Peter R. Martin: Historical Vocabulary of Addiction, Vol. II

Pregnancy

 

        According to the current electronic version of the Oxford English Dictionary (OED), the noun pregnancy was formed within English by derivation and combination of the adjective pregnant and the suffix -ancy. The adjective and noun pregnant are of multiple origins, partly a borrowing from French (pregnant meaning “with child, pregnant [especially of an animal]… [of a word] full of meaning…”) and from classical Latin (praegnant-, praegnāns meaning “with child, pregnant, swollen, [as noun] pregnant woman, in post-classical Latin also imaginative, inventive [6th century], compelling, cogent [1267, c1380 in British sources]…”).

        An example of the first use of the adjective pregnant in the English language appeared in the poem Troilus and Criseyde, written circa 1374 by Geoffrey Chaucer (c. 1340s–1400), the English poet, author and civil servant (Chaucer 2021): “She cold was, and withouten sentement.. And this was hym a pregnant [v.rr. preignant, prygnant; preuaunt] argument That she was forth out of this world agon.”  This meaning of the word pregnant (“Of an argument, proof, piece of evidence, etc.: compelling, cogent, convincing; clear, obvious”) is now rarely used according to OED. 

        The first use of pregnant as may be relevant to our discussion of addiction, was employed by Guy de Chauliac (c. 1300–1368), a French physician and surgeon, in his widely translated treatise Grande Chirugerie (de Chauliac 1659): “Þe kyngez lawe forbedeþ a womman pregnant [L. pregnantem], i. wiþ childe, for to be biried vnto þe birþ go out.” According to OED, the meaning of pregnant in this last quotation is: “Of a woman or other female mammal: having offspring developing in the uterus.  Also, of the womb (obsolete).  Frequently with (the offspring), by (the male parent).”

        The definition of pregnancy in OED that pertains to the present discussion is: “The condition of a female of being pregnant or with child; an instance of this.”  A very early example of the use of the noun pregnancy in the English language was by Giovanni Florio, popularly known as John Florio (1552–1625), a linguist, poet and language tutor at the English Royal Court of James I, in his monumental work, A worlde of wordes, or most copious, and exact dictionarie in Italian and English (Florio 1598): “Pregnanza, greatnes with child, pregnancie, a being great with childe or with yoong.” 

        A quotation of the English naturalist and theologian John Ray (1627–1705) in his book based on his sermons in natural theology, The Wisdom of God Manifested in the Works of the Creation (Ray 1691), alludes to the many changes that occur in a woman’s body and psyche during pregnancy: “That extraordinary extension that is requisite in the time of their Pregnancy.”

        Pregnancy is a meaningful time in the life of all women, including those suffering from addiction, as it is coupled with major alterations in physiological and psychic functions in preparation for motherhood (Severinghaus, Engle, Smith et al. 1932; Everett and Baker 1945) and the foundation of the powerful mother-child bond (Bowlby 1966; Insel and Young 2001).  The estimated prevalence of potentially harmful intrauterine exposure to alcohol and various other drugs of abuse during pregnancy (about 15%) has been determined based on toxicologic urine screenings (Chasnoff, Landress and Barrett 1990), with the worst outcome of such exposure exemplified by the recent epidemic of overdose deaths among pregnant and postpartum women (Bruzelius and Martins 2022). 

        Pregnancy is usually not planned by women suffering from addiction (Heil, Jones, Arria et al. 2011) and is associated with severe stigma (van Boekel, Brouwers, van Weeghel et al. 2013) and adverse social and serious medical perinatal complications (Bauer, Shankaran, Bada et al. 2002) that challenge the skills of their physicians and the care paradigm employed (Stern 1966).    Nevertheless, pregnancy can be a positive experience resulting in important changes in the woman’s priorities and goals despite the challenges associated with addiction. 

        Many women now understand that alcohol/drug use during pregnancy can greatly impact the outcome of gestation, including the health of the developing fetus and neonate with consequences that can last a lifetime for their progeny.  Strongly motivated by health consequences for their child, pregnancy provides women with a unique opportunity to alter course and seek treatment for their alcohol/drug use disorder and achieve recovery (Martin 2020a) if they are treated by compassionate and knowledgeable physicians.

        It has been suggested that during pregnancy responses to drugs of abuse may significantly change (Little and Streissguth 1978; Schmidt, Lancia, Alvi et al. 2017).  Although the mechanistic underpinnings of this decreased drive to use has yet to be elucidated, it may relate to proposed effects of sex hormones on motivational properties of psychostimulants (Johnson, Thibeault, Lopez et al. 2019).  This would explain the reduction in self-administration of drugs of abuse during pregnancy — most convincingly demonstrated for alcohol (Schmidt, Lancia, Alvi et al. 2017) — as pharmacological effects of abused drugs not normally considered psychostimulants (Martin 2020c, 2021c) may have significant stimulant properties (Addicott, Marsh-Richard, Mathias et al. 2007).  Accordingly, in women suffering from addiction, pervasive pregnancy-associated changes in motivation and biology may improve the clinical course if appropriate care is made available (Higgins, Clough, Frank et al. 1995).

        Since Biblical times, it has been recognized that consumption of alcoholic beverages has the potential to harm the fetus as indicated by an admonishment to young pregnant women: Judges 13:7, “Behold, thou shalt conceive, and bear a son; and now drink no wine or strong drink.”  In ancient Carthage, newlyweds were forbidden to drink wine on their wedding night so as not to conceive malformed children (Haggard and Jellinek 1942). 

        A report to the British House of Commons by the Select Committee on Drunkenness (1834) specified that infants born to alcoholic mothers often had “a starved, shriveled and imperfect look”.  The American novelist Ernest Hemingway (1899–1961) wrote in A Farewell to Arms that beer consumed by a woman during pregnancy can often result in an abnormally small baby.  Not all physicians were concerned about whether alcohol was toxic to the fetus (Bourne, Ross and Philpott 1953) and medical proscription of drinking during pregnancy is a relatively recent development (Skogerbø, Kesmodel, Wimberley et al. 2012).

        The French pediatrician Paul Lemoine (1917–2006) first described the fetal alcohol syndrome (FAS) based on his study of 127 children from 62 “alcoholic families” (Lemoine 1968).  At first, the importance of this discovery was not fully appreciated by the medical community.  However, Lemoine’s observations gained widespread recognition after Jones and colleagues (Jones, Smith, Ulleland et al. 1973) first used the term in the English language in their publication in The Lancet: “A pattern of altered growth and morphogenesis has lately been described in eight offspring of chronic alcoholic mothers. We call this disorder the ‘fetal alcohol syndrome’.”  The noun fetal alcohol syndrome is now defined in OED as: “a syndrome encountered in children of women who consume excessive quantities of alcohol during pregnancy, characterized by intrauterine growth retardation, microcephaly, other characteristic craniofacial abnormalities, and mild to moderate intellectual disability.” 

        FAS was first considered a serious but relatively uncommon condition.  When the Institute of Medicine (IOM) concluded in their report on FAS that exposure to alcohol in the womb could result in a spectrum of defects in children (Stratton, Howe and Battaglia 1996), the scope of concern regarding toxicity of alcohol increased greatly, leading to the currently accepted term Fetal Alcohol Spectrum Disorders (FASD).  Specifically, a child with neurodevelopmental impairment whose mother had consumed alcohol during pregnancy could now be diagnosed as having been affected by alcohol even in the absence of manifestations of the complete syndrome of growth deficiency, microcephaly and the cardinal facial features.  

        Recognition in the IOM report of more subtle neurodevelopmental consequences of maternal alcohol consumption likely reflected an evolution of the field of teratogenesis (the study of disturbed fetal development due to various biological or pathological causes, defined in OED as, “The production of monsters or misshapen organisms”), leading to emergence in the scientific literature of the term behavioral teratogenesis (Werboff and Kesner 1963).  The notion of a spectrum of effects of alcohol exposure in utero is compatible with earlier observations that maternal alcohol consumption during gestation is associated with a significant reduction in birthweight of the newborn (Little 1977).  A behavioral teratogenic perspective of the consequences of prenatal alcohol exposure greatly expanded the previously understood prevalence of alcohol-related neurodevelopmental harms (10 times that of FAS), while making reliable clinical identification of FASD an even more challenging endeavor (Riley and McGee 2005). 

        Diagnosing the contribution of alcohol exposure in pathogenesis of neurodevelopmental harms sustained by the newborn can be difficult to determine because of the many confounding lifestyle variables associated with alcoholism (Evans 2004).  Additionally, drinking alcoholic beverages and smoking nicotine-containing cigarettes are very often co-travelers in women with alcohol use disorder.  Hence, to establish that the effects of alcohol exposure in utero it was necessary to statistically dissociate these from those of smoking by the mother, which itself can reduce fetal weight and cause increased mortality and morbidity (Meyer, Tonascia and Buck 1974).  It is now established that decreased body weight at birth attributable to alcohol exposure in utero is accompanied by significant changes in brain size and shape.  

        In FASD, neuropathological findings are observed in specific brain regions such as the cerebellum (particularly the anterior vermis), corpus callosum and basal ganglia (Clarren 1986).  These greatly resemble the findings in alcoholism-associated brain injury in adults, already extensively studied when FAS/D was first recognized (Martin 2021e).  In short order, the neuropathological findings accompanying alcohol exposure in utero began to be examined and correlated w ith clinical features in offspring, including observations from neuropsychological testing and electrophysiologic and neuroimaging studies (Mattson, Riley, Jernigan et al. 1992).  

        The neuropathological underpinnings of brain injury sustained during exposure to alcohol in utero (Martin, Levin, Impeduglia et al. 1989) may well have shared pathogenesis with alcoholism-associated brain injury in the adult (Victor, Adams and Collins 1971; Martin, Adinoff, Weingartner et al. 1986), but likely also involves uniquely teratogenic effects of alcohol that adversely affect brain development (Charness 2022).  More recent investigations of the mechanistic underpinnings of brain dysfunction due to prenatal alcohol exposure have begun to include studies of the role of altered neurotransmitter systems in the psychopathologic manifestations of FASD (Oubraim, Wang, Hausknecht et al. 2022).

        Women seem particularly vulnerable to drug use disorders as suggested by the fact that disease progression is significantly accelerated (telescoped) compared to men (Randall, Roberts, Del Boca et al. 1999; Hernandez-Avila, Rounsaville and Kranzler 2004).  Pregnant women suffering from drug use disorders during gestation frequently self-administer other drugs of abuse in addition to their drug of choice.  Each of these other drugs may have neurotoxic effects of their own, and hence, psychopathological consequences for mother and fetus.  These often-co-administered substances include alcohol and nicotine, which are currently legal and easily obtained, and illicit drugs, such as cocaine, opioids (heroin and fentanyl), methamphetamine and related stimulants and prescription analgesics, anxiolytics and hypnotics (Martin 2021d, 2019, 2021b and c).  Of course, the cannabinoids (Martin 2021a) can be considered either licit or illegal depending on the jurisdiction. For these reasons, determining intrauterine exposures and the mechanisms and magnitudes of harms to the fetus of each drug of abuse can be challenging (Evans 2004; Young 2012). 

        Physicians have explored the neurodevelopmental problems associated with maternal use of each of the drugs of abuse mentioned above.  Only the harmful neurodevelopmental consequences of alcohol drinking and cigarette smoking during pregnancy have been established with the highest level of certainty from among those mentioned above; the detrimental effects of maternal opioid use during pregnancy at this point appears predominantly to be shared maternal/fetal addiction to the drug.  The behavioral teratogenic effects of the individual drugs of abuse are not only confounded by coadministration of other substances, but also by the recognized consequences of associated social disadvantage, e.g., lower level of education, unemployment, poor medical care, younger age, comorbid physical and mental health problems, childhood trauma, intimate partner violence among others (Evans 2004; Louw 2018). 

        Although each of these distinct factors may negatively influence neurodevelopment and pregnancy outcomes in their own way, their harmful effects can best be conceptualized and mechanistically understood as additive or synergistic interactions of intrauterine stress exposure and genetic constitution (Defries 1964; Dayananda, Ahmed, Wang et al. 2023).  The prenatal period is a particularly vulnerable stage of brain development (Buss, Entringer and Wadhwa 2012), containing most neurogenesis and neuronal migration, with ongoing synaptogenesis, pruning, and myelination throughout the second and third trimesters (Tau and Peterson 2010).  

        The neurobiological mechanisms of intrauterine stress exposure whereby early life adversities are transformed and neurodevelopmentally embedded can involve various hypotheses, such as nutritional deprivation, environmental exposures and stressful psychosocial experiences affecting the maternal hypothalamic-pituitary-adrenal (HPA) axis, associated systemic inflammation, among many other factors.  For example, prenatal social disadvantage was demonstrated by magnetic resonance imaging (MRI) to be associated with global reductions in brain volumes and cortical folding at birth suggesting influences of poverty on brain development begin in utero and are evident early in life (Triplett, Lean, Parikh et al. 2022).  There may be lasting consequences on childhood outcomes of prenatal stress exposures, including cognitive delays and externalizing disorders (Larson 2007), which in turn, have been linked to risk of developing addiction (Martin 2020b).  

        A general practitioner from a country town in Tennessee succinctly described his clinical experiences and the devastating outcomes he observed while attending a morphine addicted woman over many pregnancies (Happel 1900):

“In the case of one mother, one child was born, which within forty-eight hours became restless and cyanotic, and in spite of simple remedies, died before the end of the third day. At that time, I did not know that she was a morphin (sic) user.  Two years later another child was born, which in every respect duplicated the history of the preceding one. About two years later a third was born, which died as did the first and second. The mother at the time was using increasing doses of morphin (sic). Two years later, a fourth child was born, which showed all the effects of morphin (sic) that the three before it had, but knowing at that time that the mother was using two drams of morphin (sic) a week—about seventeen grains a day—I began the administration of full doses of paregoric to the infant, and after gradually increasing the doses to about twenty drops every three hours, I found a steady improvement; the cyanosis disappeared on the fifth or sixth day, and after one month I was able to discontinue the use of the opiate. At no time was the child quiet during that period, except when under the influence of the drug. The digestion of the child was poor, and it had an aged, withered, pinched look. At the age of five months, it died.”

        Perlstein (1947) provides a more modern description of “congenital morphinism”:

“Symptoms… appear within twenty-four hours after birth, reach their peak by the third day and then gradually subside in five to fourteen days if the child survives.  The infant initially becomes extremely irritable, yawns and sneezes.  Restlessness, weakness, anorexia, vomiting and diarrhea ensue. Loss of weight because of inadequate dietary intake and dehydration is pronounced. In the final stages there appear cramps, tremors, coma and convulsions.”

        Progress in understanding the fetal consequences of maternal opioid use probably dates to conceptualization of “congenital neonatal narcotic addiction” (Rosenthal, Patrick and Krug 1964):

“If untreated, infants born so addicted face the risk of death within a short period of time after delivery from one or a combination of…physiological strain involved in narcotic withdrawal…, the depressant action of the opiate... [and/or] [a]nomalies resulting from faulty intrauterine development in an addicted mother which possibly includes damage directly attributable to the action of the drug on body cells.”

        Evidence-based management of the newborns of mothers who had opioid use disorder (OUD) could begin only when a scoring system for the neonatal abstinence syndrome (NAS) was “devised and implemented as both a clinical and investigative tool” to monitor “the passively opioid addicted infant” and “to test the comparative usefulness of various pharmacologic agents” for NAS treatment (Finnegan, Connaughton, Kron et al. 1975).  This scoring system became instrumental in furthering mechanistic understanding and treatment of NAS.  For example, based on NAS scores, neonates whose mothers with OUD were therapeutically maintained during pregnancy on buprenorphine as compared to methadone (the standard of care at the time) were found to need significantly less morphine, had shorter hospital stays and had a significantly shorter duration of NAS treatment (Jones, Kaltenbach, Heil et al. 2010).  Subsequently, it was firmly established that maintenance with the newer partial opioid agonist buprenorphine was associated with a significantly lower risk of adverse neonatal outcomes than from the full agonist methadone (Suarez, Huybrechts, Straub et al. 2022).  

        However, the NAS scoring system was not specific to the effects of opioid withdrawal alone, but also reflected signs in neonates due to exposure in utero to other drugs of abuse (tobacco, marijuana, cocaine) as well as psychotherapeutic agents (antidepressants, benzodiazepines, gabapentin) prescribed to the mother for treatment of mental health issues as depression and anxiety (Patrick, Dudley, Martin et al. 2015).  Accordingly, NAS is now considered a general term, eventually superseded by the more specific neonatal opioid withdrawal syndrome (NOWS) intended to denote the withdrawal consequences of opioids alone (Coyle, Brogly, Ahmed et al. 2018). 

        All the same, self-administration of different drugs of abuse is a reality for many women suffering from OUD and may in part explain the observed benefits of combining opioid agonists with adjunctive treatments for NAS such as phenobarbital or clonidine, especially if women were also using CNS depressant medications (Hamburger 1964; Speight 1977) and/or stimulants (Sussman 1963; Chasnoff, Burns, Schnoll et al. 1985).  Additionally, the use of cannabis during pregnancy alone or in combination with other drugs of abuse is of increasing concern since it has recently become legalized in many jurisdictions (Duko, Pereira, Tait et al. 2021).  

        Recent research has emerged on the behavioral teratogenic potential of opioid exposure during pregnancy and the long-term consequences of NOWS (Vishnubhotla, Zhao, Wen et al. 2022; Yen and Davis 2022).  This raises the conundrum of whether OUD women might do better with total abstinence which is distinctly counter to the observation that for decades, the indicated treatment of OUD in pregnant women was maintenance with a full opioid agonist (methadone) and then a partial opioid agonist (buprenorphine) as very effective forms of harm reduction (Young 2012; Suarez, Huybrechts, Straub et al. 2022).  Ultimately, a comprehensive treatment program combined with the opioid antagonist (naltrexone) which is not associated with NOWS may be a feasible option for some women (Towers, Katz, Weitz et al. 2020).

 

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December 29, 2022