Dentofacial manifestations of fetal warfarin syndrome in a paediatric patient

Abstract

Anticoagulant therapy is commonly indicated during pregnancy to prevent thrombosis and prevention of prosthetic heart valve-associated thromboembolic events. Warfarin is a synthetic anticoagulant with low molecular weight and can cross the placenta resulting in congenital abnormalities termed fetal warfarin syndrome. This paper highlights the case of an 8-year-old boy with warfarin embryopathy. It highlights the extraoral and intraoral findings of the case along with the cephalometric analysis and provides insight into the phenotypic variations among the different cases reported in the literature.

Background

Warfarin is an oral anticoagulant of synthetic origin that belongs to the class of vitamin K antagonists. It is a common medication used for the treatment of venous thromboembolic disease and the prevention of valvular heart ailment and prosthetic heart valves-associated systemic embolism.^{1 2} However, its use can lead to adverse effects on the mother and fetus.³ Warfarin can easily cross the placenta owing to its low molecular weight and results in a number of consequences which include spontaneous abortion, stillbirth, neonatal death and the various other congenital anomalies termed as fetal warfarin syndrome (FWS).^{4 5} The exact prevalence of this condition is unknown; however, it may be more prevalent than assumed. This is particularly true for countries where warfarin is used more commonly compared with the other anticoagulants. The lack of medical care subsequent to anticoagulant therapy or inadequate follow-up could be the contributory factors for increase in number of cases among the countries with lack of medical facilities. It has been found that among the mothers on warfarin therapy during their first trimester more than 6% of their children have likelihood of developing the congenital anomalies.^{4 5}

Teratogenic effects of warfarin have been first reported in 1965. This may occur due to exposure during the embryonic or fetal period. The period ranging from the sixth to ninth week of gestation is considered the period of greatest warfarin sensitivity.⁴ Vitamin K deficiency induced by warfarin results in haemorrhages into any of the several organs and this can be the probable reason for teratogenicity.⁶ DiSaia et al reported optic atrophy, nasal hypoplasia and intellectual disability as a manifestation of warfarin embryopathy.⁷ Craniofacial abnormalities like nasal hypoplasia have clinical implications as they can lead to respiratory distress in newborns.

There is a scarcity of literature assessing the teratogenic effects of FWS on dentition and maxillofacial region. There are few case reports published; however, none of them have analysed the cephalometric findings in the patients (table 1).^{2 8–10}

Table 1.

Dental and orofacial manifestations of fetal warfarin syndrome described in the literature

Author/ year/ country	Age at the diagnosis	Oral-facial manifestations
Silveira et al 2015/Brazil8	Followed up from birth to 8 years postnatally	Hypoplastic midface and nose Short upper lip Unerupted maxillary incisors Premature eruption of left maxillary second premolar Posterior cross-bite High arched palate
Levaillant et al 2009/France9	Followed up from 25 weeks of gestation to 2 years postnatally	Flat maxilla Flat nasal bridge
Finkelstein et al 2005/Toronto, Canada2	21 weeks stillborn (abortus) (Postmortem examination of male fetus)	Flattened nasal bridge Abnormally large dental buds Irregular ossification of cervical vertebra and hyoid bone
Barr and Burdi 1976/Michigan, USA10	A 17-week-old human fetus (abortus) (histological and anthropometric assessment during postmortem examination)	Nasal hypoplasia Solitary maxillary incisor

Case presentation

An 8-year-old boy reported to the outpatient department of paediatric dentistry with the complaint of multiple carious teeth. According to the parents, tooth decay was present for the last 12 months and there was a history of food lodgement. There was no history of pain or swelling in the associated teeth. The mother had a history of rheumatic heart disease with severe mitral valve stenosis. She underwent a prosthetic heart valve replacement for the same. Since then, she was on warfarin 5 mg daily as part of postsurgical anticoagulant therapy. However, she did not consult the treating doctor regarding her pregnancy and continued the intake of warfarin during the first trimester. It was only after the 8 weeks of gestation when she reported for follow-up, she was advised to replace the warfarin with the heparin.

Natal history had revealed that the child was born through caesarean section with full-term birth and normal birth weight. He was diagnosed with warfarin embryopathy in the form of hypoplastic nasal bone/stippling of cartilage in the femur and calcaneum. Medical history revealed difficulty in breathing due to nasal blockage till 5 years of age. General examination of the child revealed a mesomorphic body built and short and wide distal phalanges of the fingers (figure 1). Extraoral examination revealed a straight facial profile with hypertelorism and depressed nasal bridge (figure 2). The child had early mixed dentition with multiple decayed teeth (FDI notation-52,55,62,65,74,75,84,85). The fibrous gingiva with the delayed eruption was evident with maxillary right permanent first molar whereas eruption bulge was seen with maxillary central incisors (figure 3).

Figure 1.

Short and wide distal phalanges of the hands.

Figure 2.

Extraoral frontal and lateral view.

Figure 3.

Intraoral pictures. (A) Frontal view, (B) maxillary occlusal view and (C) mandibular occlusal view.

Investigations

An orthopantomogram (OPG) and lateral cephalogram were done for the radiographic assessment. OPG reveals the presence of developing permanent teeth with a delay in root development expected for dental age with teeth 11, 21, 31 and 41 (figure 4). Cephalometric examination reveals a deficient anterior nasal spine, retrognathic maxilla and an increased mandibular plane angle. An accentuated value of facial angle with resultant straight facial profile was also evident. An increase in the lower facial height was also seen in the present case. The child was in cervical vertebrae maturation (CVMI) stage 2 which indicates a peak interval of mandibular growth to begin within a year after this stage (figure 4).

Figure 4.

Orthopantomogram and lateral cephalogram.

Differential diagnosis

The differential diagnosis of the present case with nearly similar clinical and radiographic characteristics are described in table 2.

Table 2.

Differential diagnosis of fetal warfarin syndrome

Conditions	Aetiology/familial transmission/genetic alteration	Clinical presentation haematological findings
Keutel syndrome	Mutation in gene encoding matrix Gla protein Autosomal recessive	Abnormal calcification of larynx, trachea, ear and nose cartilages. Stippling of epiphyses of long bones. Spinal column vertebrae calcification Facial dysmorphism with elongated face. Maxillary hypoplasia with underdeveloped middle third of face Hearing impairment, nasal speech, recurrent otitis and/or sinusitis, repeated respiratory infections, mild intellectual deficiency, short stature and seizures were the other associated findings
Hereditary combined deficiency of the vitamin K-dependent clotting factors	Deficiency of vitamin K-dependent clotting factors and coagulation inhibiting proteins Autosomal recessive	Stippling of epiphyses in long bones, short distal phalanges of fingers Findings similar to pseudoxanthoma elasticum and osteoporosis with no routine serum circulating marker increase
Chondrodysplasia punctata 1	Chromosomal mutation involving ARSE gene X-linked recessive	Chondrodysplasia punctata a characteristic spot at the ends of their bone Stippled epiphyses disappear between 2 and 3 years of age Other features include flat nose and short fingers. Some also experience breathing difficulty, hearing loss and intellectual impairment

Treatment

A written informed consent was obtained from the patient’s parent. Haematological assessment was performed prior to the dental management of the case considering the anaemia and other coagulopathies reported in FWS patients.^{11 12} The caries risk assessment (International Caries Classification and Management System criteria) revealed that the child belongs to a high caries risk category.¹³ Oral prophylaxis was performed followed by oral hygiene instructions, brushing demonstration and fluoride varnish application. Pulpectomy was performed in teeth 74 and 85 followed by stainless steel crown. Secondary caries with teeth 55, 65 and 75 were managed with a composite restoration. Extraction of root stumps with tooth 52 and 62 was performed whereas 54 and 64 were restored with resin composite. Considering the poor prognosis, 84 was extracted followed by crown and loop space maintainer (figure 5). The orthodontic opinion was sought for midface deficiency considering the need for functional appliance therapy. No active functional mechanotherapy has started yet and the patient is under follow-up.

Figure 5.

Postoperative intraoral pictures.

Follow-up

The patient was followed up at every 3 month interval. After 3 months of recall, the patient had no signs and symptoms with respect to his oral symptoms. Oral hygiene instructions were reinforced and fluoride varnish application was done.

Discussion

This paper highlights the findings and the dental management in a case of FWS. The diagnosis was established on the basis of the history of maternal ingestion of warfarin during the first trimester (till 8 weeks of gestation) of pregnancy and hypoplastic nasal bone/stippling of cartilage in femur and calceneum.

The mother of the child in the present case was under warfarin as an anticoagulant therapy after her prosthetic heart valve transplantation which she continued during her pregnancy. Warfarin inhibits the formation of clotting factors II, VII, IX and X. It is indicated in the management of various thromboembolic disorders and in those at considerable risk of thrombosis. Warfarin due to its low molecular weight can cross the placenta and reaches the fetus.^{1 2} Therefore, fetus too receives the anticoagulant effects. To avoid the risk of anticoagulant therapy during pregnancy, women with mechanical prosthetic heart valves should be counselled before conception. In pregnant patients, for prophylaxis and management of venous thromboembolic disease, heparin is considered the preferred anticoagulant because of its efficiency and safety.¹⁴ In the present case too as soon as the treating doctor came to know about the pregnancy, the patient was switched over to the heparin thus limiting the further teratogenic effects of warfarin therapy.

The child in the present case was exposed to warfarin during the first trimester and was diagnosed with warfarin embryopathy in the form of hypoplastic nasal bone/stippling of cartilage in the femur and calceneum. These congenital anomalies have been common findings in children born to mothers with warfarin intake during the first trimester.^15–17 The appearance of the nose is often flattened and upturned and has been attributed to the nasal hypoplasia and depression of the bridge of the nose. The medical history of the child revealed difficulty in breathing due to nasal blockage till 5 years of age. The hypoplastic nasal cartilage can lead to a deep groove between the alae and the tip of the nose. Respiratory distress is seen in about 50% of neonates with FWS. This is due to upper airway obstruction as a consequence of small size of the nares and air passages.¹⁵

There is a scarcity of literature pertaining to the dental and orofacial findings in FWS. Although, some cases have highlighted the effects on facial skeleton (table 1). The child in the present case is in the mixed dentition stage with multiple carious teeth. The delay to start tooth brushing (till 3 years of age) and poor oral hygiene could be the contributory factors for increased dental caries risk in the present case. The other findings were delayed eruption of permanent teeth (FDI notation 16) and delayed tooth root maturation (FDI notation 11,21,31,41). We did not come across any research article citing these findings in cases of FWS thus emphasising the phenotypic variation. The rare occurrence of the condition and lack of characteristic oral findings could also be a reason.

Learning points.

• Maxillary (midface) hypoplasia and an elongated face are the characteristic orofacial manifestations in patients with the fetal warfarin syndrome.

• Maternal medication and history of drug intake should be assessed in newborns with abnormal developmental characteristics.

• The drug intake-related teratogenicity can be minimised with the counselling of pregnant mothers before conception and judicious use of the drugs.

• An increased caries risk in the present case could be attributed to the delay in starting the toothbrushing in child and poor oral hygiene practices.

• Dental professionals should be aware of these manifestations which shall make them more vigilant towards systemic examination and investigations.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).