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Aim The aim of this structured review was to discuss knowledge of nicotine use during pregnancy and long-term effects on children's cardiovascular function. Methods PubMed and MEDLINE were searched for original papers that covered various forms of nicotine exposure during pregnancy and this identified 314 papers published in English from inception of the databases to 1 March 2021. The research focus was prenatal exposure that had long-term effects on the cardiovascular system. The search was expanded from the reference list of the selected papers, which identified another 17 papers. Results The 34 original papers that were included covered 172,696 subjects from foetuses to 19 years of age. Cardiovascular autonomic dysfunction was discussed in 12 of the papers and 16 studies reported on blood pressure. The remaining studies covered structural or functional changes in arterial wall or heart. There were convincing data on autonomic dysfunction and increased blood pressure. Some data were conflicting and problems with misclassification of exposure were evident. Conclusion Prenatal nicotine exposure was associated with long-term developmental changes in the cardiovascular system and regulation. There were no safe periods, doses or nicotine products during pregnancy and women should abstain when planning a pregnancy.

Hypercholesterolaemia is considered a disease with intrauterine origin. Recently, we reported that prenatal nicotine exposure (PNE) induced an abnormal level of total cholesterol in rat offspring before and after birth. However, there were little data about sex differences in serum cholesterol level in PNE offspring. In addition, many previous studies reported that blood cholesterol is associated with daily diet. This study was designed to analyse the interaction among PNE, high-fat diet (HFD) and sex on cholesterol metabolism in the rat. Pregnant Wistar rats were administered 2 mg/kg nicotine subcutaneously from gestational day (GD) 11 until parturition. After weaning, pups were fed with normal diet or HFD till 24 weeks, and then, serum cholesterol phenotypes and hepatic cholesterol metabolism-related genes were tested. Results showed that PNE manifested a distinct programming effect on cholesterol phenotype and cholesterol metabolism-related genes. HFD aggregated PNE-induced hypercholesterolaemia in adult offspring and exacerbated liver cholesterol metabolism dysfunction in PNE offspring. There was no sex difference in serum cholesterol level, but there were interactions among PNE, HFD and sex on cholesterol metabolic genes in adult offspring, which indicates that cholesterol metabolism in female offspring is more likely to be affected by PNE and HFD. In conclusion, HFD exacerbated PNE-induced hypercholesterolaemia, and sex differences existed in liver cholesterol metabolic genes in PNE- or HFD-treated offspring.

Objective: To investigate the role of perinatal adversities with regard to tic severity and comorbid attention deficit/hyperactivity disorder (ADHD) symptoms in children with a tic disorder. Methods: In 75 children and adolescents with a tic disorder, we retrospectively assessed presence of pregnancy, delivery, and postnatal complications and of prenatal exposure to smoking and alcohol. Children with and without these perinatal adversities were compared regarding tic and ADHD symptom severity. Furthermore, through linear regressions, we investigated whether perinatal adversities would interact with presence in first-degree relatives of tic or any mental disorders with the tic or ADHD measure as outcome. Results: Presence of delivery complications was related to tic severity and prenatal smoking exposure to severity of comorbid ADHD symptoms. The relationship between smoking exposure in utero and ADHD symptom severity appeared to be more pronounced in children with a positive family history of mental disorders. Conclusion: This study provides evidence of a role for perinatal adversities in the etiology of tic disorders. Children with perinatal adversities may be vulnerable to develop more severe tics or comorbid ADHD symptoms in the presence of a positive family history of mental disorders, suggesting a role for gene-environment interactions.

Background: Prenatal nicotine exposure is associated with increased neonatal mortality, low birth weight, and smaller head circumference. Opioid-dependent pregnant women show a particularly high prevalence of tobacco smoking and are at greater risk for additional adverse events. However, little is known about the impact of tobacco smoking on opioid-maintained pregnant women and neonatal outcomes. Patients and Methods: This study examined the effect of cigarette smoking on 139 opioid-maintained pregnant women and their neonates. Forty-five percent of the participants were maintained on slow-release oral morphine (SROM), 39% received methadone maintenance, and 16% received buprenorphine. Participants were divided into two groups: (1) women who reported a low cigarette consumption of ≤10 cigarettes/day (56.8%) and (2) those reporting heavy consumption of ≥20 cigarettes/day (43.2%). Neonatal outcome measures were assessed, and a standardized Finnegan score was applied to determine the neonatal abstinence syndrome (NAS). Results: Fifty-two percent of the newborns did not require treatment for NAS (54% of neonates born to methadone-maintained mothers, 30% born to SROM-maintained mothers, and 95% born to buprenorphine-maintained mothers; p < 0.001). Heavy cigarette consumption was associated with significantly lower neonatal birth weight (p < 0.001), smaller birth length (p = 0.017) as well as with the severity of NAS (p = 0.03). With regard to concomitant consumption of opioids (p = 0.54), cocaine (p = 0.25), amphetamines (p = 0.90) or benzodiazepines (p = 0.09), no significant differences between heavy or low nicotine consumption were noted. Conclusion: Heavy tobacco smoking in opioid-maintained pregnant women is associated with adverse medical and developmental consequences for the newborn. Future treatment programs for this target group should focus on an individualized approach to opioid maintenance therapy in addition to offering specially tailored counseling for smoking cessation.

This study aimed to evaluate whether female adult offspring born with intrauterine growth retardation induced by prenatal nicotine exposure (PNE) are susceptible to osteoarthritis (OA) and to explore the underlying programming mechanisms. Pregnant rats were treated with nicotine or saline at 2.0 mg/kg/d from gestational d 11 to 20. The female adult offspring with or without PNE were forced with a strenuous treadmill running for 6 wk to induce OA. Nicotine's effects on fetal articular chondrocytes were studied by exposing chondrocytes to nicotine for 10 d, and dihydro-β-erythroidine, a selective α4β2-nicotinic acetylcholine receptor (nAChR) inhibitor, was used to identify the change of nicotine's effect. For adult offspring, increased cartilage destruction and accelerated OA progression were observed in the PNE group with running; the expression of α1 chain of type II collagen (Col2A1), aggrecan, SRY-type high mobility group box 9 (Sox9), and IGF1 signaling molecules in the cartilage of PNE offspring were decreased. For fetuses, elevated serum corticosteroid and nicotine levels and suppressed IGF1 levels were observed; expression of Col2A1, aggrecan, Sox9, and IGF1 were reduced. The result of chondrocytes revealed that nicotine impeded the expression of Col2A1, aggrecan, and IGF1; blocking α4β2-nAChR rescued nicotine's suppression. In conclusion, PNE increases the susceptibility of adult offspring to OA; the potential mechanism involves IGF1 low-functional programming in articular cartilage caused directly by the action of nicotine on α4β2-nAChR.

Prenatal exposure to nicotine has been associated with changes in behavioral indices in offspring. Flank marking, a scent-marking behavior in golden hamsters, appears to be controlled by arginine vasopressin (AVP) neurons in the hypothalamus. The present study examines the effects of prenatal exposure to nicotine on the vasopressinergic system associated with flank marking behavior.

This study examined changes in dendritic morphology and spine density in multiple brain regions [Zilles' areas: (i) the Cg3 region of the anterior cingulate cortex or the medial prefrontal cortex, layer III (Cg3); (ii) the dorsal agranular insular cortex, layer III (AID); (iii) the PAR I region of the parietal cortex, layer III (Par1) and (iv) the nucleus accumbens (NAc)]of Long-Evans rats following exposure to nicotine prenatally, in late adolescence, or both prenatally and in adolescence. Prenatal nicotine exposure induced enduring changes in neuroanatomical organisation that varied between male and female offspring, with males exhibiting increased dendritic complexity of neurons in AID and NAc whereas females experienced increased dendritic complexity in Par1 but decreased dendritic complexity of neurons in NAc. Similarly, nicotine given in late adolescence dramatically reorganised neural circuitry of both male and female offspring, with males exhibiting decreased dendritic complexity of neurons in Par1 and Cg3 but increased dendritic complexity in AID, and females exhibiting decreased dendritic complexity in Cg3 and NAc but increased complexity in AID. Exposure to nicotine both prenatally and in adolescence produced few neuroanatomical parameters that demonstrated a prenatal experience × adolescent drug administration interaction. Females showed additive effects in Par1, Cg3 and NAc whereas males demonstrated additive effects only in AID. Thus, the timing of nicotine exposure produced differential effects on cerebral organisation in a regionally specific manner.

Maternal smoking during pregnancy is associated with increased substance abuse in offspring. Preclinical research shows that in utero exposure to nicotine, the primary psychoactive compound in tobacco smoke, influences the neurodevelopment of reward systems and alters motivated behavior in offspring. The present study determined if prenatal nicotine (PN) exposure altered the sensitivity to the reinforcing and aversive effects of methamphetamine (METH) in offspring using a low dose, intravenous (IV) exposure method. Pregnant dams were administered nicotine (0.05 mg/kg/injection) or prenatal saline (PS) 3×/day on gestational days 8-21, and adult offspring were tested using METH self-administration (experiment 1) or METH-induced conditioned taste aversion (CTA; experiment 2) procedures. For METH self-administration, animals were trained to respond for IV METH (0.05 mg/kg/injection; fixed-ratio 3) and they were tested on varying doses the reinforcer (0.0005-1.0 mg/kg/injection). For METH CTA, rats received three saccharin and METH pairings (0, 0.3, or 0.5 mg/kg, sc) followed by fourteen daily extinction trials. Experiment 1: PN and PS animals exhibited inverted U-shaped dose-response curves; however, the PN animal’s curve was shifted to the left, suggesting PN animals were more sensitive to the reinforcing effects of METH. Experiment 2: METH CTA was acquired in a dose-dependent manner and the factor of PN exposure was not related to the acquisition or extinction of METH-induced CTA. There were no sex differences in either experiment. These results indicate that adult offspring of IV PN exposure exhibited altered motivation for the reinforcing effects of METH. This suggests that PN exposure, via maternal smoking, will alter the reinforcing effects of METH during later stages of development, and furthermore, will influence substance use vulnerability in adult human offspring.

The effect of prenatal exposure to nicotine on nicotine-induced analgesia was studied in rats. The analgesic effect of a single dose of nicotine (1 mg/kg SC) was measured by the tail-flick technique, and two subsequent studies were carried out. In the first study, 7-month-old male rats, born to dams chronically treated with nicotine during pregnancy (NIC), exhibited prolonged nicotine-induced analgesia compared to matched controls. The second study was designed to explore whether rats prenatally exposed to nicotine (NIC rats) are born with an increased sensitivity to nicotine and whether there is any sex difference. The analgesic effect of nicotine was tested on control and NIC rats of both sexes once a month from 2 to 7 months of age. At an early age, male but not female NIC rats, exhibited shorter analgesic responses to nicotine than did the matched controls. With increasing age, however, the duration of nicotine analgesia began to be prolonged in NIC rats of both sexes. Significant differences between control and NIC rats were found at the age of 6 and 7 months, in both sexes. Thus, rats prenatally exposed to nicotine are not born with an increased sensitivity to the analgesic effect of a single dose of nicotine. This phenomenon develops later, during the course of life, independently of gender.

Sleep data were collected by maternal report in a prospective longitudinal follow-up of cocaine exposed and unexposed children. There were 139 subjects: 23 with no prenatal drug exposure, 55 exposed to cocaine alone or in combination with other drugs, and 61 exposed to drugs other than cocaine. Characteristics differed between exposure groups, including birth size, caretaker changes, and maternal SES and postnatal drug use. Compared to those with no drug exposure, children with prenatal drug exposure other than cocaine experienced greater sleep problems (mean [SD], 5 [4.93] vs 7.7 [4.85], p = .026). Prenatal nicotine exposure was a unique predictor of sleep problems (R2 = .028, p = .048). Early sleep problems predicted later sleep problems (all p’s

Two studies of variables affecting voluntary ethanol consumption by adolescent male and female rats are reported. Sprague–Dawley (SD) and spontaneously hypertensive rats (SHRs) were compared in Experiment 1. Starting on postnatal day 30 all had 24-h access to 2%, then 4%, and then 6% ethanol, followed by 1-h access to the 6% until intake stabilized. During the 1-h access SHR females consumed more ethanol than all other groups. In Experiment 2, the same procedure was used to compare SD groups prenatally exposed to nicotine, with controls. Nicotine-exposed females consumed more ethanol during 1-h access than both nicotine-exposed and control males; but after using water intake as a covariate, the differences were not significant. These data show that deprivation conditions need to be considered when generalizing the results of voluntary consumption studies, and that estrogens may be a modulator of addictive behavior.

Maternal cigarette smoking is the single most widespread prenatal insult. Smoking has long been associated with adverse pregnancy outcomes, both for the mother, her fetus, and newborn. The present ...

We explored the influence of maternal smoking during pregnancy on the likelihood of smoking among offspring in adolescence and adulthood using data from two similar British birth cohort surveys, the 1958 National Child Development Study and the 1970 British Birth Survey. Similar information was available in each cohort on maternal age at delivery, offspring sex, maternal smoking during pregnancy, parental and offspring socioeconomic status, and parental smoking at the time offspring smoking was assessed at age 16 years. Offspring smoking at 16 years and at 30/33 years were the primary outcomes of interest. Our data support an association between maternal smoking during pregnancy and an increased risk of offspring smoking later in life among female offspring but not among male offspring. Female offspring of mothers who smoked during pregnancy were more likely to smoke at 16 years than were their male counterparts. Moreover, in this same subgroup, female offspring smoking at 16 years was associated with an increased likelihood of smoking at 30/33 years. Further investigation in larger studies with greater detail of factors shaping smoking in childhood and adulthood and biochemically verified outcome measures would be desirable to clarify the relationship.

161 Prenatal Nicotine Exposure Increases the Risk of Neonatal Apnea -A National Birth-Cohort Study

Female rats were treated during pregnancy (days 1–20) with nicotine (1 mg/kg SC, b.i.d.). When some aspects of maternal behavior and developmental parameters were recorded in mothers and pups, respectively, no changes were detected in the experimental group as compared with controls. However, adult offspring of nicotine-treated rats showed an increased susceptibility to ECS. These results demonstrate long-lasting deleterious effects induced by nicotine exposure during fetal life.

Studies have revealed lasting cognitive impairments, including deficits in attention and learning, in the offspring of women who smoke. Animal models have shown that prenatal nicotine can induce behavioral impairments, including deficits in learning and memory, and one study showed that only females were impaired on a maze task. The purpose of the present experiment was two-fold: 1) to attempt to replicate the reported sex difference in maze learning and 2) to assess the ability of nicotine-treated subjects to learn a maze that placed particularly heavy demands on their attentional capabilities. Pregnant mothers were given 6.0 mg/kg/day of nicotine in their drinking water. Offspring of both sexes were tested following weaning in an 8-arm-radial maze using a confinement procedure. Results showed that prenatal nicotine treatment produced significant impairments in performance in the radial-arm maze. These impairments were seen in animals of both sexes, a finding which challenges the view that only females prenatally treated with nicotine show deficits in maze learning.

Drugs may interfere with the organizing action of circulating hormones such as gonadal and adrenal steroids on the developing brain and by this mechanism induce long-lasting alterations in brain function. In the rat, prenatal exposure to nicotine on gestational days 12–19 affects sexually dimorphic behavior and causes sex-dependent neurochemical changes. Prenatal nicotine suppresses a characteristic peak of plasma testosterone in the male rat fetus and results in depressed, female-like activity of brain aromatase which converts testosterone to estradiol, at a particular, early postnatal (PN) stage (PN 6).

The association between prenatal exposure to cigarette smoke, alcohol, and coffee and the risk of febrile seizures was evaluated by extracting information from records of 2 cohorts of children linked with the Danish National Hospital Register and a follow-up of patients until Dec 1998.

A retrospective, hospital-based, case-control study of attention deficit hyperactivity disorder (ADHD) and prenatal exposure to maternal cigarette smoking, drug use, and alcohol was conducted in 280 ADHD cases and 242 non-ADHD controls at the Massachusetts General Hospital, Boston, MA.

Maternal smoking is a major risk factor for SIDS. We have previously shown that prenatal nicotine exposure impairs the cardiorespiratory response to acute hypoxemia in sleeping young lambs (Pediatr Res 41:302A, 1997). The aim of this study was to determine whether this effect is mediated by a dopaminergic mechanism.

Maternal smoking is a major risk factor for SIDS. The mechanism of action may be a nicotine mediated attenuation of the hypoxic defense as evidenced by impaired arousal and blunted ventilatory response to acute hypoxemia in young lambs exposed to an acute nicotine infusion (Hafstrom et al, Pediatr Res 39:386A, 1996). The aim of this study was to determine whether prenatal nicotine exposure alters the cardiorespiratory response to hypoxia after birth.

A new type of activity meter has been designed especially for young rats. It consists of a warmed platform for the animal, a TV camera with monitor and a microprocessor. The TV camera detects the animal as a black figure on a light background. This picture is digitalized and stored in a Z80 microprocessor. Every 200 msec a new image is compared to the foregoing one. The total number of black points that are changing from black to white and vice versa provides a measure for motor activity of the animal. Prenatally nicotine-treated rat pups were tested on the activity meter. The developmental pattern of motor activity was different for male and female pups. Motor activity of nicotine-treated male pups differed significantly from controls at postnatal days 7 and 15 while this drug effect was not seen in females.

RESUME L'effet teratologique de la Nicotine a eteetudie pendant les differents trimestres de la grossesse. Trois groupes de souris albinos Swiss gravides ont ete utilises pour chaque trimestre. Les doses quotidiennes de nicotine base administrees equivalaient a 10 cigarettes (900 μ/kg), 20 cigarettes (1,800 μ/kg) ou 30 cigarettes (2,700 μ/kg). Les groupes de controle recevaient une solution saline isotonique. Cette solution et la nicotine etaient administrees par voie sous-cutanee. Les resultats ont montre que la nicotine prenatale prolongeait la latence et retardait le debut et l'extinction des AGS chez les descendants. Ces effets etaient plus prononces pendant le troisieme trimestre et, surtout, avec les doses les plus fortes. Ces donnees indiquent que la nicotine prenatale pourrait ralentir le developpement postnatal du systeme nerveux central si elle etait donnee pendant les derniers stades de la grossesse. RESUMEN Se han estudiado, en diferentes trimestres de embarazo, los efectos teratogenicos de la nicotina. Para ello se han utilizado para cada trimestre tres grupos de ratones suizos albinos en gestacion. Las dosis diarias de nicotina utilizadas equivalian a 10 cigarrillos (900 μg/kg), 20 cigarrillos (1.800 μg/kg), o 30 cigarrillos (2.700 μg/kg). A los animales del grupo control se les administro suero salino. La medicacion y la solucion salina se administraron subcutaneamente. Los resultados demuestran que la nicotina prenatal prolonga la latencia y retrasa el comienzo y la extincion de los AGS en los recien nacidos. Estos efectos eran mucho mas pronunciados durante el tercer trimestre y, particularmente, tras largas dosis. Estas observaciones indican que la nicotina prenatal puede retrasar el desarrollo postnatal del sistema nervioso central si se administra durante los ultimos periodos del embarazo. ZUSAMMENFASSUNG Die teratologische Wirkung von Nikotin wurde wahrend verschiedener Trimester der Schwangerschaft untersucht. Fur jedes Trimester wurden 3 Gruppen trachtiger Swiss Albino Mause benutzt. Die tagliche Nikotindosis entsprach 10 Zigaretten (900 μg/kg), 20 Zigaretten (1,800 μg/kg) oder 30 Zigaretten (2,700 μg/kg). Die Kontrollgruppen erhielten Salzlosung. Die Medikamenten- und die Salzlosungen wurden subkutan verabfolgt. Die Ergebnisse zeigen, das pranatal gegebenes Nikotin die Latenz der AGS bei den Nachkommen verlangert, Anfang und Beendigung verzogert. Diese Wirkungen waren wahrend des 3. Trimesters ausgepragter, besonders bei der hochsten Dosierung. Diese Befund weisen darauf hin, das pranatales Nikotin die postnatale Entwicklung des ZNS verzogern kann, wenn es in den spateren Stadien der Schwangerschaft verabfolgt wird. Summary: The teratological effect of nicotine has been studied during different trimesters of pregnancy. Three groups of pregnant albino Swiss mice were used for each trimester. The daily doses of nicotine base used were equivalent to 10 (900 μg/kg), 20 (1,800 μg/kg), or 30 (2,700 μg/kg) cigarettes. The control groups were given normal saline. The drug and the saline solution were administered subcutaneously. The results showed that prenatal nicotine prolonged the latency and delayed the onset and extinction of audiogenic seizures in the offspring. These effects were more pronounced during the third trimester and particularly with the largest dose. These findings indicate that prenatal nicotine might delay the postnatal development of the CNS if it is given during the late stage of pregnancy.