^{<h3>Introduction</h3>}

<br/>The review is based on the available Polish literature from the last 16 years, selected by the keywords presented above. Cigarettes and alcohol are the most popular stimulants, used by millions of people around the world every day. Despite many social campaigns warning against the harmful effects of tobacco smoke and alcohol on the developing fetus, many women smoke cigarettes and drink alcohol during pregnancy. The main inclusion criterion was the Polish origin of the publications reviewed. The reasons for this limitation are the increasing alcohol consumption among women in Poland and the increasing number of smokers in the population of women of reproductive age.

<br/>According to the report of the Chief Sanitary Inspectorate, 21% of Poles over the age of 15, including 24% of men and 18% of women, smoke habitually, i.e. every day. Among smokers, 75% of them smoke traditional cigarettes, and 1% of all Poles smoke electronic cigarettes (so-called e-cigarettes). Exposure to tobacco smoke concerns approximately 34% of the Polish population by so-called passive smoking in the home environment [1].

<br/>The report of the Institute of Conscious Man states that in Poland 30.8% of men and 27.1% of women smoke tobacco products habitually. Men smoke on average about 20 cigarettes a day, and women about 15. Every year, over 70,000 Polish people die from tobacco-related diseases [2].

<br/>According to data from the National Center for Combating Addiction, in 2021, 9.70 liters of pure alcohol per capita was consumed, which was 0.45 liters more than in 2011. More than 39% of alcohol consumed in Poland was spirits, 52.5% was beer, and the remaining 8.3% was wine and mead [3]. The report Behavior of Pregnant Women shows that 11.87% of women quit smoking when they became sexually active with the intention of starting a family, and 16.1% quit at the beginning of pregnancy. Less than 6% of pregnant women smoke cigarettes, smoking an average of 4 cigarettes per day. Nearly 18% of women who do not smoke during pregnancy are exposed to tobacco smoke at home, and 9.74% at work. Three months before pregnancy, 37.18% of women drink alcohol, 4.84% of respondents drink alcohol during pregnancy, and 0.34% of pregnant women drink alcohol more than twice a week. Among alcoholic beverages consumed, women most frequently mentioned beer, red wine, and white wine. According to the report “Health behaviors of pregnant women” published in 2017, in the study group of 3413 women, one case of fetal alcohol syndrome (FAS) was observed [4].

<br/>It is estimated that every year in Poland over 100,000 children exposed in prenatal development to chemicals from tobacco smoke are born [5].

<br/>According to research conducted as part of the ALICJA project, in four provinces of south-eastern Poland, fetal alcohol spectrum disorder (FASD) occurs in 20 out of 1000 children aged 7 to 9 and full-blown FAS was observed in 4 out of 1000 children [6].

<br/>As emphasized by Kozakiewicz et al., 91% of pregnant women are aware of the harmful effects of smoking on the developing fetus, but this knowledge does not translate into smoking cessation. Nearly 30% of pregnant women reduce the number of cigarettes they smoke, and 32% change to “light” cigarettes. Many women wrongly believe that limiting the number of cigarettes smoked during pregnancy to 5 a day is appropriate and safe for the child [7].

<br/>In the case of alcohol, the situation is very similar; 84% of pregnant women are aware of FAS as a consequence of the exposure of the fetus to alcohol consumed by the mother during pregnancy. However, only 42% of women planning a pregnancy give up alcoholic beverages. Nevertheless, 25% of pregnant women drink non-alcoholic wine and beer, believing that it is safe for the fetus. According to Polish law, non-alcoholic beer and wine may contain up to 0.5% of ethyl alcohol by volume. Therefore, they should not be used interchangeably by pregnant women [8]. In the literature on the subject, one can also find reports of recommending small amounts of wine to pregnant women in accordance with the stereotype that “everything is for people, including alcohol” [9].

<br/>Most women do not admit to their addictions or minimize the problem due to fear of social criticism. The toxic effects of tobacco smoke and alcohol on fertility, pregnancy, fetal development and health and related quality of life from birth to death were scientifically confirmed in the second half of the 20^th century. According to scientific studies, there is no safe dose or safe period of pregnancy for alcohol consumption. The same applies to active and passive smoking. It should be noted that women who consume alcohol during pregnancy also smoke cigarettes, which exposes the embryo and developing fetus to a combination of alcohol and tobacco smoke.

<br/>The intrauterine period of life is characterized by the fastest rate of development [10]. The first 8 weeks of pregnancy constitute the phase of embryonic development, in which the process of morphogenesis, i.e. the formation of the embryo’s outline, takes place from fertilization to the end of the third week. The process of organogenesis, i.e. the development and differentiation of the most important organs and systems, takes place between the fourth and eighth week of pregnancy. After that, the further process of morphological and functional differentiation of tissues, organs and systems takes place, as well as the growth of the fetus, which is particularly intensive in the third trimester of pregnancy [11].

<h3>Smoking during pregnancy</h3>

<br/>Tobacco smoke is an aerosol produced by the combustion of tobacco products, such as cigarettes, pipes, cigarillos, and cigars [5, 12]. It contains over 4000 chemical substances, including compounds with proven teratogenic effects [13]. The process of burning tobacco produces two streams of smoke: the main stream inhaled by the smoker and the side stream, resulting from the oxidation of the cigarette [5, 12]. Studies on the toxicity of tobacco smoke show that the side stream is more harmful. It is estimated that side stream smoke contains about 50 times more nitrosamines and 3-4 times more benzopyrene [12]. Carbon monoxide, nitrogen oxides, ammonia and cadmium are also present in higher concentrations [13]. A person staying in a smoker’s environment who inhales tobacco smoke in the process of passive smoking (a so-called second-hand smoker) takes in higher doses of harmful substances than a smoker. One hour of exposure for a non-smoker in a smoky room is equivalent to smoking 4 cigarettes [5].

<br/>Chemical substances contained in tobacco smoke may hinder conception, and from the moment of fertilization of the egg cell, negatively affect the development of the embryo and fetus, lead to complications in the course of pregnancy, or cause its loss [14]. The components of tobacco smoke that enter the blood of a pregnant woman cross the blood-placenta barrier and affect the fetus, just as they do the body of a smoking mother. They can accumulate in its tissues, undergo bioactivation, and cross the blood-brain barrier, also affecting the neurons of the fetus. Among the chemicals found in tobacco smoke, the presence of compounds that disrupt endocrine processes, the so-called endocrine disruptor chemicals (EDCs), has been confirmed [12]. In women who smoke, hormonal regulation of the hypothalamus-pituitary-ovary axis is impaired. Increased levels of follicle-stimulating hormone (FSH) secreted by the anterior pituitary gland disrupt the normal growth and development of ovarian follicles, while decreased levels of luteinizing hormone (LH) disrupt the ovulation process. Abnormal levels of the gonadotropic hormones FSH and LH affect the synthesis of estrogens and progesterone. In women who smoke heavily, menstrual cycles are irregular and often anovulatory. Tobacco smoke and the accompanying hormonal disorders stimulate atresia of ovarian follicles, which reduces the ovarian reserve, leading to earlier menopause.

<br/>Scientific studies confirm the influence of chemicals contained in tobacco smoke on the synthesis of estradiol in ovarian follicles. In prenatal follicles, estradiol synthesis is reduced, and in preovulatory follicles it is increased [12, 15]. The substances contained in tobacco smoke also disrupt the function of the ciliated epithelium and the peristalsis of the fallopian tubes. This leads to impaired embryo transport and delayed implantation in the uterine cavity, which increases the risk of ectopic pregnancy [5, 15].

<br/>During pregnancy, all tissues and organs of the developing fetus require a large supply of oxygen. Reactive oxygen species (free radicals) produced in the body of the mother and fetus affect the replication, differentiation, and maturation of developing cells. Appropriate amounts of them are necessary for proper implantation and development of the embryo and protection of the fetus from maternal infections. Active smoking, similarly to inhaling tobacco smoke, increases the production of free radicals, and their excessive levels in the early period of pregnancy can lead to its loss or disorders of organogenesis, resulting in various fetal defects. In advanced pregnancy, free radicals can lead to placental dysfunction and the consequences associated with it [5].

<br/>Nicotine, the main alkaloid of tobacco smoke, easily penetrates the body and its cells. It is absorbed in the respiratory system, through the oral mucosa and directly through intact skin. Swallowed with saliva in the acidic environment of the stomach, it is absorbed very slowly. In the alkaline environment of the lung alveoli, it quickly diffuses through the cell membrane of pneumocytes and is absorbed into the blood [15]. It easily crosses the blood-brain barrier. Just 7 seconds after lighting a cigarette, it reaches the brain and begins to affect neurons, reaching concentrations in the cerebral vessels from 3 to 6 times higher than in venous blood. Nicotine is metabolized mainly in the liver and excreted in the urine, its elimination lasting from 70 to 140 minutes [5]. In pregnant women, nicotine very easily penetrates the blood-placenta barrier and in the fetal blood reaches concentrations 15% higher than in the mother. It is also found in amniotic fluid, where its concentration is 88% higher than the concentration in maternal plasma.

<br/>In early pregnancy, nicotine disrupts placental development. Thickening of the villous endothelium and reduced vascularization are already visible at the end of the first trimester. Focal necrosis of the syncytiotrophoblast, reduced pinocytotic activity and microvilli damage have been observed in the placentas of smoking women [16].

<br/>Syncytiotrophoblast cells damaged by nicotine reduce the production of placental hormones, b-human chorionic gonadotropin (b-hCG) and progesterone, which are essential for the proper course of pregnancy [12]. Miscarriages of genetically healthy embryos in smoking women occur twice as often as in non-smoking women [5].

<br/>Nicotine is a potent agonist of nicotinic acetylcholinergic receptors (nACh-R), leading to increased blood pressure and heart rate in pregnant women. It also stimulates release of the catecholamines adrenaline, noradrenaline, and acetylcholine from the adrenal medulla. The released catecholamines cause blood vessel constriction, including those supplying blood to the uterine muscle [13, 15]. Hypoxic uterine muscle in the first trimester of pregnancy may cause abnormal positioning of the placenta in the uterine cavity. In smoking women, placenta praevia occurs twice as often as in non-smokers. From the second trimester of pregnancy, when the placenta is already formed, catecholamines may reduce blood flow in the intervillous space by about 20%. Reduced blood flow in the placenta limits the access of oxygen and nutrients to the fetus, which may lead to premature separation of the placenta [5]. The risk of this pregnancy complication in smoking women is 90% [16].

<br/>Tobacco smoking increases the concentration of cyanides in the blood, which block the enzymes of the respiratory cycle and inactivate carbonic anhydrase in erythrocytes, thus impairing the blood’s ability to carry oxygen [5]. In addition, carbon monoxide contained in tobacco smoke, after being absorbed into the blood, shows an affinity for hemoglobin, forming carboxyhemoglobin with it, which also limits the supply of oxygen to the fetus [16, 17]. Data from the literature show that the fetus has a limited supply of amino acids, vitamin B12 and C, and, due to the decreased expression of the glucose transport protein GLUT1, also glucose. The restriction of nutrients necessary for the proper development and growth of the fetus causes intrauterine growth restriction (IUGR) and low birth weight of the newborn [12]. Restriction of fetal growth in the second trimester and abdominal and head circumference in the third trimester associated with tobacco smoking during pregnancy has been confirmed. Scientific studies also confirm the effect of smoking in the final period of pregnancy on the fetal heart rate and respiratory movements, as well as a reduced number of fetal movements sensed by the mother [16]. Cigarette smoking causes a temporary acceleration of the fetal heart rate to 200  beats per minute and chronic fetal hypoxemia, leading to increased fetal hemoglobin concentration [13].

<br/>The poorer nutritional status of a woman who smokes during pregnancy and her reduced immunity increase the risk of genital tract infections, and thus premature rupture of membranes (PROM) and premature birth [18]. Additionally, smoking 10 cigarettes a day shortens the duration of pregnancy by 3.5 days.

<br/>Newborns of mothers who smoke during pregnancy are more likely to be born with congenital malformations. The most common harmful effects of tobacco smoking include ventricular septal defect, hydrocephalus, foot deformities, cleft lip and palate, central nervous system (CNS) defects, microcephaly, pigmented nevi, and hemangiomas [5, 12].

<br/>In 1985, Filip Nieburg called the disorders occurring in children of mothers who smoked more than 5 cigarettes a day during pregnancy, analogously to FAS, fetal tobacco syndrome (FTS) [13]. Children with FTS are born with a birth weight reduced by about 200 g and a smaller head circumference compared to children of non-smokers born after the same duration of pregnancy, often stillborn or born prematurely [11]. A newborn of a smoking mother may experience symptoms of nicotine withdrawal immediately after birth, manifesting as increased crying, anxiety, sleep disorders, and feeding problems. In infancy, there is a higher risk of sudden infant death syndrome (SIDS) [5].

<br/>Later in life, there are frequent respiratory diseases, allergic conditions, lower intelligence quotient (IQ), difficulties in learning to speak and write, as well as neurological dysfunctions and emotional disorders [11]. In 2013, the WHO issued recommendations on the effects of active and passive smoking during pregnancy. These recommendations emphasized the need to identify risk groups among women and to undertake appropriate interventions. The WHO recommends conducting health education and raising public awareness of the harmful effects of smoking, as well as taking actions to support women in quitting the addiction [19].

<br/>In recent years, electronic cigarettes (e-cigarettes) and heat-not-burn systems (HnB) have become popular [5, 14]. An e-cigarette is an electrical device that heats liquid substances contained in a cartridge, enabling inhalation of released portions of nicotine [5]. HnB systems are electronic devices that heat cartridges or capsules containing tobacco [14]. Although smoking an e-cigarette or using an HnB system does not expose the user to inhalation of carbon monoxide, tar and other chemicals contained in traditional tobacco smoke, it may be harmful to the developing fetus. No studies have been published to date to evaluate the influence of e-cigarettes on fetal development and the course of pregnancy.

<h3>Alcohol consumption during pregnancy</h3>

<br/>Ethyl alcohol, like its main metabolite acetaldehyde, has a teratogenic effect. In pregnant women, it readily crosses the blood-placenta barrier, and after about 40 minutes, it reaches a concentration in the fetus blood similar to that in the mother’s blood. Due to the enzymatic immaturity of the liver, the fetus has a low ability to eliminate alcohol, so the concentration of alcohol in the fetal body lasts twice as long as in the mother’s body. Alcohol in the fetus has an affinity for tissues with the highest water content [20, 21]. The brain structures most at risk from its harmful effects are those responsible for motor coordination, memory, and cognitive processes necessary for functioning in everyday life. These are the hippocampus, corpus callosum, cerebellum, basal nuclei, and frontal lobes [22].

<br/>The period of morphogenesis and organogenesis, i.e. up to the eighth week of pregnancy, is considered to be the time of greatest risk to the fetus. Short-term exposure to alcohol for up to 6 hours in the developing embryo may lead to hypomethylation of nucleic acids in cells forming the dorsal zone of the neural tube, forebrain and hindbrain structures, and fibers innervating the heart. Long-term exposure to alcohol for over 44 hours may cause disorders in the cells of the dorsal and ventral zones along the entire length of the neural tube. Alcohol reduces the proliferative activity of neurons and the concentration of growth factors of neural tissue, which leads to a decrease in brain tissue mass. It also disrupts the metabolism of folates, choline, and vitamin A, which are necessary for the proper development of neural tissue [20]. There is an increased concentration of vitamin A (retinol) in the fetal tissues, which increases the risk of congenital malformations [23].

<br/>Along with the CNS, between the third and sixth week of pregnancy, the heart, lower and upper limbs, and the organs of vision and hearing are most at risk from the harmful effects of alcohol. Between the sixth and eighth week, the skeletal system, external genitalia, palate, and teeth are at risk. Alcohol’s effects during organogenesis cause major structural defects, and during the fetal period, minor structural defects and functional abnormalities are observed [11]. In the embryonic phase, it can also lead to embryonic death and/or miscarriage. Studies have shown that consuming 60 g of alcohol per week increases the risk of miscarriage almost fourfold, and stillbirth threefold [23], as well as premature abruption of the placenta [20].

<br/>Intrauterine fetal death can occur at any stage of pregnancy. Alcohol consumption increases the formation of free oxygen radicals, which in the process of creating peroxide groups damage cell membranes, thus destroying fetal tissues. The cells of the dorsal zone of the neural tube are particularly susceptible to the harmful effects of alcohol and free radicals, from which the rudiments of the skull and face and internal organs develop in further development [24]. Studies have confirmed the toxic effects of alcohol on the developing lungs of the fetus and the more frequent occurrence of bronchopulmonary dysplasia. As a result of damage to type II pneumocytes, surfactant secretion is reduced, which increases the risk of collapse of the lung alveoli after birth and the development of acute respiratory failure. Alcohol disrupts the functions of B and T lymphocytes and macrophages, which reduces the immune response of the fetus, increasing the risk of infection and perinatal death. Premature newborns are particularly susceptible to the development of systemic infection – sepsis [20].

<br/>In pregnant women who drink alcohol, placental disorders in the transport of glucose, amino acids, B vitamins, vitamin K, iron, and zinc have also been reported. In children of mothers who drink during pregnancy, the risk of IUGR is 30% [21]. The effects of alcohol consumption during pregnancy depend, among other factors, on the stage of pregnancy, alcohol dose, frequency of drinking, the use of other psychoactive substances, and maternal factors such as age, health condition, nutritional status, and lifestyle [20, 22, 25]. It is estimated that a single alcohol intoxication is more dangerous to the fetus than drinking the same dose of alcohol over a longer period of time. According to the literature, alcohol is more dangerous to the fetus than drugs [20].

<br/>For 30 years, the French pediatrician Paul Lemoine observed children born to women who consumed alcohol during pregnancy. After analyzing 127 cases, he published his observations in 1968, noting low birth weight, psychomotor development disorders, congenital malformations, microcephaly, and facial dysmorphia. In 1973, Kenneth Jones and David Smith, based on the observations of l8 children of mothers addicted to alcohol, described similar symptoms, calling them fetal alcohol syndrome (FAS) [26, 27].

<br/>In subsequent years, research on FAS showed that most children only had some of the symptoms of the syndrome. In 1978, Sterling Clarren and David Smith introduced the term fetal alcohol effects (FAE) to describe partial FAS [9].

<br/>In 1996, scientists from the American Institute of Medicine (IOM) replaced FAE with two terms: alcohol-related birth defects (ARBD) and alcohol-related neurodevelopmental disorder (ARND) [9, 28].

<br/>In children of mothers who consumed alcohol during pregnancy, congenital defects occur at a rate of 1,7 per 1,000 births. The most common are heart defects: ventricular septal defect, atrial septal defect, aortic root defect, kidney defects, vision defects, hearing defects, skeletal defects, and nail hypoplasia [20].

<br/>ARND refers to individuals without facial dysmorphic features who have intellectual and behavioral disorders similar to FAS [29]. In 2004, developmental disorders resulting from the exposure of the fetus to ethyl alcohol were defined by Ann Streissguth and Kieran O’Malley as fetal alcohol spectrum disorder (FASD). According to the definition adopted at that time, FASD is the set of all physical, psychological, behavioral symptoms, and social competences that may occur in children of mothers who consumed alcohol during pregnancy [30]. As scientific research shows, there are no two identical cases of FASD, which leads to difficulties in making the correct diagnosis. Neurological disorders, intellectual disability, microcephaly, and growth disorders may also occur in individuals who were not exposed to alcohol in utero. There are many syndromes with disorders resembling FAS [28].

<br/>Full-blown FAS is the most severe form of developmental disorders resulting from prenatal exposure to alcohol. It is a triad of symptoms, which include prenatal and/or postnatal growth retardation, characteristic facial features, and CNS dysfunction. Characteristic facial features referred to as dysmorphic features are the most specific symptom of FAS. The three following symptoms are listed as key to the diagnosis of the syndrome: narrowed palpebral fissures, absent or shallow philtrum, and absent or narrowed upper lip. Other facial dysmorphic features that may occur in FAS, in addition to those listed above, include small, widely spaced eyes, drooping eyelids, a short, upturned nose, a flattened midface, an underdeveloped jaw, large or malformed ears, a narrow forehead, and microcephaly.

<br/>With age, limited growth and facial dysmorphic features become less visible. Anatomical and functional disorders of the CNS occur throughout life. CNS dysfunction concerns changes in the brain as well as neurological symptoms [27]. In the neonatal and childhood period, the child may exhibit a lack or weakening of the sucking reflex, restless short or shallow sleep, tearfulness, and hypersensitivity to light and sound. Height and weight are inappropriate for the child’s age. The child is inactive from birth, which affects speech development; the child’s vocabulary is very limited, accompanied by speech defects. The child is hyperactive, with a high level of activity, poor attention control, weakened memory, motor function disorders, and impaired executive abilities [25].

<br/>The child is forgetful, disorganized, unable to use the knowledge and experience gained in kindergarten and at school, and dependent on others. Easily discouraged, the child has difficulties in reading, writing, and counting, and is unable to tell time on a clock [28]. The average IQ of children with FAS is below 70 [23]. The child has difficulties in social contacts, is unable to communicate with other people, is impulsive and emotionally unstable, does not control his/her behavior, does not follow instructions, and has impaired social adaptation in the broad sense. Children with FAS are helpless, trusting, and overly compliant, which makes them susceptible to manipulation and exploitation; they often become victims of violence or come into conflict with the law [28].

<br/>If the mother consumes excessive amounts of alcohol before delivery, the newborn may experience symptoms of acute fetal alcohol intoxication immediately after birth. This includes impaired consciousness, muscle hypotonia, lack of reflexes, and absence of spontaneous breathing [31]. The newborn of a mother who drinks habitually during pregnancy develops fetal-neonatal alcohol withdrawal syndrome (NAS). Symptoms appear on the second to third day of life. These include excessive agitation, with incessant crying, increased muscle tone, and problems with sucking and vomiting [21, 31]. The criteria used in the diagnosis of FASD include the American criteria, the Washington standards, and the Canadian criteria. All of the above criteria take into account the same diagnostic factors. These are: three key features of facial dysmorphia, CNS dysfunction, prenatal and/or postnatal growth retardation, and exposure to alcohol in utero [32].

<br/>The American criteria are the first diagnostic criteria for FASD, published by the IOM in 1996. They distinguish two diagnostic categories: FAS and alcohol-related disorders (alcohol related effects). The 4-digit Diagnostic Code (Washington standard) was developed in 1997 at the University of Washington by Susan Astley and Sterling Clarren. The standard assesses the intensity of expression of each of the 4 assessed criteria on a four-point Likert scale. These are: growth retardation, facial dysmorphia, CNS disorders, and prenatal exposure to alcohol. On the above scale, 1 means no occurrence of a given feature, and 4 is full occurrence. A score of 1111 indicates no FASD features, while 4444 indicates full-blown FAS [9, 28].

<br/>The Canadian criteria were developed in 2005, combining the American IOM criteria and the Washington standards. The last modification of the above criteria in 2015 introduced two diagnostic entities – FASD with sentinel facial features and FASD without sentinel facial features – and the descriptive term “At risk for neurodevelopmental disorder or FASD associated with prenatal alcohol exposure”. This term applies to young children who do not meet the diagnostic criteria for FASD but who exhibit developmental disorders characteristic for confirmed prenatal alcohol exposure. In the new Canadian model, prenatal and/or postnatal growth retardation has been removed from the diagnostic criteria for FASD, and the key facial dysmorphic features have been reduced to two. CNS disorders include disorders in the damage of brain structures, motor, verbal and intellectual functions, attention, memory, executive functions and abstract thinking, school achievements, social behavior and competences, the occurrence of fear and anxiety, and depressive states and mood disorders [33].

<br/>The current recommendations of the Polish Society of Gynecologists and Obstetricians and the State Agency for Solving Alcohol Problems [32] recommend Canadian criteria in FASD diagnostics as well as the screening and brief intervention (SBI) procedure. The SBI procedure involves assessing the average alcohol consumption in the last 3 months before pregnancy or during pregnancy using the T-ACE, TWEAK, AUDIT, AUDIT-C, and QDS screening tests and determining the associated risk level during pregnancy. Depending on the specific risk level, specific actions are recommended. In the case of low risk, this involves providing educational materials, while in the case of increased risk, interventions aimed at motivating abstinence from alcohol are recommended. In the case of high risk, referral to an addiction treatment center is recommended [32].

<br/>In Poland, September 9 has been designated as World FAS Day since 2001. The nines in the date symbolize the nine months that should be spent without alcohol. FAS is incurable, but it can be prevented by completely abstaining from alcohol before getting pregnant and throughout pregnancy.

<h3>Disclosures</h3>

<br/>This research received no external funding.

<br/>Institutional review board statement: Not applicable.

<br/>The authors declare no conflict of interest.

<h3>References</h3>