Pregnancy In A Case Of Methemoglobinemia

Author Information

Dudhe M*, Khadkikar R**, Saxena N*, Chauhan AR***
(* Third Year Resident, ** Assistant Professor, *** Additional Professor. department of Obstetrics and Gynecology, Seth GS Medical College & KEM Hospital, Mumbai, India)


Methemoglobin is an oxidized form of hemoglobin with iron in the ferric form instead of the usual ferrous form, which results in decreased availability of oxygen to the tissues. Methemoglobinemia occurs when red blood cells contain methemoglobin higher than 1%. It is a well-known but frequently forgotten cause of hypoxia and respiratory distress in patients of all ages. [1] As most patients are asymptomatic, congenital form may be diagnosed for the first time during pregnancy. We report a primigravida with congenital methemoglobinemia who was treated with injection methylene blue prior to emergency lower segment cesarean section (LSCS) for abruptio placentae.


Methemoglobin, along with carboxyhemoglobin and sulfhemoglobin, are types of dyshemoglobin   i.e. a type of haemoglobin that does not bind with oxygen. [2]
Tissue hypoxia is due to reduction in levels of free haemoglobin and hence difficulty in release of oxygen. Congenital methemoglobinemia is a rare genetic abnormality in which patient is mostly asymptomatic and only presents with cyanosis which may be present since birth. [3] During pregnancy, it may lead to uteroplacental insufficiency causing intrauterine growth retardation, oligohydramnios, severe preeclampsia and abruption. [4]

Case Report

A 23 year old primigravida,  known case of  congenital methemoglobinemia was admitted in our tertiary care hospital at 34 weeks’ of gestation for evaluation of pedal edema. Significant finding at this time was methemoglobin level of 25%. Hematologist opinion was sought; no active treatment was advised except to continue tablet vitamin C twice daily. Obstetric evaluation and other investigations were normal hence patient was discharged.
On past history, patient had mild cyanosis since birth but was diagnosed with congenital methemoglobinemia only 4 years ago, when she presented with breathlessness not responding to oxygen along with slate grey cyanosis. At that time, cardiovascular and respiratory system examination were normal and all routine investigations were normal. G6PD enzyme activity was normal. However, methemoglobin levels were significantly elevated (44%), and nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase activity was decreased. She was started on tablet vitamin C and multivitamin twice a day. At 38 weeks of gestation, patient was readmitted in early labour. On examination, she had cyanosis, her pulse was 92/ min, blood pressure was 130/ 90 mm of Hg, urine albumin was 2+. Blood drawn for investigations was chocolate brown in colour. ABG showed oxygen saturation of 92 %. In view of foetal distress and signs of abruption, decision for emergency LSCS was taken. Urgent haematology opinion was sought; repeat urgent methemoglobin levels were not possible hence based on recent report of methemoglobin 25 %, patient was given intravenous 1 mg/ kg (50 mg) methylene blue in 500 ml normal saline over 30 minutes prior to commencement of LSCS. Patient underwent emergency LSCS in view of abruptio placenta under general anaesthesia, with high doses of oxygen. LSCS was uneventful; she delivered a male child of 2.6 kg with Apgar score of 9/10. Repeat methemoglobin level postoperatively was 3.3%. Patient was stable and was discharged on day 7.  

Hemoglobin can transport oxygen only when the iron is in ferrous form. When hemoglobin loses an electron, the iron atom is converted to the ferric state, forming methemoglobin. This causes leftward shift of the oxygen-hemoglobin dissociation curve, hence decreased release of oxygen to the tissues, and hence clinical manifestations.
Normally, the methemoglobin level is < 1 %; this low level is maintained by 2 mechanisms. The first is the hexose-monophosphate shunt pathway within the erythrocyte, where oxidizing agents are reduced by glutathione. The second mechanism requires NADH and nicotinamide adenine dinucleotide phosphate (NADPH) to reduce methemoglobin to its original ferrous state. Methemoglobinemia results from a redox imbalance, either due to decrease in the activity of reducing enzymes (congenital form) or excessive oxidization of haemoglobin (acquired form).
Congenital methemoglobinemia is very rare and is of two types: one due to NADH methemoglobin reductase enzyme deficiency, which is autosomal recessive and the other due to an abnormal oxygen affinity hemoglobin termed hemoglobin M, which is autosomal dominant; our patient had the former deficiency.[1]
Acquired form is more common, and may occur when erythrocytes are affected by oxidizing agents like acetaminophen, anticonvulsants, nitrofurantoin, sulphonamides, valproic acid, dapsone, nitroglycerin, topical anaesthetic agents like benzocaine, and volatile organic compounds.[2] Occasionally it may occur secondary to pathologic conditions like sepsis, sickle cell crisis, and gastrointestinal infections in children.[2]

Presence of cyanosis without any cardiopulmonary disorder or decrease in oxygen saturation, and an appearance of “more blue than sick” are diagnostic.[1] Symptoms depend upon percentage of methemoglobin in blood:

3 – 15 %
grayish skin color
15 - 30 %
cyanosis and chocolate brown blood
30 – 50 %
dyspnea, headache, fatigue, dizziness, syncope, with oxygen saturation as low as 80 %, as seen in our case
50 – 70 %
tachypnea, metabolic acidosis, cardiac arrhythmias, seizures, CNS depression and coma [2]

Organs with high oxygen demands i.e. central nervous system and cardiovascular system are usually the first to manifest toxicity. Main symptoms include central cyanosis not responding to oxygen, and in severe cases altered mental status, convulsions and coma leading to death when level rises to 70%.
Most common complications during pregnancy include anemia, threatened abortion, preterm labor, pregnancy induced hypertension, IUGR, and placental abruption. [4] These changes may be a result of hypoxia, excessive production of free radicals, resultant oxidative damage to cellular membranes and DNA.  Monitoring of methemoglobin concentrations in maternal blood is a reliable indicator of effects of free radicals and oxidative states. Our patient presented with pregnancy induced hypertension and placental abruption for which emergency LSCS was performed. Environmental toxins like nitrogen oxides, sulphur dioxide and their metabolites over longer periods, cause maternal vascular endothelial dysfunction from early pregnancy. There is no definitive treatment for hereditary methemoglobinemia which is a chronic and mild condition. Treatment depends upon symptoms and level of methemoglobin. Chronic mild forms are given ascorbic acid (which acts as reducing agent), riboflavin and N-acetylcystine to reduce oxidative damage.
Primary emergency treatment includes administration of intravenous methylene blue in symptomatic cases. It is a thiazine dye with dose-dependent antiseptic and oxidizing properties.  Methylene blue activates NADPH methemoglobin reductase, resulting in reduction of  methylene blue to methylene leucoblue, which transforms methemoglobin into normal hemoglobin by a non-enzymatic mechanism. Methylene blue restores the iron in hemoglobin to its normal oxygen-carrying state by providing an artificial electron acceptor for NADPH methemoglobin reductase. Methemoglobin level falls significantly 30 to 60 minutes after the first dose; in our case we commenced LSCS within 30 minutes of methylene blue. [2] Rapid intravenous administration or higher doses can cause thoracic pain, dyspnoea, hypertension, diaphoresis and haemolysis. It should be administered carefully in patients with renal failure; it is slowly excreted by the kidneys and the urine has a bluish tint.
Exchange transfusion or hyperbaric oxygen is suggested treatment options in resistant cases and in G6PD deficient individuals in whom methylene blue is contraindicated. Combined efforts of hematologist, obstetrician and anesthetist contributed towards effective management of this case.


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2.   Nascimento TS, Pereira ROL and Mello HLD, Costa J. Methemoglobinemia: from Diagnosis to Treatment. The internet journal of obstetrics and gynecology. 2008; 58(6):651-664
3.      Pepper G, Weinstein HG, and Heller P. Congenital methemoglobinemia in pregnancy. The journal of American medical association. 1961; 177(5):328-330. Available from:
4.   Mohorovic L. The role of methemoglobinemia in early and late complicated pregnancy. Medical hypothesis. 2007;68(5):1114-1119. Available from:


Dudhe M, Khadkikar R, Saxena N, Chauhan AR. Pregnancy In A Case Of Methemoglobinemia -A Rarity. JPGO 2015. Volume 2 No. 1. Available from: