anxiety of delivery   Aspiration of gastric contents

decrease the risks of high spinal and motor block. It allows women to move (walking epidural) during labor.
Advantages: Regional analgesia provides excellent pain control during labor and delivety. Its increased use in labor and for vaginal and cesarean delivety has led to significant reduction in maternal morbidity and mortality.

I INFILTRATION ANALGESIA (TABLE 34.19)
Perinea! infiltration: For episiotomy-perineal infiltration anesthesia is extensively used prior to episiotomy. A 10 mL syringe, with a fine needle and about 8-10 mL 1% lignocaine hydrochloride (xylocaine) are required. The perineum on the proposed episiotomy site is infiltrated in a fanwise manner (Fig. 34.6) starting from the middle of the fourchette. Each time prior to infiltration, aspiration to exclude blood is mandatory. Episiotomy is to be done about 2-5 minutes following infiltration.
For outlet forceps or ventouse-Perineal and labial infiltration: The combined perinea! and labial infiltration is effective in outlet forceps operation or ventouse traction. A 20 mL syri­ nge, a long fine needle and about 20 mL of  1 % lignocaine hydrochloride are required. The needle is inserted just posterior to the introitus. About 10 mL of the solution is infiltrated in a fan­ wise manner on both sides of the midline (as for episiotomy). The needle is then directed anteriorly along each side of the vulva as far as the anterior-third to block the genital branch of the genitofemoral and ilioinguinal nerve. Five milliliter is required to block each side (Fig. 34.6).
Local abdominal for cesarean delivery: This method is rarely used where regional block is patchy or inadequate. Technique: The skin is infiltrated along the line of incision with diluted solution of lignocaine (2%) with normal saline. The subcutaneous fatty layet; muscle, rectus sheath layers are infiltrated as the layers are seen during operation. The operation should be done slowly for the drug to become effective.
PATIENT-CONTROLLED    ANALGESIA    (PCA):   Narcotics   are administered by mother herself from a pump at continuous or intermittent demand rate through intravenous route. Total dose is limited as there is a lockout inte1val. This offers better pain control than high doses given at a long intetval by the midwife. Maternal satisfaction is high with this method. Drugs commonly used are fentanyl, meperidine or remifentanil.
I GENERAL ANESTHESIA FOR CESAREAN SECTION The following are the important considerations of general anesthesia for cesarean section:
■   Cesarean section may have to be done either as an elective or emergency procedure.
Chapter 34: Pharmacotherapeutics in Obstetrics    ....  A


■   Ryle's  tube  aspiration  of  gastric  contents  is  to  be  done, especially when the stomach contains food materials.
■   A large number of drugs pass through the placental barrier and may depress the baby.
■   Uterine contractility may be diminished by volatile anesthetic agents like ether and halothane.
■   Halothane and isoflurane cause cardiac depression, hepatic dysfunction and hypotension.
■   Hypoxia and hypercapnia may occur.
■   Time  interval  from  uterine incision  to  delive1y  is  related directly to fetal acidosis and hypoxia.
■   Longer the exposure to general anesthetic before delivery, the more depressed is the Apgar score.
Risk factors for high gastric aspiration in pregnancy:
(a) Gravid uterus increases intra-abdominal pressure and the intragastric pressure.
(b) The gastroesophageal sphincter is distorted and is less competent.
(c) Increased progesterone levels in pregnancy-(i) delays gastric emptying, (ii) relaxes gastroesophageal sphincter.
Aspiration of gastric contents with a pH <2.5 cause
pulmonary hemorrhage, inflammation and edema. Pa02
decrease significantly due to lung injury (Table 34.21). Preoperative preparations: These safety measures should be
taken to prevent complications of general anesthesia.
■   Preoperative medication with sedatives or narcotics is not required as they cause respiratmy depression of the fetus.
■   Fasting of about 6 hours is preferable for an elective surgery. 11   High-risk women in labor should preferably not be allowed
to eat.
■   Ryle's tube aspiration of gastric contents is to be done when the stomach contains food materials.
■   H2-blocker (Ranitidine 150 mg orally) should be given night before (elective procedure). H2 receptor blocking agent and metoclopramide are to be given IM, especially to women with
high risks (obesity).
■   Non-particulate antacid (0.3  molar sodium citrate 30 mL) is given orally before transferring the patient to theater to neutralize the existing gastric acid.
•   While on the theater table, left lateral tilt of the woman is main­ tained with a wedge on the back. This is to avoid aortocaval compression as it is detrimental to both mother and fetus.
■   Metoclopramide  (10  mg  IV)  is  given  after  minimum  3 minutes of preoxygenation to decrease gastric volume and to increase the tone of lower esophageal sphincter.

■   Intubation with adequate cricoid pressure following induction should be done.
11   Uterine incision: Delivery (U-D) interval is more predictive of neonatal  status  (Apgar  score).  Prolonged  U-D  interval of more than 3  minutes results in lower Apgar  scores  and neonatal acidosis.
■   Awake extubation should be a routine.
Preoxygenation with 100% oxygen is administered by tight mask fit for more than 3 minutes. Induction of anesthesia is done with the injection of thiopentone sodium 200-250 mg (4 mg/kg) as a 2.5% solution intravenously.
Muscle relaxants:  Succinylcholine is commonly used immediately after the induction drug to facilitate intubation. It is a short-acting muscle relaxant with rapid onset of action.
Intubation: An assistant is asked to apply cricoid pressure as soon as the consciousness is lost. Intubation is done with a cuffed endotracheal tube and the cuff is inflated. Presence of obesity, severe edema, neck abnormalities, short stature or airway abnormalities make intubation difficult.
Anesthesia is maintained with 50% nitrous oxide, 50% oxygen and a trace (0.5%) of halothane. Relaxation is maintained with nondepolarizing muscle relaxant (vecuronium bromide 4 mg or atracurium 25 mg). After delivery of the baby, the nitrous oxide concentration should be increased to 70% and narcotics are injected intravenously to supplement anesthesia. Opioids injection oxytocin is given IV to stimulate uterine contraception.
Complications of general anesthesia: Aspiration of gastric contents (Mendelson' s syndrome) is a serious and life-threatening one. Delayed gastric emptying due to high level of serum progesterone, decreased motility and maternal apprehension during labor is the predisposing factor. The complication is due to aspiration of gastric acid contents (pH <2.5) with the development of chemical pneumonitis, lung damage, atelectasis and bronchopneumonia. Right lower lobe is commonly involved as the aspirated food material reaches the lung parenchyma through the right bronchus. Clinical presentation: Tachycardia, tachypnea, bronchospasm, rhonchi, rales, cyanosis, decreased
PaO2  and hypotension. X-ray chest reveals right lower lobe involvement.
Management: Immediate suctioning of oropharynx and nasopharynx is done to remove the inhaled fluid. Bronchoscopy may be needed if there is any large particulate matter. Continuous positive pressure ventilation to maintain arterial oxygen saturation of 95% is done. Pulse oximeter is a useful guide. Antibiotics are administered when infection is evident. Role of corticosteroid is doubtful.
Other complications of general anesthesia are: (i) Failure in intubation and ventilation, (ii) Nausea, vomiting and sore throat.


 '·*iH
►   Commonly used antihypertensives in pregnancy are: Labetalol, hydralazine and nifedipine. Methyldopa, hydralazine, labetalol, nitroglycerine and sodium nitroprusside are used for hypertensive crisis. ACE inhibitors should be avoided in pregnancy.
►   Commonly used tocolytics are: Calcium channel blockers, magnesium sulfate, oxytocin antagonists and nitric oxide donors, betamimetics (terbutaline, ritodrine, isoxsuprine), indomethacin.
►   Tocolytics are used to delay preterm labor for a short-term period (48 hours). Delay in delivery for 48 hours is for corticosteroids to work and to allow intrauterine transfer of the fetus to a center equipped with NICU facilities. Side effects and the precautions of use must be known.
►   Anticonvulsants used in pregnancy are: Magnesium sulfate, diazepam and phenytoin. Mg5O4 is the drug of choice in eclampsia.
►   While breastfeeding, the benefits of breast milk must be weighed against the risk drug exposure to the neonate. Information as regards
some commonly used drugs are available (Table 34.15).
Contd...
II Chapter 34: Pharmacotherapeutics in Obstetrics Contd...
►  Teratogens exert their effects through different mechanisms. The hazards of drugs depend upon the placental transfer of drugs and the period of gestation. Information as regards some commonly used drugs are available (Table 34.16).
►   Opioid analgesics are commonly used in labor. They work primarily as a sedative. Of the inhalation methods, premixed nitrous oxide and oxygen are commonly used.
►  Epidural analgesia is the safe, effective and simple method of regional anesthesia. One must know the contraindications and complications of its use. In Obstetrics, it is especially beneficial for some cases (Box 34.5 and Table 34.20).
►   Pudenda! block is good for perinea! analgesia and is used for forceps and vaginal breech delivery. ►   Spinal anesthesia has some advantages but it should be used carefully to avoid the side effects.
►   Complications of general anesthesia could be reduced when few preoperative safety measures are taken.
►  Mendelson's syndrome is a serious complication of general anesthesia. This can be prevented when the safety measures are taken beforehand.
►  Epidural analgesia prolongs the second stage of labor by 20-30 minutes without any adverse effects to the fetus and the neonate. ►   Neuraxial analgesia in cases with preeclampsia is beneficial. General anesthesia worsens hypertension during laryngoscopy and intubation. ►   Breastfeeding is not affected with the use of neuraxial or opioid analgesia or general anesthesia.
►   Opioid analgesics have adverse effects for the women, the fetus and the neonate. Risks or respiratory depressions are for the both.
►   Labor is a stressful process. This is associated with adverse metabolic response due to the pain. Analgesia in labor can reduce the stress. ►   Epidural analgesia-increases the duration of second stage of labor by 20-30 minutes and the rate of instrumental vaginal delivery
(forceps or ventouse). It does not increase the rate of cesarean delivery.
►   General anesthesia is less commonly used these days. Intubation may be at times difficult or failed. Aspiration of gastric contents is a cause for maternal mortality.


Induction of Labor








CHAPTER OUTLINE
❖ Methods of Induction of Labor ►  Medical Induction
►  Surgical Induction


►  Low Rupture of the Membranes	❖ Combined Method (LRM)
►  Stripping the Membranes




Induction  of  Labor  (IOL) means initiation of uterine contractions ( after the period of viability) by any method (medical,  surgical or combined) for the purpose of vaginal delivery. The patient and the family members are informed about the benefits, potential complications and the possibility of cesarean deliveiy. Overall induction rate is I 0%. Augmentation of labor is the process of stimulation of uterine contractions (both in frequency and intensity) that are already present but found to be inadequate.
PURPOSE OF INDUCTION OF LABOR: When the risks of continuation of pregnancy either to the mother or to the fetus is more, induction is indicated (Boxes 35.1 to 35.3). Before induction, one must ensure the gestational age as well as pulmonary maturity of the fetus. Rarely, preterm induction may have to be done. The incidence of stillbirth increases with prolonged pregnancy; while at 37 weeks it is I in 1000, increasing to 3-5 in 1000 at 42 weeks and beyond. For women >40 years, the incidence at 39-40 weeks is 2 in 1000.
Elective induction of labor means initiation of labor at  term  pregnancy  without  any  acceptable  medical  or obstetric indication. It is done for the convenience of the patient, obstetrician or the hospital. Unless for a selective


■    Pre-eclampsia, eclampsia (hypertensive disorders in pregnancy). ■  Maternal medical complications:
•  Diabetes mellitus.
• Chronic renal disease.
• Cholestasis of pregnancy. •   Postmaturity.
a   Abruptio placentae.
■   Fetal Growth Restriction (FGR). ■   Rh-isoimmunization.
11      Premature rupture of membranes.
11      Fetus with a major congenital anomaly. •   Intrauterine death of the fetus.
■  Oligohydramnios, polyhydramnios.
11      Unstable lie-after correction into longitudinal lie.
•  Maternal request (not routine)/advanced maternal age.

patient (e.g., who has history of rapid labor) the social indications should  not  be  recommended.  The  major risks are iatrogenic prematurity and increased cesarean delivery for failed induction (Table 35.1).

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■  Contracted pelvis and cephalopelvic disproportion. ■  Malpresentation (breech, transverse or oblique lie).
■  Previous classical cesarean section or hysterotomy (scarred uterus). ■   Uteroplacental factors: Unexplained vaginal bleeding, vasa
previa, placenta previa.
11     Active genital herpes infection (in 3rd trimester). 11      High-risk pregnancy with fetal compromise.
11      Heart disease. ■  Pelvic tumor.
■   Elderly primigravida with obstetric or medical complications. ■  Umbilical cord prolapse.
■   Cervical carcinoma.



■   Postmaturity/prolonged pregnancy (main cause). ■  Pre-eclampsia/eclampsia.
■  Intrauterine fetal death.
■  Premature rupture of the membranes. ■  Antepartum hemorrhage.
■  Chronic hydramnios. ■  Maternal request.

Table 35.1: Dangers of Induction of Labor. Maternal                                              Fetal
■   Psychological upset when there	♦   Iatrogenic prematurity. is induction failure and cesarean    ♦   Hypoxia due to uterine section is done.                                     dysfunction.
■  Tendency of prolonged labor due    ♦   Prolonged labor. to abnormal uterine action.
■  Increased need of analgesia during labor.
■   Increased operative interference. ■  Increased morbidity.
■   Hazards  related  to  individual method (Box 35.4).
I... ·· Im Chapter 35: Induction of Labor
t


Table 35.2: Parameters to be assessed prior to Induction. Maternal	Fetal
■  To confirm the indication for IOL.	♦  To ensure fetal ■   Exclude the contraindication of IOL.                gestational age.
■   Assess Bishop score {score >6,	♦  To estimate feta I favorable) {Table 35.3).                                 weight: clinical and
■  Perform clinical pelvimetry to assess	USG.
pelvic adequacy.	+  Ensure fetal lung ■  Adequate counseling about the risks,           maturation status.
benefits and alternatives of IOL with	♦  Ensure fetal
the woman and the family members.	presentation and lie ■   Counseling for the need of cesarean        +  Confirm fetal well­
delivery in case of failure of induction.	being.

PARAMETERS TO  ASSESS  PRIOR TO  INDUCTION  OF LABOR: When induction is considered for fetal interest, one  must  ensure  the   gestational  age  and  maturity (pulmonary) of the fetus. However, induction for maternal interest may compel to ignore the fetus (Table 35.2).
Cervical ripening is a series of complex biochemical changes in the cervix which is mediated by the hormones. There is alteration of both cervical collagen and ground substance. Ultimately, the cervix becomes soft and pliable (Table 35.4).

METHODS OF INDUCTION OF LABOR

♦     Medical	♦  Surgical	♦  Combined I MEDICAL INDUCTION
DRUGS USED
♦   Prostaglandins PGE2, PGE1  ♦ Oxytocin ♦ Mifepristone Prostaglandins (Table 35.6): Act locally (autocrine
and paracrine hormones) on the contiguous cells. PGE2
and PGF2a-both  cause  myometrial  contraction.  But
PGE2   is primarily  important for  cervical  ripening
whereas PGF2a for myometrial contraction. PGE2  has greater collagenolytic properties and also sensitizes the
myometrium to oxytocin. Intracervical application of

Table 35.3: Predictive factors for successful Induction of Labor.
Period of gestation	 Pregnancy at term or post-term-more the success.
Preinduction score	 Bishop score  6 is favorable. Dilatation of the cervix is most important.
Sensitivity of the uterus	 Positive oxytocin sensitivity test is favorable.
Cervical ripening	Favorable in multiparous and in cases with PROM.
Presence of Fetal Fibronectin   Favorable for successful IOL. {fFN) in vaginal swab (>50 ng/
ml)
Other positive factors	Maternal height >5', normal BMI, EFW <3 kg.

dinoprostone (PGE2-0.5 mg) gel is the gold standard for cervical ripening. It may be repeated after 6 hours for 3
or 4 doses if required. The woman should be in bed for 30 minutes following application and is  monitored for uterine activity and fetal heart rate. Side effects are few.
PGE2  (tablet, gel or controlled release pessary) should be used as the first-line agent (NICE).
Misoprostol  (PGE1)  is currently  being  used  either
transvaginally or orally for induction of labor (ACOG, 2003). Oral use of misoprostol is less effective than vaginal administration. A dose of 25 µg vaginally every 4 hours is found either superior or similarly effective to that of
PGE2  for cervical ripening and labor induction. With the above dose schedule, the risk of uterine hyperstimulation,
meconium-stained liquor and fetal heart irregularities are reduced. Total 6-8 doses are used. Buccal and sublingual use  of  misoprostol  can  avoid  the  first  pass  hepatic circulation and can maintain the serum bioavailability similar   to   that   of   vaginal   use.   Side   effects  are: Tachysystole,  meconium  passage  and  possibly  uterine rupture (Boxes 35.4 and 35.5). It is contraindicated in woman with previous cesarean birth.



Table 35.4: Methods of Cervical Ripening. Pharmacological methods
Oxytocin Prostaglandins {PGs)
■  Dinoprostone {PGEJ Gel, tablet, controlled release pessary
■  Misoprostol (PGE1):Tablets
Progesterone-receptor antagonists: Mifepristone (RU 486)
Relaxin: A protein hormone from corpus luteum, dissolutes cervical connective tissue.

Hyaluronic acid
Estrogen


Nonpharmacological methods
A. Mechanical methods: ■  Mechanical dilators
■  Foley catheter {single balloon) ■  Transcervical (30 ml) balloon
catheter
■  Osmotic (hygroscopic) dilators, Laminaria tents (natural) or Dilapan (synthetic)
■  Extra-amniotic Saline Infusion (EASI)
B. Surgical methods:
■   Sweeping of membranes
■  Amniotomy (artificial rupture of membranes)


Advantages of Foley catheter for labor induction
♦  Lower risk of uterine tachysystole and FHR changes. ♦  Reduced risk of cesarean delivery.
♦  Induction to delivery interval, is the same when compared to PGE  gel.
2
♦  Less stringent monitoring. ♦  Low cost.
♦  More suitable for women at risk (eclampsia, FGR). ♦  Easier to store.
♦  Can be used in scarred uterus.
♦   Used  with  Extra-amniotic Saline  Infusion  {EASI), improved results, .I- infection rate.

Use (off-label) of misoprostol (PGE1) for cervical ripening is safe and effective (ACOG-2003)
Chapter 35: Induction of Labor	Im ••Box  ?;S:,Maflageme:i.t of ,c"'"T"'f .-,.   .:'-',,.;. . =  - tl  l' ,   "'•:i '>•  r• '>;u_"r:'S','. ,,,,d.')l'
 =-tv..,.•..   {=.,•f' !"' l: ":.-      -
,
.,
omp[i a 11msf !9.Y!!ng
l  !l  i_op
9f Lab.%
2

♦  Oxytocin:
•  Water intoxication.                              •   Hypotension. • Uterine tachysystole.                           •   FHR changes.
♦  ARM
•  Cord prolapse.                                      •   Infection. •  Chorioamnionitis.                                 •   Bleeding.
•  Sweeping of membranes
•  Vaginal bleeding.	•   PROM. ♦  Misoprostol
• Tachysystole.	•   FHR changes.
•  Meconium-stained liquor.	•   Uterine rupture. ♦  Foley catheter
• Vaginal bleeding.	•   Febrile morbidity. ♦  Mechanical dilators
• Maternal and neonatal infections. ♦  Any method
•  Placental abruption.	•   FHR changes. •  Cesarean delivery.

Comments: With favorable preinduction cervical score (Table 35.5), there is very little to choose but where the score is poor, prostaglandin has got a distinct advantage over oxytocin (Table 35.6).
Oxytocin is an endogenous uterotonic that stimulates uterine contractions. Oxytocin receptors present in the myometrium are more in the fundus than in the cervix.


♦  Oxytocin infusion: To decrease/stop. ♦  Hypotension: Infuse IV crystalloids.
♦  Uterine tachysystole with category II or Ill. FHR changes. Injection terbutaline 0.25 mg SC.
♦  Additional measures: •  Left lateral position.
• 02  inhalation.
• IV infusion-crystalloids.
♦  Delivery by cesarean section (when no improvement).

Receptor  concentrations  increase  during  pregnancy and  in labor  (cf.  prostaglandins).  Oxytocin  acts  by­ (a)  receptor  mediation;  (b)voltage-mediated  calcium channels;  and  (c)  prostaglandin production.  Because of short half-life (3-4 minutes) plasma levels fall rapidly when intravenous infusion is stopped. Oxytocin is effective for induction of labor when the cervix is ripe.  It is less effective as a cervical ripening agent. Regimen of use: Low dose: between 1.0 and <4 mU/min. High dose: Between 4 and 6 mU/min. Dose is increased in eve1y 20-30 min.
Mifepristone  (progesterone  receptor antagonists) blocks both progesterone and glucocorticoid receptors. RU 486, 200 mg vaginally daily for 2 days has been found to ripen the cervix and to induce labor.


,Ta_ble 35.S: Bishop's (Edward Harry Bi hop) preinduction'   ;i  I  "Zo;in /syste (modified).	,_ Score

Parameters
Cervix
• Dilatation (cm) • *Effacement (%) •  Consistency
•  Position
Head: Station


0

Closed 0-30 Firm
Posterior
-3


1

1-2 40-50
Medium Midline
-2


2	3

3-4	5+
60-70                                       ?!80 Soft                                           -
Anterior	-
-1,0	+ 1,+2

Total score= 13; Favorable score= 6-13; Unfavorable score= 0-5
* Cervical length (cm)	>4	2-4	1-2	<1 * Modification (1991) replaces effacement(%) with cervical length in cm.

Table 35.6: Merits and demerits of Oxyt cin   d Pro;tagiandins in medic I lnd ction'of Labor.


Cost Stability
Administration Effectiveness



Side effects


Systemic side effects
Antidiuretic Hormone (ADH) effect

Oxytocin Cheaper
Needs refrigeration Intravenous (IV) infusion
Less with:
•
•
"
Low Bishop score. IUFD
Lesser weeks of pregnancy.
Uterine hyperstimulation mainly with high dose (ceases following stoppage of infusion).
Less; water intoxication.
In high dose

Prostaglandins (PGE ' PGE1) PGE2 costly, PGE1  less costly.
PGE2 needs refrigeration; PGE1  is stable at room temperature. lntravaginally or orally.
More effective in those cases as it has got more collagenolytic properties and it also sensitizes the myometrium to oxytocin .


Low-dose schedule has got minimal side effects. Tachysystole (rare)-(may need injection terbutaline 0.2 mg SC).
Vaginal route use has got minimal side effects.
No such
Im Chapter 35: Induction of Labor
Table 35.7: Methods of induction of labor and the common clinical conditions.

Medical methods
■  Intrauterine fetal death.
■  Premature rupture of membranes.
■  In combination with surgical induction (ARM).


Surgical methods
■  Abruptio placentae. ■  Chronic hydramnios.
■  Severe pre-eclampsia/eclampsia.
■  In combination with medical induction.
■  To place scalp electrode for electronic fetal monitoring.


Combined methods
■  To shorten the induction-delivery interval (commonly done). Medical methods followed by surgical or surgical methods followed by medical.

















Fig. 35.1: Artificial rupture of the membranes (ARM) using amnihook.

Mechanical methods are effective. Advantages are­ low cost, low risk of tachysystole (Table 35.4).
Disadvantages: Infection.
I SURGICAL INDUCTION METHODS (Table 35.7)
■   Artificial {low) Rupture of the Membranes (ARM/ LRM) {Fig. 35.1).
■   Stripping the membranes

Low Rupture of the Membranes (LRM)
Mechanism  of  onset  of  labor:  May  be  related with-(a)  stretching of the cervix;  (b) separation  of the membranes (liberation of prostaglandins); and (c) reduction of amniotic fluid volume.

Effectiveness  depends  on: (l) State of  the  cervix; (2)  Station of the presenting part. Induction delivery interval is shorter when  amniotomy is  combined with oxytocin than when either method is used singly.
Advantages of amniotomy:  (a) High success rate; (b) Chance to observe the amniotic fluid for blood or meconium;  (c) Access to  use fetal scalp electrode or intrauterine pressure catheter or  for  fetal  scalp  blood sampling. Early amniotomy at 1-2 cm or late amniotomy at  5  cm  cervical  dilatation  is  used  for  inductions  or augmentation of labor.
Limitation: It cannot be employed in an unfavorable cervix (long, firm cervix with os closed). The cervix should be at least one finger dilated (Table 35.8).
Indications: Table 35.7.
Contraindications: Intrauterine fetal death, maternal AIDS, genital active herpes infection.
Immediate beneficial effectsofARM
♦    Lowering  of the blood  pressure in pre-eclampsia-eclampsia.
♦    Relief of maternal distress in hydramnios. ♦    Control of bleeding in APH.
♦    Arrest of progress in abruptio placentae and initiation of labor.
♦    Shortens the duration of labor.
These benefits are to be weighed against the risks invo­ lved in the indications for which the method is adopted.
HAZARDS OF ARM
♦    Once the procedure is adopted, there is no scope of
retreating from the decision of delivery.


Table 35.8: Merits and demerits of Oxytocin and Low Rupture of the Membranes (amniotomy) as an isolated method.


Exclusive indications

Oxytocin	'
IUD


Amniotomy (LRM)
■  APH
■  Hydramnios
■  Severe pre-eclampsia/eclampsia



Prerequisites

Effectiveness

Special benefits


Hazards


Can be employed irrespective of the state of the cervix and the station of the head.
Quite satisfactory and the procedure can be repeated at intervals.
Reversibility of the decision


P. 468, Table 35.6


The cervical canal must be at least one finger dilated and the head should preferably be engaged.
If the procedure fails to initiate labor within 4 hours, should be supplemented by oxytocin, if required.
(a)  Observation of liquor for blood or meconium stain, (b) Access to uterine cavity for the use of-(i) fetal scalp electrode-electronic monitoring, (ii) fetal scalp blood sampling, (iii) intrauterine pressure catheter.
P.490
Chapter 35: Induction of Labor

♦   Chance of umbilical cord prolapse-the risk is low with engaged head.

♦   Amnionitis-it is the infection of the chorion, amnion and the amniotic fluid (chorioamnionitis). Aseptic procedure reduces the risk.
Induction delivery interval is reduced with proper sele­ ction of cases with favorable Bishop's score.
♦  Accidental injury to the placenta, cervix or uterus, fetal parts or vasa previa. Care taken during rupture of the membranes minimizes the problem.
♦   Liquor amnii embolism (rare).
I LOW RUPTURE OF THE MEMBRANES (LRM)
It is widely practiced nowadays with  high  degree of success.  The  membranes below  the presenting  part overlying the internal os are ruptured to drain some amount of amniotic fluid.

Contraindications:
i. Woman with HN infection.
ii. Woman with Group B Streptococcus infection.
iii. It is preferably avoided in chronic hydramnios, as there is risk of sudden massive liquor drainage.
Sudden  uterine  decompression  may  precipitate early placental separation (abruption). In such a case controlled ARM is done.
Procedures: Preliminaries: It is an indoor procedure. The patient is asked to empty her bladder. The procedure may be conducted in the labor ward or in the operation theater if the risk of cord prolapse is high.
Actual steps (Fig. 35.2):
■    FHR status is monitored before and after the procedure. ■    The patient is in lithotomy position.
11        Surgical asepsis to be taken.
■   Two  fingers  are  introduced  into  the  vagina  smeared  with antiseptic ointment. The index finger  is  passed  through the cervical canal beyond the internal os. The membranes are swept­ free from the lower segment as far as reached by the finger.
■    With  one  or  two  fingers  still  in  the  cervical  canal  with the  palmar   surface   upwards,   a  long  Kocher's   forceps














Fig. 35.2: Methods of low rupture of membranes by Kocher's artery forceps.





a
 
,
 
.,
.
,
,,
·""' 

m
Figs. 35.3A and B: (A) Kocher's artery forceps; (Bl Showing the tip of the Kocher's forceps.

(Figs.  35.3A and B)  with the blades closed or an amnion hook is introduced  along  the palmar aspect of the fingers up to the membranes,
■    The blades are opened to seize the membranes and are torn by twisting movements. Amnihook is used to scratch over the membranes. This is followed by visible escape of amniotic fluid,
If the head is not engaged, an assistant should push the head to fix it to the brim of the pelvis to prevent cord prolapse. If the head is deeply engaged and the drainage ofliquor is insignificant, gentle pushing of the head up, facilitates escape of desired amount of amniotic fluid.
After the membranes rupture, the following are to be assessed:
■  a.  Color of the amniotic fluid; b.  Status of the cervix;
c.  Station of the head;
d.  Detection of cord prolapse, if any;
e.  FHR pattern is again checked. In high-risk cases, scalp electrode for fetal monitoring is applied.
■  A sterile vulva! pad is placed. Prophylactic antibiotic may be prescribed.
■  Monitoring the progress (Box 35.6). Hazards: See above.
I STRIPPING THE MEMBRANES
Stripping (sweeping) of the membranes means digital separation  of the chorioamniotic membranes from the wall of the cervix and lower uterine segment.  It is thought to work by release of endogenous prostaglandins from the membranes and decidua. Manual exploration of the cerix triggers Ferguson reflex which promotes oxytocin release from maternal pituitary. Sweeping of the membranes is done prior to ARM. It is simple, safe and beneficial for induction of labor.



♦  Patient should be in bed.
♦  Monitoring of uterine contractions.
♦  Monitoring of fetal heart rate.	♦  Monitoring of drug use (Oxytocin dose increment/repeat dose for PGs).
Im Chapter 35: Induction of Labor
As an isolated procedure, stripping the membranes off from its attachment from the lower segment is an effective procedure  for  induction  provided  cervical  score  is favorable. It is used as a preliminary step prior to rupture of the membranes. It is also used to make the cervix ripe.
Criteria to be fulfilled for membrane stripping are: (a) The fetal head must be well applied to the cervix; (b)  The cervix  should  be  dilated so  as  to  allow  the introduction of the examiner's finger.
Comments: Each method has got its limitations and hazards. For induction of labor, each case should be judged on individual basis.
Mechanical: Dilators-act by release of endogenous prostaglandins  from  the  membranes  and  maternal decidua   to   induce   labor   and  cervical  ripening. Hygroscopic  dilators,  e.g.,  laminaria  (desiccated seaweed),  lamicel  (magnesium  sulfate  in  polyvinyl alcohol)  act  by  absorption  of water. They swell and forcibly dilate the cervix. Mechanical dilators are as safe
and effective as PGE2 in cervical ripening.
Cervical  balloon  catheter causes cervical ripening with  release  of  the  interleukins  (IL-6,  IL-8),  Matrix Metalloproteinase (MMP-8) and hyaluronic acid synthetase. Balloon volumes may be low (30 mL) or high (60-80 mL).



Transcervical balloon catheter (Foley catheter) and extra-amniotic saline infusion are effective for cervical ripening (Fig 45.4).

COMBINED METHOD

The  combined  medical  and  surgical  methods  are commonly used to increase the efficacy of induction by reducing the induction-delivery interval. The oxytocin infusion is started either prior to or following rupture of the membranes depending mainly upon the state of the cervix and head brim relation (Flowchart 35.1). With the head nonengaged,  it is preferable to induce with prostaglandin gel or to start oxytocin infusion followed by ARM. The advantages of the combined methods are:
1.  More effective than any single procedure;
2.  Shortens  the  induction-delivery  interval  and thereby-(a)  minimizes the risk of infection,  and (b) lessens the period of observation.

ACTIVE MANAGEMENT OF LABOR (Syn: Augmentation of Labor)
Active management of labor was introduced by O'Driscoll and his colleagues in 1968 at National Maternity Hospital, Dublin. The term "Active" refers to the active involvement


Flowchart 35.1: Scheme for induction of labor.

Induction of labor


Medical	Surgical


Exclusive indication IUFD.


ex-favorable.


Oxytocin
or prostaglandin E/E1

Prostaglandin E,, E/oxytocin.


ex-unfavorable.


Prostaglandins more effective.


Amniotomy (LRM)

♦ APH
♦ Severe pre-eclampsia • Eclampsia

Special advantages
• Observation of the amniotic fluid for blood or meconium. ♦ Use of scalp electrode for fetal monitoring.
• Fetal scalp blood sample.
• Use of intrauterine pressure catheter.


Combined (common)



ex-unfavorable

Vaginal prostaglandin E2 gel/E/oxytocin infusion

ex-favorable

Amniotomy + Oxytocin


Cervix-ripe

Amniotomy + Oxytocin
Chapter 35: Induction of Labor    Im Amnion    Chorion






-'-1...--fl-- Extra-amniotic
saline



Fig. 35.5: Electronic fetal monitor with abdominal transducers.

Table  35.9:   Advantages  and  contraindications  of  Active Management of Labor.
Advantages	Contraindications



Fig. 35.4: Extra-amniotic Saline Infusion (EASI) through a Foley catheter that is placed through the cervix. The 30-ml balloon is inflated with saline and pulled snugly against the internal os. Room-temperature normal saline is infused through the catheter port.

of the consultant obstetrician in the management  of primigravid labor.
■   Active management applies exclusively to primigravi­ das with singleton pregnancy and cephalic presentation who are in spontaneous labor and with clear liquor.
■  Husband or the partner is present during the course of labor.
■   Partograph is maintained to record the progress of labor (Fig. 35.6).
The essential components of Active Management of Labor (AMOL):
■   Antenatal  classes to  explain  the  purpose  and  the procedure of AMOL (prenatal education)
■  Woman is admitted in the labor ward only after the diagnosis of labor (regular painful uterine contractions with cervical effacement)
■  One-to-one nursing care with partographic monitor­ ing oflabor (Fig. 35.6)
■  Amniotomy (ARM) with confirmation of active labor
■  Oxytocin augmentation if cervical dilatation is slower in the active phase (>5 cm dilatation) of labor.
■   Epidural analgesia if needed for pain relief.
■  Fetal monitoring by intermittent auscultation or by continuous electronic monitoring (Fig. 35.5)
■  Active involvement of the consultant obstetrician.
■   The duration of active first stage  (from 5 cm to 10 cm) usually is S.12 hours in a primi and 10 hours in a multi.
The key to active management involves strict vigilance (one-to-one  care),  active and informed intervention

•  Less chance of dysfunctional labor   ■  Early (<5 cm dilatation) +  Maintains maternal and fetal	amniotomy and
wellbeing	oxytocin augmentation. •  Shortens the duration of labor          ■  Presence of obstetric
(<12 hours)	complication.
♦  Fetal hypoxia can be detected           ■  Any medical interven­ early                                                         tions when cervical
+  Low incidence of cesarean birth	dilatation <5 cm. ♦  Less analgesia                                     ■  Presence of fetal •  Less maternal anxiety due to	compromise
support of the caregiver and	■  Multigravia (not a prenatal education                                 routine)

in time.  The  incidence  of operative  delivery  is  not increased and less analgesia is required (Table 35.9).
Aim:  To expedite delivery within 12 hours without increasing maternal morbidity and perinatal hazards.
Active management of labor: Objective is-(a) early detection of any delay in labor; (b) diagnose its cause; and (c) initiate management.
Emotional support in labor: Stress and anxiety during labor can make labor prolonged. Presence of a support­ ive companion  during  labor  (husband/female relative of choice) reduces the duration of labor, need of analge­ sics and oxytocin augmentation. Such social support is a low-cost useful inte1vention. Stress-induced high levels of endogenous adrenaline is thought to inhibit uterine con­ tractions via stimulation of uterine muscle beta receptors
(Ch. 13, p.109).
Limitations of Active Management of Labor:  It is employed only in selected cases and in selected centers where  intensive  intrapartum  monitoring by  trained personnel is possible. It requires more staff involvement in the antenatal clinic and labor ward.

PARTOGRAPH
Partograph is the graphic representation of   !]  - •·
·
·
.
 
  
l]
!] · : 
the progress of labor in  terms of women's	§1,
cervical dilatation and  descent of the fetal presenting part,  against time (Philpott and
1B Chapter 35: Induction of Labor
WHO LABOR CARE GUIDE

Section 1


Name
Ruptured membranes (Date

Parity	Labor onset	Active labor diagnosis [Date
Time	]    Risk factors


1-- -+m-,--,--+--+--+--++---+-+-I -1   -11 1--  -----1
 	10	11	12	I
 .---------ACTIVE FIRST STAGE---------   - SECOND STAGE --


Section 2

Companion	N
Painrelief	N
Oral fluid	N
Posture	SP

Baseline      <110, ..160 deceFleHrRation
FHR
l
Section 3	Amniotic fluid    M+++, B
Fetal position	P,T
Caput	+++




Section 4







Section 5






Section 6





Section 7

Moulding	+++

Pulse	<60, .. 120
fi
Systolic BP     <80,i.140
Diastolic BP
,90
Temperature"(     i.37.S
<35.0,
I cootractions / P++,A++ I	I	I	I	I	I	I	I	I	I	I	I	I I! I! I! I! I! I! I 10
Urine
Contrctioos
perlOmin
Duration of
2    5
s:,
>
<20, >60
I: I: I I: I: I
9        • 1h	In active first stage, plot 'X' to
Cervix	record cervical dilatation. Alert
8      z.2.Sh
IP lXI
trlggered when lag time for
 	7         , lh	currentcervlcal dllatation is
} 1;1111111111111se   : !::::  ;  p;. t f  -l  te z       Oxytocin (U/1., drops/min)
e
o
■
6       , Sh
5       ,6h
 

Medicine
!e    1-------,1---t--t--+--+--+--+--+-t--+--+--+---, IJ ....	·-··-·
1111111·1
11
1··r····1
I  I  I  I  I  I  IITn
 
IV fluids

INSTRUCTIONS: CIRClE ANY OBSERVATIOU MEETING THE CRITERIA IN THE 'ALERT' COLUMN,ALERTTHE SEtllOR MIDWIFE OR DOCTOR ANO RECORD THE ASSESSMENT ANO ACTION TAKEN. IF LABOR EXHtlDS BEYOND 12HOURS, PLEASE CONTINUE ON A NEW LABOR CARE GUIDE.
Abbreviations:     Y -Yes, II -/lo, D -i!dined, U -Unkno1m, SP -Supine, MO-Mobile, E - Early, L - Late, V -Variable, I -lnmt. C -Clear, M -Meconi um, B -Blod, A-Anterio!, P -Posterio!, T -Transverse. P+ - Protein, A+ -Acetone


Fig. 35.6: Partograph (modified WHO) representing graphically the important observations in labor. WHO Labor Care Guide with the sections of: Patient's details, supportive care, baby, woman, labor progress, medications and shared decision making.


Castle, 1972). Regular recording of important clinical parameters has been maintained covering the wellbeing of the woman and baby.
The components of a partograph are {Fig. 35.6): Labor Care Guide (WHO) has made the important changes:


■  Active phase of labor starts from 5 cm of cervical dilatation  (earlier 4  cm).  Fixed  1  cm/hour  'alert' line and the corresponding 'action line' has been changed with evidence-based time  limits  at each cm of cervical dilatation during active first stage of
Chapter 35: Induction of Labor	Im~-­

labor. It allows the variability in the rates of progress of labor between women. The lines have been removed but the parameters remain the same.
•  A companion of choice for all women throughout labor and child birth is recommended.
•  Duration and frequency of uterine contractions are recorded.  The strength of uterine contractions is no longer  recorded,  as it is difficult to quantify clinically.
■  The parameters are highlighted when there is deviations from expected observations of any labor. The corre­ sponding response is recorded by the care provider.
■  There is increased uterine contractions in intensity and duration in the second stage labor. The combined propulsive  and maternal voluntary expulsive  effort make the second stage a more critical time. This stage needs more vigilance and intensified monitoring for both the mother and her baby.
■  In the 'assessment; the care giver has to record the overall assessment. The care plan is formulated in discussion with the woman. In the 'plan' section, the care plan is documented.
■  Labor Care Guide (WHO) is designed for an individual woman's care. This is aimed for positive child birth experience.

Plotting ofpartograph-P. 494.
Recordings as regard to areas: ■ Women	■  Baby
■ Labor progress	■ Medications    ■ Shared decision making.
Assessment:  •  Fetus:  FHR  every 30  minutes  and every  15 minutes in second stage.  •  Woman:  Pulse; BP,  temperature,  urine  output  every  hour;  uterine contractions (frequency) per 10 min (:52, >5) and duration (<20 sec, >60 sec).
Labor progress:• Cervix [dilatation (cm) with hour] (plot X};  descent  (Plot  O};  •  Medication:  oxytocin; analgesic, IV fluid and • Shared decision making following assessment and plan.
Advantages of a partograph: (i) A single sheet of paper can provide details of necessary information at a glance; {ii) No need to record labor events repeatedly; {iii)  It can predict deviation from normal progress of labor early.  So,  appropriate steps could be taken in  time;  {iv)  It  facilitates  handover  procedure;  (v) Introduction of partograph in the management of labor (WHO,  1994) has reduced the incidence of prolonged labor and cesarean section rate. There is improvement in   maternal  morbidity,   perinatal  morbidity   and mortality.





►   Theobald and associates in 1948 described the use of oxytocin for labor induction,
>  Currently, there is rise in the incidence of induction of labor globally (US: 23.4%, UK: 21 %, Asian countries 12.1 %, Sri Lanka: 35.5%)
>  Induction of labor means initiation of uterine contractions (after fetal viability) for the purpose of vaginal delivery, Augmentation
is the process of stimulation of uterine contraction that are already present but found to be inadequate.
>  Induction of labor should be done when benefits of delivery to either the mother or the baby outweigh the risks of pregnancy
continuation.
>  Indications and contraindications must be carefully judged to avoid the dangers of induction of labor,
>   Methods of cervical ripening are  many,  Bishop's  preinduction  cervical  score  (Table 35.5)  can  predict  the  success  of induction,
Score <!6 is favorable,
>  Methods of induction may be medical, surgical or combined, depending upon the individual case, Each method has got its merits and demerits (Tables 35.6 to 35.8).
>   Cervical remodeling (ripening) is achieved by collagen breakdown and rearrangement. There is also changes in the glycosamino­
glycans, increased hyaluronic acid and production of cytokines and white blood cell infiltration, ►  There is rise in the number of nonindicated induction of labor (induction on maternal request),
>  Induction of labor with sweeping of the membranes is effective, Combined use of amniotomy  (ARM) and  IV oxytocin is  more
effective than ARM alone,
►   Foley catheter, a non-pharmacological method, has many advantages for labor induction. Risks of uterine tachysystole, fetal heart rate changes, cesarean delivery are low (Table 35.4).
>   Active management of labor needs some criteria to be fulfilled, It has many advantages, Contraindications are to be maintained, >  Partograph is a composite graphical record of labor events  (maternal and fetal)  entered against time on a single sheet of  paper (Fig. 35.7), It has many advantages. It can predict deviation from normal progress of labor early so that early steps could be taken.
►   Recommendations on intrapartum care for a positive child birth experience (WHO) are to be followed.

Population Dynamics and
Control of Conception






CHAPTER OUTLINE
❖ Control of Contraception ►  Family Planning
► Contraception
❖ Methods of Contraceptions ► Temporary Methods
►  Intrauterine Contraceptive Devices ❖ Steroidal Contraceptions
►  Combined Oral Contraceptives (Pills)
► Centchroman (Chhaya/Saheli)
►  Progestogen-only Contraceptions


►  Emergency Contraception (EC)
►  Summary of Oral Contraceptives ❖ Drug Interaction and Hormonal
Contraception ❖ Sterilization
► Couple Counseling ►  Male Sterilization
►  Female Sterilization ❖ Barrier Methods
► Condom (Male)
►  Female Condom (Femidom)


►  Diaphragm
► Vaginal Contraceptives
►  Fertility Awareness Method
►  Contraceptive Counseling and Prescription
►  Sterilization Counseling ► Prescription
❖ Ongoing Trials and Selective Availability
►  Transcervical Sterilization



I INTRODUCTION
Rapid population growth (96% in LMIC countries) is a critical issue worldwide. Family  planning methods save women's  lives  preventing  unintended  pregnancies. Slower  population  growth  conserves  resources, improves health and living standards.
Benefits of fertility control are interrelated. Benefits are improved quality of life, better health, less physical and emotional stress of life, better education, job, and economic opportunities. Benefits are enjoyed by the couple, the child­ ren, other family members, the community and the Country.
Contraception and fertility control are not synony­ mous. Fertility control includes both fertility inhibition (contraception) and fertility stimulation. While the fertility stimulation is related to the problem of the infertile couples, the term contraception includes all measures, temporary or permanent, designed to prevent pregnancy due to the coital act.
Ideal contraceptive methods should be highly (100%) effective,  acceptable,  safe,  reversible,  cheap,  having non-contraceptive benefits, simple to use and requiring minimal motivation, maintenance and supervision.

CONTROL OF CONCEPTION I FAMILY PLANNING
AIMS: The aims  of family welfare  planning are:  (1) To  bring down population growth,  so as to ensure a better standard of living; (2) From economic and social point of view-the already existing population of nearly


l, 705 million, there is deficiency in basic needs of food, clean water,  clothing,  housing,  education  and proper health care.  Spacing of birth and small family norm will improve the health of the mothers and their children so that a healthier society can emerge;  (3)  To reduce the maternal and infant mortality  rates;  (4)  To  prevent pregnancies that are  too  early,  too  frequent and too many and the number of unsafe abortions.

OBJECTIVES Conception control:
a   To bring down the birth rate to a realistic minimum during a given period of time. The term 'eligible couple' is applied to couples with wives in the reproductive age group of 15-45 years and who require the use of some sort of family planning method. In India Total Fertility Rate (TFR) currently is 2.4 and target is to reduce it to 2.
■   To bring about certain  social  changes like:  (a)  To educate and motivate the sexually active and fertile couple to accept the small family norm; (b) To increase the literacy rate, especially amongst women in rural areas; (c) To raise the marriageable age of both boys and girls. Low age of marriage not only contributes to the increased birth rate but adversely affects the health of the woman. In 1978, the Indian Parliament approved the Bill fixing the minimum age of marriage at 21 years for men and 18 years for women;  (d)  To maximize the access of good quality, wide variety, client-oriented family planning services and to fulfill the unmet need of contraception.


I CONTRACEPTION
Contraception and fertility control are not synonymous. Fertility  control  includes  both  fertility  inhibition ( contraception) and fertility stimulation. While the fertility stimulation  is related to the problem  of  the  infertile couples, the term contraception includes all measures, temporary   or   permanent,   designed   to   prevent pregnancy due to the coital act.

Chapter 36: Population Dynamics and Control of Conception     la Withdrawal	Others (2%)
method (5%)
Rhythm---­
method (3%)	 Female sterilization (24%)
Male condom
(21%)	 Male sterilization (24%)



Ideal contraceptive methods should be highly (100%) effective, acceptive, safe, reversible, cheap, having non­ contraceptive  benefits,  simple  to  use  and  requiring minimal motivation, maintenance and supervision.


IUD (17%) Pills (16%)