Sulphasalazine Induced Hepatotoxicity, A Risk factor of Meconium Aspiration Syndrome in neonates: A Case Study


SK. Mohammed Firdoz*, T. Vinay Kumar, P. Divya Jyothi, Undrakonda Ajay, G. V. Naveen Kumar, K. Paul Pratheek

Department of Pharmacology, Nirmala College of Pharmacy, Mangalagiri, Guntur, Andhra Pradesh, India.

*Corresponding Author E-mail:



Meconium aspiration syndrome (MAS) may be defined as a respiratory distress which develops due to the aspiration of meconium (first feces of newborn infant). It remains as one of the most common causes of neonatal respiratory distress. Among the maternal complication Maternal Hepatitis was most common 2(3.5%) which was supported in another study by Vineeta Gupta, B.D. Bhatia and O.P. Mishra (1996) in BHU showed of the various antenatal complications studied, where only hepatitis was significantly associated with Meconium aspiration syndrome.[2] In this case a pregnant woman suffering with high grade fever with chills and arthralgia was treated with sulphasalazine for 5 days then the liver parameters were elevated in her due to sulphaselazine hepatotoxicity, it further lead to the development of meconium aspiration syndrome in newborn baby. So the treatment with sulphasalazine was discontinued and the hepatotoxicity was treated with liver protectants. In this case as a clinical pharmacist our main intervention is to avoid the use of sulphasalazine in pregnant women.


KEYWORDS: Sulphasalazine hepatotoxicity, Meconium aspiration syndrome, Maternal Hepatitis, Respiratory distress and Rheumatoid arthritis.




The disease modifying anti -rheumatoid drug, sulfasalazine is commonly used to treat RA and psoriatic arthritis (PsA). The estimated incidence of serious hepatotoxicity was higher (4 per 1,000 users) in a cohort of patients with inflammatory arthritis. The majority of cases occur within the first month of starting sulfasalazine therapy, and these can present either as a hepatocellular or cholestatic pattern of liver injury. About 25% of patients are jaundiced and a proportion of these rapidly develop hepatic failure.[1] Among the maternal complication Maternal Hepatitis was most common 2(3.5%) which was supported in another study by Vineeta Gupta, B.D. Bhatia and O.P. Mishra (1996) in BHU showed of the various antenatal complications studied, where only hepatitis was significantly associated with Meconium aspiration syndrome.[2]


Meconium is a thick viscous, dark green substance which is composed of intestinal epithelial cells, mucus, lanugo, intestinal secretions such as bile.[3] Meconium aspiration syndrome (MAS) may be defined as a respiratory distress which develops shortly after birth with radiographic evidence of aspiration pneumonitis in the presence of meconium stained amniotic fluid (MSAF).[4,5] Meconium aspiration syndrome remains one of the most common causes of neonatal respiratory distress.[6] The overall frequency of MSAF varies between 5 to 25%. Meconium aspiration syndrome occurs in 5% of infants born through MSAF. [7]


Pathophysiology of MAS:

MAS results from aspiration of meconium during intrauterine gasping or during the first few breaths. Fetal hypoxic Stress can stimulate colonic activity, resulting in the passage of meconium and also stimulates fetal gasping movements that result in meconium aspiration in-utero. Mounting evidence suggests that a chronic in utero insult may be responsible for most cases of severe MAS as opposed to an acute peripartum event. [8, 9]



The pathophysiology of MAS is complex. Aspirated meconium can interfere with normal breathing by several mechanisms.


The pathophysiologic mechanisms of hypoxemia in MAS include

(a) Acute airway obstruction,

(b) Surfactant dysfunction or inactivation,

(c) Chemical pneumonitis with release of vasoconstrictive and inflammatory mediators, and

(d) PPHN (Persistent pulmonary hypertension of newborn) with right-to-left extra-pulmonary shunting.


The common disturbances of lung function in MAS include hypoxemia and decreased lung compliance. [10]


A. Acute airway obstruction:

Depending on the consistency and amount of meconium aspirated, meconium may lead to either partial or complete airway obstruction leading to hyperinflation or atelectasis of the alveoli. The gas trapped may rupture resulting in air leak syndromes such as pulmonary interstitial emphysema, pneumothorax, and pneumomediatinum. [10]


B. Surfactant dysfunction or inactivation:

Presence of meconium in the alveoli can inactivate the endogenous surfactant and decrease the production of surfactant proteins A and B. [12,13] this causes atelectasis of the lung and can increase ventilation perfusion mismatch. The exact mechanisms for meconium-induced inactivation of pulmonary surfactant are not clearly understood. However, several components of meconium, especially fat-soluble (free fatty acids, cholesterol, and triglycerides), and water soluble (containing bilirubin, bile acids, enzymes, etc.) ones impair lung function. [13] Meconium can impair pulmonary surfactant by a combined action of cholesterol and bile acid present in meconium. [14] Meconium may also change the viscosity and ultrastructure of the surfactant, decrease the levels of surfactant proteins, and also accelerate the conversion from large, surface active aggregates into small, less active forms. The surfactant dysfunction is enhanced by leakage of plasma protein through an injured alveolar capillary membrane, as well as the proteolytic enzymes, and oxygen-free radical release from activated cells during the inflammation. [10]


C. Chemical pneumonitis with release of vasoconstrictive and inflammatory mediators:

Meconium aspiration leads to chemical pneumonitis. Meconium is a good chemo attractant for neutrophils [15]. Within a few hours, neutrophils and macrophages are found in the alveoli, larger airways, and lung parenchyma. Meconium is also a source of pro-inflammatory mediators such as interleukins (IL-1, IL 6, and IL 8), tumor necrosis factors. Thus it may induce inflammation either directly or indirectly through the stimulation of oxidative bursts in neutrophils and alveolar macrophages and may injure the lung parenchyma or lead to vascular leakage causing toxic pneumonitis and hemorrhagic pulmonary edema [16].


D. PPHN (Persistent pulmonary hypertension of newborn) with right-to-left extra-pulmonary shunting.:

Acute intrapulmonary meconium contamination induces a concentration dependent pulmonary hypertensive response, with 15–20% of infants with the MAS showing PPHN.


PPHN in infants with MAS may be caused by

(a) Pulmonary vasoconstriction secondary to hypoxia, hypercarbia, and acidosis,

(b) Hypertrophy of the postacinar capillaries as a result of chronic intrauterine hypoxia, and

(c) Pulmonary vasoconstriction as a result of pulmonary inflammation. [10]



Maternal case report:

A 20 years pregnant woman (35 weeks gestation) admitted in the hospital with chief complaints of high grade fever with chills, joint pains and itching. There she was treated with

T. Hydroxychloroquine 200mg OD is given to treat Malaria.

T. Sulphaselazine 1gm OD is given to treat Arthritis.

T. Prednisolone 5mg OD is given to treat allergic reactions.

T. Naproxen 5oomg SOS

T. Cetrizine 10mg BD is given to treat itching


After 5 days, while receiving 1.5 g per day sulphasalazine, she developed high grade fever with chills, melena & icterus. Now she admitted here for further management. On physical examination, she had hepato-splenomegaly and cholelithiasis.



Table:1- Vitals








100.2 F

100 F

98 F

98.6 F

98.6 F

Blood pressure

120/80 mmHg

100/60 mmHg

110/70 mmHg

100/60 mmHg

140/90 mmHg

Pulse rate






Respiratory rate









Table:2- Hematology















(3.8-5.8 million cells/cumm)







(4-11 thousand cells per microliter)







(1-4 lac cells/cumm)







Table:3- Liver function tests







Total bilirubin







Direct Bilirubin (0-0.6mg/dl)






Indirect bilirubin (0-0.4mg/dl)






SGOT (6-38 IU/L)

1616 IU/L

1962 IU/L

911 IU/L

1263 IU/L

1216 IU/L

SGPT (6-38 IU/L)

991 IU/L

1328 IU/L

1018 IU/L

859 IU/L

773 IU/l

Alkaline phosphatase (36-142 IU/L)

407 IU/L

390 IU/l

375 IU/l

342 IU/l

331 IU/L

Serum Albumin (3.5-5.5gm/dl)






Serum Globulin (2-3.5gm/dl)








Graph: 1 - Level of Bile salts



Graph: 2- Levels of SGOT , SGPT& Alkaline phospatase




Graph:3 - Levels of Serum Albumin and Globulin:



The criteria used for diagnosing meconium aspiration syndrome were:

·      Presence of meconium stained amniotic fluid.

·      Tachypnea, retractions, grunting or other abnormal signs on physical examination consistent with pulmonary disease (i.e. onset of respiratory distress within 24 hours of life).

·      Need for supplemental oxygen or ventilator support.

·      A compatible chest radiograph (Abnormal chest roentgenograms consistent with aspiration pneumonitis). [11]


Neonatal case report:

New born Baby has chief complaints of respiratory distress and severe pulmonary artery hypertension due to the aspiration of meconium.




The chest x-ray reveals that patchy pneumonitis on right side




Fig1: -Chest X-ray of newborn


Neurosonogram shows mild increased echogenicity noted in bilateral periventricular white matter.



Fig2:-Neurosonogram of newborn


2D ECHO shows left ventricular ejection fraction of 68%


Table:4 – Vitals of Neonate













SPO2 %







After delivery endotracheal intubation was done and bag and tube ventilation was given. Only Oro-tracheal suctioning was done.


Stomach wash was given to prevent further vomiting and aspiration of meconium stained fluid from stomach.

Treatment chart:

1.    O2 inhalation

2.    Inj. Ceftazidime 65mg OD

3.    Inj. Amikacin 37.5mg OD

4.      Inj. Metronidazole 7.5mg/kg IV OD

5.      10% dextrose 60ml/kg/day



In our case a pregnant woman was treated with sulphasalazine. Liver toxicity from sulfasalazine is a rare but serious side effect. It can range from mild elevation in liver function tests to hepatic failure and cirrhosis. After reaching the gut, sulfasalazine is broken down by the colonic bacteria into its metabolites, i.e., sulfapyridine and 5-aminosalicylic acid. Sulfapyridine is absorbed in the gut and eliminated after acetylation by enzyme N-acetyltransferase which can have variable activity based on the patient’s genotype. Patients who have genotypes for slow acetylation are found to be more predisposed to sulfasalazine-induced liver toxicity. [17, 18] Hepatotoxicity can arise either from direct toxicity of the drug or its metabolites. Injury can be hepatocellular which presents with disproportionate elevation in serum aminotransferases or cholestasis which presents with disproportionate elevation in alkaline phosphatase. The pattern of liver injury can have elevation in bilirubin and abnormal tests for liver synthetic function. [19, 20] It further lead to development of meconium aspiration syndrome in her baby which was aspirated.



In this case study we have found that treatment of pregnant women for arthralgia and other related complications with sulphasalazine can cause severe hepatotoxicity depending up on genotypes which in turn causes a rare respiratory distress meconium aspiration syndrome in neonates. We conclude that the clinical pharmacist intervention is to replace sulphasalazine in slow acetylates with an alternative drug.



We would like to thank Manipal super-specialty hospital for permitting us to conduct the study and we thank and pray for those patients whose information we have used for the study.



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Received on 12.10.2018         Modified on 17.11.2018

Accepted on 18.12.2018      © RJPT All right reserved

Research J. Pharm. and Tech. 2019; 12(3): 1201-1205.

DOI: 10.5958/0974-360X.2019.00200.2