Neonatal Abstinence Syndrome

Epidemiology and Etiology

Epidemiology

• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 6.5 per 1,000 hospital births per year in the United States
• 433% increase in neonatal abstinence syndrome (NAS) from 2004 to 2014, mainly from patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship‘ use of opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
• Drugs most likely to cause NAS: opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics, heroin Heroin A narcotic analgesic that may be habit-forming. It is a controlled substance (opium derivative) listed in the U.S. Code of federal regulations, title 21 parts 329. 1, 1308. 11 (1987). Sale is forbidden in the United States by federal statute. Nephrotic Syndrome, and methadone Methadone A synthetic opioid that is used as the hydrochloride. It is an opioid analgesic that is primarily a mu-opioid agonist. Opioid Analgesics
• Length of hospital stay: 7 times longer than normal postnatal hospitalization Hospitalization The confinement of a patient in a hospital. Delirium of 2–3 days
• Increased admissions to neonatal intensive care unit (NICU)
• Increased risk of sudden infant death syndrome Sudden Infant Death Syndrome Sudden infant death syndrome (SIDS) describes the sudden death of an otherwise healthy infant (< 1 year of age) with no identifiable cause. Sudden infant death syndrome is the leading cause of death in children between 1 and 12 months of age in the United States. Sudden Infant Death Syndrome (SIDS) ( SIDS SIDS Sudden infant death syndrome (SIDS) describes the sudden death of an otherwise healthy infant (< 1 year of age) with no identifiable cause. Sudden infant death syndrome is the leading cause of death in children between 1 and 12 months of age in the United States. Sudden Infant Death Syndrome (SIDS))
• Newborns with NAS are likely to have low birth weight, premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis birth, developmental delays, and birth defects similar to those seen in fetal alcohol syndrome Fetal alcohol syndrome An umbrella term used to describe a pattern of disabilities and abnormalities that result from fetal exposure to ethanol during pregnancy. It encompasses a phenotypic range that can vary greatly between individuals, but reliably includes one or more of the following: characteristic facial dysmorphism, fetal growth retardation, central nervous system abnormalities, cognitive and/or behavioral dysfunction, birth defects. The level of maternal alcohol consumption does not necessarily correlate directly with disease severity. Alcohol Use Disorder.  

Etiology

Different substances are associated with NAS.

• Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics: morphine Morphine The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. Opioid Analgesics, heroin Heroin A narcotic analgesic that may be habit-forming. It is a controlled substance (opium derivative) listed in the U.S. Code of federal regulations, title 21 parts 329. 1, 1308. 11 (1987). Sale is forbidden in the United States by federal statute. Nephrotic Syndrome, methadone Methadone A synthetic opioid that is used as the hydrochloride. It is an opioid analgesic that is primarily a mu-opioid agonist. Opioid Analgesics, fentanyl Fentanyl A potent narcotic analgesic, abuse of which leads to habituation or addiction. It is primarily a mu-opioid agonist. Fentanyl is also used as an adjunct to general anesthetics, and as an anesthetic for induction and maintenance. Opioid Analgesics, and prescription opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics such as oxycodone Oxycodone A semisynthetic derivative of codeine. Opioid Analgesics and hydrocodone Hydrocodone Opioid Analgesics
• Cocaine Cocaine An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. Local Anesthetics
• Alcohol
• Cigarettes ( nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants)
• Antidepressants including selective serotonin reuptake inhibitors Selective Serotonin Reuptake Inhibitors Serotonin Reuptake Inhibitors and Similar Antidepressants ( SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants), serotonin-norepinephrine reuptake inhibitors Serotonin-Norepinephrine Reuptake Inhibitors Serotonin Reuptake Inhibitors and Similar Antidepressants ( SNRIs SNRIs Serotonin Reuptake Inhibitors and Similar Antidepressants)
• Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
• Barbiturates Barbiturates A class of chemicals derived from barbituric acid or thiobarbituric acid. Many of these are gaba modulators used as hypnotics and sedatives, as anesthetics, or as anticonvulsants. Intravenous Anesthetics

Pathophysiology

The pathophysiology of NAS is complex and not clearly understood. 

• Drugs transfer across the placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity to the fetus
  • Lipophilic and low-molecular-weight drugs cross the placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity and the fetal blood-brain barrier Blood-brain barrier Specialized non-fenestrated tightly-joined endothelial cells with tight junctions that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. Systemic and Special Circulations easier than hydrophilic Hydrophilic Aminoglycosides drugs. 
  • Examples of lipophilic drugs include opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics, cocaine Cocaine An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. Local Anesthetics, alcohol, benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines, and barbiturates Barbiturates A class of chemicals derived from barbituric acid or thiobarbituric acid. Many of these are gaba modulators used as hypnotics and sedatives, as anesthetics, or as anticonvulsants. Intravenous Anesthetics. 
• The drugs cannot be metabolized or excreted due to the immaturity of the fetal liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy and kidney.
• Drugs accumulate in the fetal tissues, altering levels of neurotransmitters such as norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS, dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS, serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS, and gamma-aminobutyric acid ( GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS).
• After delivery, abrupt discontinuation of the drug(s) results in a withdrawal syndrome.

Clinical Presentation

Presentation can vary depending upon different factors, including:

• Presence of more than one substance
• Level of mother’s drug usage
• Gestational age Gestational age The age of the conceptus, beginning from the time of fertilization. In clinical obstetrics, the gestational age is often estimated as the time from the last day of the last menstruation which is about 2 weeks before ovulation and fertilization. Pregnancy: Diagnosis, Physiology, and Care of exposure
• Timing of the last dose prior to birth
• Gestational age Gestational age The age of the conceptus, beginning from the time of fertilization. In clinical obstetrics, the gestational age is often estimated as the time from the last day of the last menstruation which is about 2 weeks before ovulation and fertilization. Pregnancy: Diagnosis, Physiology, and Care at birth: premature infants Premature infants A human infant born before 37 weeks of gestation. Sudden Infant Death Syndrome (SIDS) appear to have less severe presentations than full-term infants
• Prenatal conditions: nutrition, infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, stress
• Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics 
• Presence of other medical conditions in the infant
• Presence of maternal comorbid psychiatric conditions

Diagnosis

• Detailed medical history and toxicology testing from the mother
• Physical examination of neonate Neonate An infant during the first 28 days after birth. Physical Examination of the Newborn
• Toxicology testing of neonate Neonate An infant during the first 28 days after birth. Physical Examination of the Newborn (see table below)
• Laboratory testing
  • If suspicion for infection: complete blood count (CBC), serum glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance, serum calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes, thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy function testing, blood cultures
  • If there is maternal history, presence of high-risk behavior, lack of prenatal care Prenatal care Prenatal care is a systematic and periodic assessment of pregnant women during gestation to assure the best health outcome for the mother and her fetus. Prenatal care prevents and identifies maternal and fetal problems that adversely affect the pregnancy outcome. Prenatal Care, or sexually transmitted infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease ( STIs STIs Sexually transmitted infections (STIs) or sexually transmitted diseases (STDs) are infections that spread either by vaginal intercourse, anal sex, or oral sex. Symptoms and signs may include vaginal discharge, penile discharge, dysuria, skin lesions (e.g., warts, ulcers) on or around the genitals, and pelvic pain. Some infections can lead to infertility and chronic debilitating disease. Sexually Transmitted Infections (STIs))
• Differential diagnosis
  • Especially important to consider alternative diagnoses when there is a lack of history and toxicology results are not available
  • Hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia, hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia, brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification injury, hypoxic-ischemic encephalopathy Encephalopathy Hyper-IgM Syndrome, sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock, hyperthyroidism Hyperthyroidism Hypersecretion of thyroid hormones from the thyroid gland. Elevated levels of thyroid hormones increase basal metabolic rate. Thyrotoxicosis and Hyperthyroidism, and myoclonic jerks

Hospital course

• Symptoms can start within hours after birth.
• Opioid-exposed infants should be observed for at least 3–7 days.
• Discharge requirements:
  • Completely weaned off medication and maintains NAS score less than 8 for 48 hours 
  • Medically cleared: established follow-up with pediatric and subspecialty physicians Physicians Individuals licensed to practice medicine. Clinician–Patient Relationship
  • Socially cleared:
    • Established maternal substance use disorder treatment plan
    • Home environment assessment
    • Established support systems
    • Education on properly caring for an infant including risk of sudden infant death syndrome Sudden Infant Death Syndrome Sudden infant death syndrome (SIDS) describes the sudden death of an otherwise healthy infant (< 1 year of age) with no identifiable cause. Sudden infant death syndrome is the leading cause of death in children between 1 and 12 months of age in the United States. Sudden Infant Death Syndrome (SIDS) ( SIDS SIDS Sudden infant death syndrome (SIDS) describes the sudden death of an otherwise healthy infant (< 1 year of age) with no identifiable cause. Sudden infant death syndrome is the leading cause of death in children between 1 and 12 months of age in the United States. Sudden Infant Death Syndrome (SIDS))
    • Follow-up with mental health services arranged, if needed

Management

The goal of management is to minimize the severity of NAS signs through supportive measures and, in severe cases, the use of pharmacological measures. 

Non-pharmacologic therapy for infants

• Maintain temperature stability
• Breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding if possible
• Fluid resuscitation Resuscitation The restoration to life or consciousness of one apparently dead. . Neonatal Respiratory Distress Syndrome if needed
• Scheduled, adequate nutrition
• Pacifier usage
• Skin-to-skin if possible
• Swaddling
• Vertical rocking
• Positioning (side-lying in C-shaped position)
• Minimal sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology stimulation
• Dark, quiet room
• Rooming-in mother and infant

Pharmacologic therapy for infants

• If infants continue to display NAS symptoms that are not ameliorated by supportive measures
• Modified Finnegan Neonatal Abstinence Scoring System (FNASS):
  • Gold-standard assessment tool to determine initiation of treatment, medical management, and discharge planning
  • Assesses severity of symptoms
  • Should be initiated within the first 24 hours after birth 
  • Scoring should be done consistently at least every 3–4 hours
  • If 3 consecutive scores of > 8 or 2 scores > 12: prompt treatment
• Other screening Screening Preoperative Care testing test available include:
  • Neonatal drug withdrawal scoring system (the Lipsitz)
  • Neonatal narcotic withdrawal index (NNWI)
  • Neonatal withdrawal inventory (NWI)
• Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
  • First-line treament: morphine Morphine The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. Opioid Analgesics
    • Monitor for respiratory suppression Suppression Defense Mechanisms!
  • Alternatives:
    • Methadone Methadone A synthetic opioid that is used as the hydrochloride. It is an opioid analgesic that is primarily a mu-opioid agonist. Opioid Analgesics: Beware of QT prolongation!
    • Buprenorphine Buprenorphine A derivative of the opioid alkaloid thebaine that is a more potent and longer lasting analgesic than morphine. It appears to act as a partial agonist at mu and kappa opioid receptors and as an antagonist at delta receptors. The lack of delta-agonist activity has been suggested to account for the observation that buprenorphine tolerance may not develop with chronic use. Opioid Analgesics: Be careful in infants with alcohol exposure due to the additive effect
  • Adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination therapies:
    • Clonidine Clonidine An imidazoline sympatholytic agent that stimulates alpha-2 adrenergic receptors and central imidazoline receptors. It is commonly used in the management of hypertension. Sympathomimetic Drugs 
    • Phenobarbital Phenobarbital A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates gamma-aminobutyric acid action on gaba-a receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations. First-Generation Anticonvulsant Drugs (useful in infants exposed to opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics and barbiturates Barbiturates A class of chemicals derived from barbituric acid or thiobarbituric acid. Many of these are gaba modulators used as hypnotics and sedatives, as anesthetics, or as anticonvulsants. Intravenous Anesthetics/ benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines)
• Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines: reintroduction of the benzodiazepine followed by slow taper to discontinuation
• Stimulants Stimulants Stimulants are used by the general public to increase alertness and energy, decrease fatigue, and promote mental focus. Stimulants have medical uses for individuals with ADHD and sleep disorders, and are also used in combination with analgesics in pain management. Stimulants:  Phenobarbital Phenobarbital A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates gamma-aminobutyric acid action on gaba-a receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations. First-Generation Anticonvulsant Drugs can be used for extreme cases.
• Alcohol:  benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines, slowly tapered
• Antidepressants: if the infant develops seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures →  anticonvulsant Anticonvulsant Anticonvulsant drugs are pharmacological agents used to achieve seizure control and/or prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action including ion-channel (Na+ and Ca+2) blocking and GABA reuptake inhibition. First-Generation Anticonvulsant Drugs
• Nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants: focus on tapering cigarette smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases during the prenatal period Prenatal period Prenatal and Postnatal Physiology of the Neonate

Prognosis

• Correlates with the gestational age Gestational age The age of the conceptus, beginning from the time of fertilization. In clinical obstetrics, the gestational age is often estimated as the time from the last day of the last menstruation which is about 2 weeks before ovulation and fertilization. Pregnancy: Diagnosis, Physiology, and Care of exposure 
• Amount of substance able to cross the placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity into fetal tissues, in particular, the fetal central nervous system Central nervous system The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. Nervous System: Anatomy, Structure, and Classification 
• Genetic variations in fetal receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors expression such as mu-opioid receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (OPRM1) and catechol-o-methyltransferase (COMT) affect the severity of NAS
• Maternal involvement in an addiction Addiction Substance use disorders are a significant cause of morbidity and mortality, especially among adolescents and young adults. A substance-related and addictive disorder is the continued use of a substance despite harmful consequences; these include significant impairment to one’s health or relationships or failure to fulfill major responsibilities at work, school, or home because of substance use. Substance-Related and Addictive Disorders treatment program is important, as it tends to lead to fewer neurodevelopmental delays.

Clinical Relevance

Fetal alcohol spectrum disorder Fetal alcohol spectrum disorder Fetal alcohol spectrum disorder (FASD) is a group of neonatal pediatric disorders caused by maternal alcohol consumption during pregnancy. The term entails a range of physical and neurodevelopmental effects. Classification is based on severity and clinical presentation. Fetal Alcohol Spectrum Disorder: a group of conditions that can occur in neonates whose mothers consume heavy amounts of alcohol during their pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care. Problems may include characteristic craniofacial changes, short height, low body weight, small head size, low intelligence, behavior issues, and hearing impairments.