NeoQuest November 2023: Limb Discoloration in a Newborn

A 34-weeks gestation male infant is born via uncomplicated vaginal delivery following preterm labor. Maternal history is significant for lack of prenatal care. The infant’s physical examination is notable for purple discoloration of the left arm from the elbow to fingertips, an undetectable left radial pulse, and a decreased left palmar grasp (Figure 1A).  A left-arm radiograph is negative for fracture, and a Doppler ultrasound of the left upper extremity is obtained (Figure 1B). 

Figure 1. A. Infant’s left upper extremity following delivery. B. Left upper extremity Doppler ultrasound of the left brachial artery (ANT BA) along the longitudinal axis. From: Stadd K, Gall A, Kochan M. Preterm infant with bruising and discoloration of upper extremity after birth. Neoreviews. 2023;24(11)e748–752¹

What in utero exposure is the most likely cause of these findings? 

1. Carbamazepine
2. Cocaine
3. Maternal antiphospholipid antibodies
4. Methadone
5. Warfarin

Answer: B. Cocaine

Explanation:

The infant’s left upper extremity discoloration (Figure 1A) is due to ischemia from a completely occlusive left brachial artery clot, as seen in the Doppler ultrasound image (Figure 1B). Of the answer choices listed, vasoconstriction from in utero exposure to cocaine (Option B) is the most likely etiology of the infant’s arm findings. Cocaine readily crosses the placenta and blood-brain barrier.² An animal study has shown that cocaine and its metabolites may remain in the myometrium and placental membrane for a week and exert continuous effects on the developing fetus.³ Infants exposed to cocaine in the first trimester have higher occurrences of prematurity and low birth rates than infants exposed later in pregnancy.⁴ Fetal cocaine exposure is strongly linked to fetal growth restriction, preterm birth, low birth weight, and vascular complications, including placental abruption, neonatal stroke, and thrombosis, such as in the infant in the vignette.⁵ Cocaine blocks the reuptake of sympathomimetic neurotransmitters, including serotonin, a major systemic and cerebral vasoconstrictor.⁶ During pregnancy, cocaine’s vasoconstrictive effects have been shown to increase maternal mean arterial blood pressure and decrease uterine blood flow, resulting in significant fetal hypoxemia.⁷ Placental abruption is strongly associated with cocaine use shortly prior to delivery.⁷

Cocaine also exerts prothrombotic effects by potentiating the response of platelets to arachidonic acid, which leads to elevated thromboxane levels and more robust platelet aggregation.⁶ The infant in this vignette has a limb-threatening arterial thrombus most likely secondary to in utero cocaine exposure. In preterm infants with limb-threatening arterial thrombi, low-dose tissue plasminogen activator may be considered for urgent thrombolysis.⁸

Carbamazepine (Option A) is an anti-epileptic medication in which in utero exposure is associated with an increased risk of hemorrhagic disease of the newborn.⁹ Some studies suggest that certain anti-epileptic medications, including carbamazepine, phenobarbital, and topiramate, induce fetal hepatic enzymes resulting in vitamin K deficiency.⁹ In utero exposure to carbamazepine has been associated with several fetal anomalies, including craniofacial defects, growth restriction, and neural tube defects.¹⁰ Carbamazepine has not been implicated in neonatal vasospasm or thromboses following fetal exposure.

Antiphospholipid antibody syndrome is an autoimmune disease defined by the occurrence of venous and/or arterial thrombosis and adverse obstetric outcomes in the setting of maternal antiphospholipid antibodies (aPLs).¹¹ Some maternal aPLs (Option C) can cross the placenta (specifically, anticardiolipin antibodies and anti-β-2 glycoprotein I antibodies) and contribute to perinatal thrombosis.¹¹ However, studies have shown that the passive transfer of aPLs in utero is usually insufficient to cause neonatal thrombosis alone.¹¹ Additional risk factors that increase the risk of neonatal thrombosis in the setting of aPLs include neonatal arterial and venous catheterization, sepsis, asphyxia, and inherited thrombophilias.¹¹

Methadone (Option D) is used for the treatment of opioid use disorder.¹² In utero exposure to methadone and other opioids are associated with neonatal opioid withdrawal syndrome.¹² This diagnosis encompasses a spectrum of clinical presentations most often involving the neurologic, gastrointestinal, and autonomic systems arising from hypersensitive opioid (μ) receptors.¹² Studies have not linked in utero exposure to methadone to any known teratogenic effects on the fetus.¹³

Warfarin (Option E) is commonly prescribed to provide prophylaxis against clot formation in hypercoagulable systemic disease states, valvular heart disease, and the presence of prosthetic valves.¹⁴ In utero exposure to warfarin in the first trimester carries the highest risk of fetal warfarin syndrome (15–25% of fetuses exposed during the first trimester).¹⁴ Fetal warfarin syndrome is commonly associated with nasal hypoplasia and a depressed nasal bridge (Figure 2). Abnormal focal bone calcification is a common musculoskeletal anomaly associated with fetal warfarin syndrome that can be seen as stippling in bone epiphyses on limb radiographs (Figure 3).¹³ Intrauterine warfarin exposure later in gestation can also impair vitamin K function, increasing the risk of hemorrhagic disease of the newborn.¹⁴

 

Figure 2. A neonate with midface hypoplasia and a depressed nasal bridge as a result of fetal warfarin syndrome. From: Singh A, Naranje KM, Poddar B. A neonate with a depressed nasal bridge. Neoreviews. 2016;17(6):e352–e355¹⁴

 

Figure 3. Right upper extremity radiograph of a neonate with fetal warfarin syndrome showing stippling of the right humeral epiphysis (red arrow). From: Singh A, Naranje KM, Poddar B. A neonate with a depressed nasal bridge. Neoreviews. 2016;17(6):e352–e355¹⁴

Did you know?
In addition to acute complications at birth, prenatal exposure to cocaine is associated with long-term developmental differences in growth (Figure 4), motor skills, behavior, and cognition.^4,15

Figure 4. Weight gain during the first trimester in cocaine-exposed and non-exposed fetuses. Children who were exposed to cocaine during the first trimester grew at a slower rate than those who were not exposed. From: Richardson GA, Goldschmidt L, Larkby C. Effects of prenatal cocaine exposure on growth: a longitudinal analysis. Pediatrics. 2007;120(4):e1017–e1027⁴

Which thrombotic conditions occur more frequently in term infants compared to preterm infants and why?
To find the answer, please refer to the following article: Manco-Johnson M, Nuss R. Neonatal thrombotic disorders. Neoreviews. 2000;1(10):e201–e205¹⁶

 
NeoQuest November Authors:
Angelina June MD, Fairfax Neonatal Associates
Faith Kim MD, Columbia University

References:

1. Stadd K, Gall A, Kochan M. Preterm infant with bruising and discoloration of upper extremity after birth. Neoreviews. 2023;24(11):e748–752
2. Oji-Mmuo CN, Corr TE, Doheny KK. Addictive disorders in women: the impact of maternal substance use on the fetus and newborn. NeoReviews. 2017;18(10):e576–e586
3. De Giovanni N, Marchetti D. Cocaine and its metabolites in the placenta: a systematic review of the literature. Reprod Toxicol. 2012;33(1):1–14
4. Richardson GA, Goldschmidt L, Larkby C. Effects of prenatal cocaine exposure on growth: a longitudinal analysis. Pediatrics. 2007;120(4):e1017–e1027
5. Gouin K, Murphy K, Shah PS; Knowledge Synthesis Group on Determinants of Low Birth Weight and Preterm Births. Effects of cocaine use during pregnancy on low birthweight and preterm birth: systematic review and metaanalyses. Am J Obstet Gynecol. 2011;204(4):340.e1–12
6. Fonseca AC, Ferro JM. Drug abuse and stroke. Curr Neurol Neurosci Rep. 2013;13(2):325
7. Wallen, LD, Gleason CA. Prenatal drug exposure. In: Avery's Diseases of the Newborn. Philadelphia, PA: Elsevier;2018
8. Ade-Ajayi N, Hall NJ, Liesner R, et al. Acute neonatal arterial occlusion: Is thrombolysis safe and effective?  J Pediatr Surg.  2008;43(10):1927–1932
9. Kazmin A, Wong RC, Sermer M, Koren G. Antiepileptic drugs in pregnancy and hemorrhagic disease of the newborn: an update. Can Fam Physician. 2010;56(12):1291–1292
10. Güveli BT, Rosti RÖ, Güzeltaş A, et al. Teratogenicity of antiepileptic drugs. Clin Psychopharmacol Neurosci. 2017;15(1):19–27.
11. Magalhães CS,  Souza Rugolo L,  Trindade C. Neonatal antiphospholipid syndrome. Neoreviews. 2014;15(5):e169–e176
12. Kainth D, Kathiresan P, Bhad R, Rao R, Verma A. A hyperalert newborn. Neoreviews. 2022;23(6):e413–e415
13. Kaltenbach K, Finnegan LP. Perinatal and developmental outcome of infants exposed to methadone in-utero. Neurotoxicol Teratol. 1987;9(4):311–313
14. Singh A, Naranje KM, Poddar B. A neonate with a depressed nasal bridge. Neoreviews. 2016;17(6):e352–e355
15. Martin MM, Graham DL, McCarthy DM, Bhide PG, Stanwood GD. Cocaine-induced neurodevelopmental deficits and underlying mechanisms. Birth Defects Res C Embryo Today. 2016;108(2):147–173 
16. Manco-Johnson M, Nuss R, Neonatal Thrombotic Disorders. Neoreviews. 2000;1(10):e201–e205.