|Year : 2007 | Volume
| Issue : 1 | Page : 33-40
Asthma & Pregnancy
Pranab Baruwa, Chiranjita Phukan
Department of T.B. & Respiratory Medicine, Gauhati Medical College, Guwahati-781 032., India
House No. - 52, MRD Road, New Guwahati -81 020, Assam.
| Abstract|| |
Adenoid cystic carcinoma is a rare but distinctive salivary gland type malignant neoplasm that arises infrequently in the respiratory tract, where it is largely seen in the trachea or large airways. A 29-year-old female who presented with a peripheral lung mass due to pulmonary adenoid cystic carcinoma is reported in view of its unusual location, early age of presentation and lack of such reports in the recent literature.
Keywords: Adenoid cystic carcinoma, Peripheral lung tumors.
|How to cite this article:|
Baruwa P, Phukan C. Asthma & Pregnancy. Lung India 2007;24:33-40
| Introduction|| |
Asthma has been reported to affect 3.7 to 8.4 % of pregnant women making it the most common potentially serious but treatable medical problem to complicate pregnancy  . Clinical and epidemiological studies, however have failed to provide convincing evidence of any consistent change in the natural history of asthma during pregnancy. The largest and the most recent studies suggest that maternal Asthma is associated with increased risks of poor maternal and fetal outcomes while better-controlled Asthma is associated with decreased risks , . The conclusion of the meta analysis agree that Asthma follows a rule of thirds during pregnancy as one third of the pregnant women get better, one third of the women get remain same and one third worsen in symptoms  . Most pregnant Asthmatic women continue the same disease course during successive pregnancies as their first pregnancy  . In the large cohort study most exacerbations of Asthma symptoms occur during the 24th and 36th week of gestation although increased symptoms are rare during the last 4 weeks of pregnancy. 90% has no symptoms during labor and delivery and within three months of delivery nearly 7.5% of women go back to their pre-pregnancy status  .
Physiological Changes During Pregnancy
Profound alterations of the respiratory and cardiovascular physiology accompany pregnancy. These conditions contribute to exacerbations of many of the disorders of the lung during pregnancy.
I) Respiratory system changes:
Anatomical changes include change in chest wall conformation, diaphragm elevation and progesterone induced stimulation respiratory centre. 
Physiological changes are:
- Increase in minute volume due to progesterone stimulated increase in Tidal Volume.
- Lung volume and capacities:- Inspiratory Capacity and Tidal Volume are increased. The FRC, ERV, RV are decreased because of the loss of lung volume resulting from elevation of the diaphragm. TLC is mildly decreased or remains unchanged. Collectively this measures suggest that although pulmonary functions are altered during pregnancy, it is not compromised and therefore in the absence of any respiratory condition like asthma it dose not induce any stress on respiratory function of the pregnant patient woman.
- ABG-with increased minute ventilation, alveolar ventilation increases leading to Respiratory Alkalosis. This is partially compensated by a metabolic acidosis generated by the kidney. As a result of Respiratory Alkalosis the gravida's 'Normal' ABG may appear at abnormal. In this context the 'Normal' pH may range from 7.4 to 7.47 and normal PCo2 ranges from 25 mm of Hg to 32 mm of Hg  .
II) Cardiovascular system changes
- Due to increased plasma volume and increased red cell mass, blood volume expands from 20% to 100% above preconception levels.
- Cardiac output is elevated by 30% to 60% by term and heard rates raises by 10 to 20 beats per minutes.
- Vascular resistance decreased as a result of progesterone induced relaxation of arteriolar smooth muscle. Thus both systolic and diastolic blood pressure display a minor decrease.
Determinants of Fetal Oxygenation
Fetus develops in an environment of low oxygen tension relative to the mother. The maternal uterine blood vessels and the fetal umbilical blood vessels run in parallel and oxygen is exchanged passively. Consequently fetal oxygen pressure can never exceed the maternal venous oxygen pressure. Therefore mechanisms used to exchange fetal oxygenation are :
- Fetal Hb, which has high affinity for oxygen relative to adult Hb.
- Increased perfusion rate of some fetal organs as compared to adult organs. Fetal oxygen delivery can be impaired by respiratory, cardiovascular and hematological problems in the fetus.
Even with these adoptive measures small medication in maternal Po2 seen in acute asthma episode can lead to poor uteroplacental perfusion. Obviously these scenarios can be detrimental to the well being of the fetus.
Effects of Asthma on Pregnancy
Controlled studies that have evaluated outcomes of pregnancy in asthmatic compared with non-asthmatic women have suggested that maternal asthma increases the risk of perinatal mortality, pre-eclampsia, complicated labour, low birth weight infants and preterm births compared with non - asthmatic women , . An increasing hypothesis regarding adverse fetal outcome is that there may be abnormal levels of the placental enzyme, which may lead to reduce fetal growth in asthmatic mothers. The enzyme 11b hydroxy steroid dehydrogenase type 2 presents excess maternal cortisol from reaching the fetus by metabolizing cortisol to its inactive form cortisone. Studies have demonstrated reduced enzyme activity in neonates with intrauterine growth retardation  Mechanism postulated to explain the possible increased perinatal risk have included:
- Hypoxia and other physiological consequences of poorly controlled asthma
- Medications used to treat asthma
- Pathogenic or demographic factors associated with asthma but actually could not by the disease or its treatment
In pregnant women uncontrolled asthma has been associated with respiratory symptoms, emergency department visit, hospitalization, respiratory failure, preeclampsia or death  .
Effects of Pregnancy on Asthma
Asthma may worsen, improve or remain unchanged during pregnancy  . The mechanisms responsible for the altered asthma course during pregnancy are unknown. Some studies have shown significant variation in diseases severity during pregnancy. The percentage of patients who improved ranges from 12% to 69%; those who worsen ranges from 4% to 44%; and those whose diseases course did not change ranged from 15% to 93%  . Worsening of asthma during pregnancy may be due to a multitude of contributing factors - allergen exposure, upper respiratory tract infection gestroesophageal reflux, medication non-compliance, illicit drug use etc. Patients with particular risk include patents with severe asthma prior to conceptions and patients whose asthma has worsened in prior pregnancies.
The result of various studies have demonstrated that more severe preconception asthma tends to worsen during pregnancy where as less severe asthma tends to remain unchanged or tends to improve  . Moreover there is a definite relation between rhinitis course and asthma course during pregnancy. Kircher et.al  identified 568 pregnant women's usual disease course. They found that those women who experienced improvement in asthma symptoms during pregnancy also had improvement in rhinitis symptoms. This suggest that the same mechanism may influence both levels of airway during pregnancy, and possibly that rhinitis management during pregnancy may improve asthma.
Diagnosis & Differential Diagnosis of Dyspnoea in Pregnancy
Diagnosis of Asthma during pregnancy uses the same technique as in the general population, Spirometry - before and after administration of short acting bronchodilator.  Measurement of FEV1 & FVC are used in establishing & following the course of Asthma. Pregnancy has no effect on forced expiratory volume in 1 sec (FEV1), forced vital capacity FVC & forced expiratory flow.  Therefore a reduction in FEV1/FVC should not be thought of as a normal pattern in pregnancy but related to obstruction by diseases just like in the non pregnant patient. At each visit, spirometry should be performed as correction of broncho constriction is necessary to prevent decreased fetal oxygestation.
Differential Diagnosis of Dyspnoea in Pregnancy
- Physiological Dyspnoea of Pregnancy: It is a benign symptom. It is due to changes in the chest wall configuration, diaphragm positioning and altered respiratory centre sensitivity, Some gravida have an increased awareness of the physiological dyspnoea caused by progesterone stimulation of the respiratory centre and decreased RV and decreased FRC resulting from increased uterine volume  .
- Pulmonary Edema
- Pulmonary Embolism
- Worsening Asthma
- Severe Asthma
- Pregnant patients can also suffer from various haematological and cardiac diseases which can produce anemia and lead to dyspnoea.
Drug Therapy in Asthma
Ideally no medicines should be used during pregnancy especially during the first trimester, as this is time of highest risk of congenital organ malformations. However in patients with severe or chronic or under treated Asthma, the risk of harm to the fetus outweighs any small risk for the medications used to control Asthma. As there are few safety studies on medication use during pregnancy, the Food and Drug Administration (FDA) has developed categories for drugs (A, B, C, D and X) as guidelines for choosing agents whose perceived benefit outweighs the risk for use during pregnancy.
β - adrenergic agonist
The principal action of β2 agonist is to relax airway smooth muscle by stimulating β2 receptors, thus increasing cyclic AMP and producing functional antagonism to bronchoconstriction. Most of studies and data available are on salbutamol whose safety and efficacy is well established. The NAEPP working group on Asthma and Pregnancy 2003 included one experimental animal study and six human studies as evidence for review on the safety of bronchodilators. It was concluded that animal studies were generally negative although some agents produced anomalies at high doses. The 6 human studies included one case report and 5 clinical studies that included 6667 pregnant women of whom 1929 had asthma and 1599 women exposed to p2-agonist. There was no evidence of fetal injuries from these drugs, either systematically or by inhalation.
β2- Agonist use was reported in over 600 patients in the Kaiser Permanente prospective study of asthma during pregnancy  . In the Michigan Medicaid Study, salbutamol was the most commonly used β2- agonist (n - 1090)  . These studies found no association between the use of β2agonist in pregnant women and increased risk of congenital malformations or other adverse pregnancy outcomes.
Regarding long acting β2-agonists, animal studies have not been reassuring and few human data exist on the safety of Salmeterol or Formetorol during pregnancy. Though limited data are available on the use of Salmeterol or Formetorol on pregnancy, they can be used in pregnancy if required as the pharmacologic and toxicologic profiles are similar to the short acting inhaled β2 agonist with the exception of their prolonged retention in the lung  . Moreover benefit risk consideration favour salmeterol use during pregnancy in these patients whose asthma is not controlled by medium dose inhaled steroids.
Use of parental and oral β2 agonists should be avoided because of lack of safety data, increased risk of side effects eg; tremor and the potential to initiate lab our and inhibit delivery  .
Non-selective β agonists such as Epinephrine, that carry a risk of uterine vasoconstriction due to its alpha-adrenergic effects, are probably best avoided.  Epinephrine is also linked to congenital defects in animals. The NAEPP Working Group however concluded that the occasional episodic use of epinephrine for acute exacerbation of asthma is unlikely to produce chronic hemodynamic changes such as those seen in the animal studies  . It is the definitive treatment for anaphylaxis.
Theophylline the most commonly used methylxanthine provides mild to moderate bronchodilatation in asthma. Although its mechanism of action is yet to be established, at low serum concentration theophylline may be mildly anti-inflamatory. The NAEPP working group on Asthma and Pregnancy 2003 included seven experimental animal study and eight human studies as evidence for review on the safety of Theophylline. The experimental animal studies confirm association of high dose Theophylline and adverse pregnancy outcomes in animals. The eight human studies consisting of two case reports and six clinical studies included a total of 57163 pregnant women of whom 3616 had asthma and 660 women had taken theophylline. These Studies and clinical experience confirms the safety of theophylline at recommended doses.
In a prospective study of effects of asthma drugs on 2205 pregnancies by Triche et al, 2003 there was an association between maternal theophylline use and preterm birth and Pre-eclampsia, but the numbers of mothers exposed to theophylline in their cohort was small (n = 15).  Kaiser study found no independent association of theophylline exposure with an increased risk of preclampsia, preterm birth or lower birth weight infants in 429 women after adjusting for confounders  . In a study of 824 pregnant women who had asthma, and 678 women who did not have asthma theophylline was used by 429 of the women and not associated with increase in incidence of major congenital malfunctions, maternal preclampsia, preterm birth, low birth weight or being small for gestational age  .
In a prospective double blind randomized controlled trial on pregnant women with moderate asthma, no difference was made in asthma exacerbation, treatment failure or maternal or perinatal outcomes among the women in the Beclomethasone dipropionate group versus theophillyne (used as monotherapy) cohort  Women taking Theophylline however reported a higher frequency of side effects and discontinuation of medication.
Pregnancy is associated with hypo-albuminemia and decreased theophylline binding. When theophylline is used during pregnancy, low doses of theophylline are recommended with maintenance of serum theophylline at 5-12 mcg/ml  Timed release preparation permit easier dosing with less fluctuation in serum theophylline concentrations. A case of transplacental toxicity also has been reported with fetal theophylline levels of 8.6mcg/ mL at one hour of life  . Concomitant use of cimetidine & Erythromycin causes increase in theophylline serum levels. High doses have been observed to cause jitteriness, tachycardia and vomiting in mothers and neonates.
Theophylline may be considered as a alternative adjunctive long - acting bronchodilator therapy, but not preferred for moderate to severe asthma when inhaled corticosteroid alone does not provide adequate control of patient's asthma. Theophylline is not useful as adjunctive therapy for treatment of acute exacerbation  .
Ipratropium bromide is a quaternary derivative of atropine. It can be used as adjunctive therapy of acute exacerbation of asthma. Although there are no available human data, animal studies are reassuring.  Therefore nebulized Ipratropium can be considered in women presently with acute asthma who do not improve substantially with first inhaled β2-agonist treatment alone  .
Concern has been raised regarding a possible cause of inhaled corticosteriods as well as oral steroids on intra uterine growth retardation. The NAEPP working group on Asthma and Pregnancy 2003 included three experimental animal studies and ten human studies(eight of pregnant women and two of newborns from the Swedish birth registry ) as evidence for review on the safety of inhaled steroids. These eight studies included a total of 21,072 pregnant women, of whom 16900 had asthma and 6113 had taken inhaled steroids. The NAEPP working group concluded that: a) the risk of asthma exacerbations associated with pregnancy can be reduced and lung function (FEV1) improved with the use of inhaled corticosteroid therapy. b) No studies have related inhaled corticosteroid use to any increase congenital malfunctions or other adverse perinatal outcomes  .
Few more recent studies have shed more light on these concerns. Norjavaara and Gerhardsson de Verdier et al 2003 searched for an association between inhaled Budesonide use during pregnancy and adverse perinatal outcomes and sought data which included information from 2968 pregnant women enrolled in the Swedish Medical Birth Registry who reported used of inhaled Budesonide. These women gave birth to infants of normal gestational age, birth weight and length with no increased risk of still birth or multiple birth  .
Another study described the incidence of small for gestational age infants, an important measure of intra uterine growth retardation in the offspring of 396 exposed mothers enrolled into the registry for Allergic and Asthmatic pregnant patients of the American College of Allergy Asthma & Immunology. Beclomethasone was the most commonly used inhaled steroid. The incidence of small for gestational age infant was 7.1% compared with the expected incidence of 10%. There was no significant relationship identified between specific inhaled steroids use and the incidence of-inhaled steroid used and the incidence of small for gestational age infants or mean birth weight  . In summary, the data provided by these studies suggest that the currently available inhaled steroids used at clinically relevant doses do not impair IUG.
On the basis of a prospectively monitored cohort of 824 pregnant women who had asthma and 678 pregnant women who did not had asthma it was concluded that there is no significant relationship between congenital malfunction and exposure to corticosteroids (oral, inhaled or interventions) in the first trimester or at any gestational age  . They also found no independent relationships between inhaled corticosteroids and preeclampsia, preterm births, low birth weight infants  . In summary, the data provided by these studies suggest that the currently available inhaled steroids used at clinically relevant doses do not impair IUG.
Inhaled corticosteroids are now recognized as the most effective anti- inflammatory drugs and the preferred treatment for the management of all levels of persistent Asthma in pregnant women. Although systemic absorption of inhaled corticosteriods can occur the low plasma concentrations achieved by inhalation make it unlikely that fetal effects can be seen.  It is important that no data indicate that the other preparations are unsafe. Therefore, inhaled corticosteroid other than budesonide may be continued in patients who were well controlled by these agents prior to pregnancy  .
Oral (systemic) Corticosteroids
The NAEPP working group on Asthma and Pregnancy 2003 included nine experimental animal studies and eight human studies as evidence for review on the safety of oral steroids. The animal studies demonstrated a steroid mediated clef lip or decrease in fetal growth in animals. One of the meta analyses used 6 cohort studies that included 51,380 pregnant women of whom 535 had taken oral steroids.  The other Meta analysis included used four case control studies ,,, that included 4321 pregnant women, of whom 1998 had asthma and 213 had taken oral steroids.
Evidence on the safety of oral corticosteroids during pregnancy is conflicting. Oral corticosteroids use, especially during the first trimester of pregnancy, is associated with and increased risk (0.2 - 0.3%) for isolated cleft lip with or without cleft palpate.  Oral corticosteroids use during pregnancy in patients that have asthma is associated with an increased incidence of pre-eclampsia and an increase in the delivery of both preterm and low birth weight infants. , The available data however makes it difficult to separate the effect of corticosteroids on these outcomes and the effects of severe or uncontrolled asthma. Indeed the recent epidemiological studies have suggested that subjects with asthma may be at increased risk of experiencing pregnancy - induced hypertension  . It has been hypothesized that common factors may lead to bronchial muscle hyper reactivity and vascular hyper reactivity. Vascular hyper reactivity in the form of B - adrenergic hypo reactivity and x- adrenergic hyper reactivity has been reported in subjects with asthma  .
Because severe asthma has been associated with maternal and/or fetal mortality, risk benefit considerations favour the use of oral corticosteroids when indicated in the longterm management of severe asthma or severe exacerbation during pregnancy.
If appropriate use of high dose inhaled corticosteroids and long acting inhaled B2 agonist is insufficient in managing symptoms, the addition of systemic corticosteroid therapy is warranted. Aggressive dose should be employed on a short-term basis e.g. 2mg/kg/day to a maximum daily dose of 60g of prednisone equivalent 
For patients who require long-term systemic corticosteroid 
- Use the lowest possible dose (single dose daily or on alternate day).
- Monitor patients daily for adverse side effect of corticosteroids.
- When control of asthma is achieved discontinue systemic corticosteroid or attempt to decrease dose. Depending on the duration of systemic corticosteroid administration care must be exercised in their withdrawal to avoid disease exacerbation and/or serious Hypothalamic - Pituitary - Adrenal (HPA) crisis.
The Kaiser study reported no increased risk of any adverse perinatal outcomes in pregnancies on infants of 243 mothers who received Cromolyn.  The Michigan Medicaid Study reported a relative risk of total congenital malfunctions of 0.9 in infants of 191 exposed mothers.  Wilson reported an incidence of 1.4% congenital malfunction in 296 full term infants of crymonyl treated mothers.  One prospective cohort study found no significant relationship between use of Cromolyn in the first trimester or any time in the pregnancy and increased incidents of major congenital malfunction, maternal pre-eclampsia, preterm birth, low birth weight or being small for gestational age  . It is well tolerated with an excellent safety profile in pregnancy. Nevertheless strong evidence demonstrates that Cromonyl is not as effective as inhaled corticosteroids  . Thus Cromonyl is an alternative but not preferred treatment for mild persistent asthma especially with the recent reassuring safety data in inhaled corticosteroids  .
Leukotriene Receptor Antagonist:
Leukotriene modifiers comprises of two pharmacological classes of compounds available as oral tablets:
- Leukotriene receptor antagonist eg. Monteleukast and Zafirlucast.
- 5- lipoxygenase pathway inhibitors eg. Zileuton.
In one observational study of 2205 pregnant women, 873 pregnant women with asthma, of whom 9 used Leukotriene modifiers did not experience adverse effects, but the number of women was small  Minimal human data are currently available on leukotriene modifiers during pregnancy. Animal studies have been reassuring for Montelukast and Zafirlukast but not necessary for Zileuton which cannot be recommended  .
Montelukast and Zafirlucast may be considered as alternative but not preferred as long term controlled medication. These may be considered for use during pregnancy for patients who have a favourable response to the drug before they became pregnant.  When initiating new treatment for pregnancy, Leukotriene receptor antagonists are an alternative but not preferred treatment option for asthma.
Omalizumab an IgG monoclonal antibody directed against IgE is used for use in moderate to severe allergic asthma that has not responded to moderate to high doses of inhaled corticosteroids. No teratogenic effects were seen in animal studies, however because of the newness of this drug it should be prescribed cautiously during pregnancy.
Allergen Immunotherapy is a significant disease modifying treatment but because of the slight but possible risk of an anaphylactic reaction, the strength of the allergen extract should not be increased during pregnancy  .
The latest position paper on the use of asthma and allergy medications during pregnancy by a joint committee of the American College Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma and Immunology (ACAAI) was published in 2000 as guidelines for use in Asthma during pregnancy.
Management of Acute Exacerbation of Asthma During Pregnancy:
Asthma exacerbation during pregnancy should be managed aggressively because: - A maternal Po2 < 60 mm Hg with Hb saturation of <90% may be associated with fetal hypoxia.
Pregnant women should be to recognize signs and symptoms of early asthma exacerbation. Decrease in fetal movement may be an early sign of asthma exacerbation. In general home treatment begins with inhaled salbutamol (2-4 puffs 20 mins apart for 1 hr). A good response is characterized by relief in symptoms, ability to resume normal activities or PER > 80% of personal best.  If response is incomplete or if fetal activity is decreased patient is advised hospitalization.
Continuous fetal monitoring if the fetus is potentially viable is advisable. Salbotamol delivered by Nebulizer (2.5 mg in 2.5 ml of Normal saline driven with Oxygen) is recommended every 20 min 1st hr  . Oral systemic corticosteroid are started if FEV1 or PEF is less than 50% predicted; if there is no immediate response to Salbutamol or if patient recently took oral corticosteroid. Corticosteroid should be given orally in patients with lower FEV1 or PEF and intravenously with impending respiratory arrest.  O 2 inhalation to achieve O 2 saturation >95% is recommended in all patients  . Ipatropium is recommended in severe exacerbation as additional therapy  . Patient should be reassessed for use of accessory muscles, wheezing and FEV1 or PEF before and after each bronchodilator ABG is done if patient is in severe distress. Repeated assessment of all patients is recommended after inhaling medications.
Management of Asthma During Labour and Delivery:
Acute effects of asthma is very rare in labour due to Endogenous steroid production in women receiving steroid tablets are at a theoretical risk of maternal hypotholamic pituitary - adrenal axis supression. Women with asthma may safely use all forms of pain relief in labour  .
Some studies show an association between asthma and an increased caeserean rates, but this may be due to planned caeserean section rates or induction of labour rather than due to any direct effect of asthma as an intrapartum indication The risk of post partum exacerbations is increased in women having caeserean section due to their severity of asthma or to factors such as post-operative pain with diaphragmatic splinting, hypoventilation and atelectasis , .
Prostaglandin E1, E2 may be safely used for labor inductions or induced abortion or PPH.  Prostaglandin F2 alpha used to treat PPH due to uterine atony may cause bronchospasm.  Asthma medications should be continued during labor and delivery. If systemic steroid have been used in the previous 4 weeks then stress dose of steroid (eg.Hydrocortisone100mg8hrlyI.V) should be administered during labor and for 24 hour period after delivery to prevent maternal adrenal crisis  . If anesthesia is required regional blockade is preferable to General Anaesthesia  Epidural anesthesia has the benefit of reducing O 2 consumption & minute ventilation during labor.
Drug therapy in breast-feeding mothers
Asthmatic women should be encouraged to breast feed. Medicines used in asthma including steroid tablets are not contraindicated to breast-feeding. However maternal use of theophylline may cause irritability, feeding difficulties or jitteriness in sensitive infants.  Proportion of oral or I.V. Prednisolone recovered in breast milk is less than 0.1%.  For maternal doses of at least 20mg once or twice daily the nursing infant is exposed to minimal amounts of steroid with no clinically significant risk  .
| Conclusion|| |
Medical literature suggests that commonly used drugs in pregnancy have a high benefit to risk ratio in pregnant patients. Maternal and fetal risks of uncontrolled asthma are much greater than the risks from conventional asthma medication. Drug therapy for pregnant asthma is same as for non-pregnant asthma patients. Acute severe Asthma is an emergency and should be treated vigorously. Inhaled corticosteriod should be used whenever indicated. Intravenous or oral theophylline should be used whenever indicated but Leukotriene antagonists should not be commenced during pregnancy. Frequent monitoring of mother and fetus is necessary to ensure a symptom free pregnancy and a healthy baby.[Table 1],[Table 2],[Table 3]
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[Table 1], [Table 2], [Table 3]