Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate

INTRODUCTION — Use of tobacco products, including cigarette smoking, smokeless tobacco, and electronic cigarettes (e-cigarettes), during pregnancy is one of the most important modifiable risk factors associated with adverse maternal, fetal, and neonatal outcomes. Screening and intervention for tobacco use during pregnancy can be powerful tools to achieve smoking cessation. Pregnancy also provides an opportunity to educate the pregnant person's partner or family members on the benefits of tobacco cessation for themselves, the patient, and the baby.

This topic will review the scope of this problem based on data for cigarette smoking, which is the most commonly used tobacco product. The scope of the problem, the pathophysiology of tobacco use in pregnancy, and clinical effects of cigarette smoking on maternal, fetal, and neonatal outcomes will be reviewed here. Discussions of treatment options for smoking cessation in pregnancy, general issues of substance use during pregnancy, and smoking cessation in a nonpregnant population are presented separately:

●(See "Tobacco and nicotine use in pregnancy: Cessation strategies and treatment options".)

●(See "Alcohol intake and pregnancy".)

●(See "Substance use during pregnancy: Screening and prenatal care".)

●(See "Overview of smoking cessation management in adults".)

In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender diverse individuals.

OUR APPROACH AND KEY COUNSELING POINTS — When counseling patients about the risks of smoking, the clinician juggles competing concerns. While one goal of counseling is to provide information, there is also a risk of creating fear or alienating the patient. Many individuals have guilt about smoking while pregnant.

We take the following approach:

●Ask all pregnant patients regularly about tobacco use, including cigarettes, smokeless tobacco, cigars, water pipes (ie, hookahs), and e-cigarettes or vaping products [1,2]. Screening is typically done by asking if the patient currently uses any of these products. (See 'Screening methods' below.)

●Educate patients and partners about the consequences of tobacco use for both mother and fetus. Using a visual infographic may help convey these concerns.

•Maternal – In addition to the usual health concerns related to use of tobacco products, smoking has been associated with subfertility. (See 'Maternal' below.)

•Fetal – In utero tobacco exposure has been associated with:

-Nearly 50 percent increased risk of stillbirth. (See 'Stillbirth and neonatal death' below.)

-A two- to fivefold increased risk of preterm premature rupture of membranes (risk varies by gestational age). (See 'Preterm premature rupture of membranes' below.)

-A 1.5 to 3.5 increased risk of low birth weight (ie, birth weight <2500 grams). (See 'Reduction in birth weight' below.)

-Up to 3.5 times the risk of placental abruption. (See 'Placental abruption/placenta previa' below.)

-Approximately double the risk of preterm birth, particularly prior to 32 weeks of gestation. (See 'Preterm birth' below.)

-Other potential effects include a small increase in miscarriage risk and a possible increase in some congenital malformations. (See 'Congenital malformations' below and 'Gestational diabetes' below.)

●Discuss potential consequences of tobacco product use on the child at birth and long term.

•Studies of neonates (from birth to 28 days of age) born to mothers who smoke have reported increased signs of stress, irritability, and hypertonicity compared with those of mothers who do not smoke. (See 'Neonatal effects' below.)

•Maternal smoking approximately doubles the risk of sudden unexpected infant death (SUID, formerly sudden infant death syndrome [SIDS]), defined as infant death <1 year of age. (See 'Long-term effects' below.)

●Review the impact on breastfeeding, including decreased milk volume production, lower milk fat concentration, and, consequently, shorter duration of breastfeeding. While the data are specific to smoking, the effect is presumably similar for other tobacco products. (See 'Breastfeeding' below.)

●Discuss that exposure to secondhand smoke during pregnancy also appears to have adverse effects, including stillbirth and low birth weight. (See 'Effects of secondhand smoke' below.)

●For patients who are ready to reduce or quit tobacco use, discuss strategies and treatment options.

•(See "Tobacco and nicotine use in pregnancy: Cessation strategies and treatment options".)

•(See "Patient education: Smoking in pregnancy (The Basics)".)

EPIDEMIOLOGY — Increased public health education efforts have contributed to generally declining smoking rates, although women continue to smoke while pregnant [3]. In England, the percent of pregnant women who smoked at the time of giving birth declined from 15 to 11 percent between 2006 and 2014 [4]. A study of United States birth certificate data from 2014 similarly reported that 11 percent of American women reported smoking cigarettes in the three months before pregnancy and approximately 8 percent reported smoking at any time during pregnancy [5]. Smoking rates were highest in the first trimester (8.2 percent) and lowest in the third trimester (6.6 percent). Most women who quit during pregnancy did so between the first and second trimester. Those who initiated prenatal care in the third trimester or had no care during pregnancy had the highest rates of smoking (15 percent). Subsequent analysis of 2016 United States data noted a small reduction in percent of women who smoked during pregnancy (7.2 percent) [6]. In 2016, women with the highest rates of smoking were those aged 20 to 24 years, of non-Hispanic American Indian or Alaska native ethnicity, and with a high-school or lower education level.

The true prevalence of smoking during pregnancy is difficult to discern, not only because of incomplete records, but also because most studies rely on self-reported smoking behavior and are therefore subject to underreporting. Studies that use biochemical markers, including exhaled carbon monoxide and urinary cotinine, have shown that pregnant individuals underreport both tobacco-use status and the extent of tobacco use [7-12]. Published nondisclosure rates range from 24 to 50 percent. Exposure to secondhand smoke in the environment can result in detectable cotinine levels in the blood, saliva, or urine of those who do not actively smoke; however, the level is typically lower than in individuals who actively smoke.

IDENTIFYING MATERNAL TOBACCO USE

Rationale for screening — Identifying maternal cigarette use allows for targeted interventions to prevent adverse pregnancy outcomes. In 2002 in the United States, 5 to 8 percent of preterm births, 13 to 19 percent of term infants with intrauterine growth restriction, 5 to 7 percent of preterm-related deaths, and 23 to 34 percent of sudden infant death syndrome deaths were attributed to prenatal smoking (data on stillbirth were not available in this study) [13]. (See 'Adverse outcomes' below.)

Further benefits of screening may include identification of individuals at risk of intimate partner violence and other substance use [14]. The Pregnancy Risk Assessment Monitoring System (PRAMS) survey, which included data on nearly 200,000 women, reported that those who experienced physical abuse were twice as likely to smoke before or during pregnancy, compared with those who did not experience physical abuse [15]. This study suggested that additional and targeted screening for intimate partner violence in individuals who smoke during pregnancy may prove beneficial. Additional information on these topics is presented elsewhere:

●(See "Intimate partner violence: Diagnosis and screening", section on 'Pregnancy'.)

●(See "Substance use during pregnancy: Screening and prenatal care".)

Screening methods — All pregnant patients should be asked regularly about tobacco use, including cigarettes, smokeless tobacco, cigars, water pipes (ie, hookahs), and e-cigarettes (ie, vaping) [1,2,16]. In clinical practice, screening for tobacco use is done by asking patients if they have ever used tobacco products, if they used tobacco products when they found out they were pregnant, and whether they use tobacco products now. Patients who smoke should be asked the number of cigarettes smoked per day. The approach to screening is presented in detail separately. (See "Tobacco and nicotine use in pregnancy: Cessation strategies and treatment options", section on 'General questions (5 A's) to smoking cessation'.)

Limitations — The strong social norms discouraging smoking among pregnant persons lead some patients to fail to disclose their true smoking status as detected by measurement of urine cotinine, a nicotine metabolite [11,17]. As an example, a retrospective cohort study comparing maternal urinary cotinine levels with self-reported cigarette use noted 16.5 percent of women tested positive for high-level nicotine exposure, and an additional 7.5 percent tested positive for low-level exposure despite a self-reported cigarette use rate of 8.6 percent [18]. Urinary cotinine screening of pregnant individuals is feasible in practice and could increase detection of tobacco smoke exposure among pregnant persons. Cotinine is found in urine, blood, and saliva for approximately five days after exposure to tobacco smoke.

Use of other tobacco and nicotine products — Tobacco is also smoked in cigars, pipes, and water pipes. Dissolvable tobacco products (chewing tobacco, snuff, snus) are not smoked but are placed in the mouth and absorbed through buccal mucosal membrane. Electronic nicotine delivery systems (ENDS; also known as electronic cigarettes or e-cigarettes) use an electronic delivery system that aerosolizes nicotine, producing a vapor similar to cigarettes, but contains fewer traditional toxins [19].

In a nationally representative survey of United States women from 2016 to 2018, 2.7 percent of women aged 18 to 44 years used ENDS in the three months prior to pregnancy, while 1.1 percent used them during the last three months of pregnancy [20]. According to the 2015 PRAMS, studies among Oklahoma and Texas women reported 7 percent used an ENDS around the time of pregnancy [21]. For women who used both cigarettes and ENDS at any time, 38 percent reported using both in the three months before pregnancy. When asked about reasons for ENDS use, 45 percent of women believed that ENDS "might help with quitting or reducing cigarette smoking," and 45 percent also believed ENDS to be less harmful to the mother compared with smoking cigarettes. However, contrary to perceived safety, preliminary animal studies suggest that ENDS use negatively impacts respiratory, neurocognitive, cardiovascular, and metabolic function in exposed children [22]. (See "Vaping and e-cigarettes".)

Adverse pregnancy outcomes associated with use of these products have been reported, but data are limited [23-28]. All of these products expose the pregnant woman and fetus to nicotine and other harmful or potentially harmful substances, are not associated with any health benefits, and should be avoided in pregnancy.

PATHOPHYSIOLOGIC EFFECTS OF SMOKING ON PREGNANCY

Potential mechanisms — Several mechanisms have been observed or proposed to explain the adverse pregnancy outcomes associated with maternal smoking. These include impaired fetal oxygenation, altered fetal development and physiologic response, and toxin exposure. Data on the mechanisms associated with e-cigarette use are mainly derived from animal models at this time [29,30].

●Reduced oxygen delivery – Smoking in pregnancy causes impaired oxygen delivery to the fetus by several possible mechanisms. Pathologic evaluations of the placentas of individuals who smoke have shown structural changes, including a reduction in the fraction of capillary volume and increased thickness of the villous membrane when compared with those who do not smoke [31-33]. Both of these factors may contribute to abnormal gas exchange within the placenta. Exposure to cigarette smoke also acutely decreases intervillous perfusion, possibly via nicotine-induced vasospasm [34].

●Carbon monoxide and nitrous oxide – The release of carbon monoxide during smoking results in the formation of carboxyhemoglobin, which has multiple effects on systemic and fetal oxygen delivery. Carboxyhemoglobin is cleared slowly from the fetal circulation and diminishes tissue oxygenation via competitive inhibition with oxyhemoglobin and a left-shift of the oxyhemoglobin dissociation curve (figure 1). In addition, smoking-induced oxidative stress may increase placental production of mitochondrial reactive oxygen species as well as nitric oxide [35]. Nitric oxide reacts with superoxide radicals to produce peroxynitrite, which can damage placental function.

●Impaired fetal development – Nicotine use during pregnancy is associated with impaired fetal development.

•Human data – In a study that used serial three-dimensional transvaginal ultrasound images to assess embryonic morphological development between 7+0 and 10+3 weeks using the Carnegie developmental stages, maternal smoking ≥10 cigarettes per day in the periconception period was associated with delayed Carnegie stages compared with nonsmokers (adjusted model β ≥10 cigarettes/day -0.35, 95% CI -0.65 to -0.06 [36]. The difference amounted to a time delay of 0.9 days. In pregnancies conceived via IVF or ICSI, the effect was greater (adjusted model β ≥10 cigarettes/day -0.510, 95% CI -0.83 to -0.19) with a delay of 1.6 days. Periconceptional smoking was associated with a smaller femur length and larger head circumference in the second trimester as well as a dose-dependent lower birth weight. The investigators noted that the association between these observations identified by ultrasound parameters could be partially explained by delayed embryonic morphological development. While more data are necessary, this study provides support that smokers (especially those smoking 10 or more cigarettes per day) should be encouraged to reduce or quit smoking prior to conception to avoid these early effects that appear to contribute to persistent changes in fetal growth parameters. Furthermore, it should provide encouragement for reproductive endocrinologists to recommend abstinence during periconception in their patients.

•Animal data – In animal models, nicotine increases vascular resistance and reduces uterine blood flow [37,38]. Chronic prenatal exposure to nicotine in these models results in abnormal secretion of neurochemical mediators in the brain, as well as pathologic behavior among the offspring [39]. Further, animal models suggest that nicotine can directly impair lung development due to interaction with nicotinic acetylcholine receptors (nAChR). Using a primate model, one group demonstrated abundant expression of nAChR in fetal lung tissue [40]. In a subsequent study, continuous subcutaneous infusion of nicotine into pregnant rhesus monkeys resulted in significant decreases in lung weight and volume and an increase in airway resistance [41]. Prenatal nicotine exposure also can blunt the cardiorespiratory response to postnatal hypoxemia in sheep [42]. Similarly, term human infants with significant cotinine levels at delivery are limited in their ability to maximize and vary their heart rate during the first four hours of life [43].

●Exposure to toxins – Beyond nicotine, smoking exposes the mother and fetus to multiple potential toxins. More than 2500 other directly toxic substances are found in cigarettes, such as ammonia, polycyclic aromatic hydrocarbons, hydrogen cyanide, vinyl chloride, and nitrogen oxide [44]. In addition, there are over 4000 chemicals in mainstream tobacco smoke, which is drawn through the tobacco column and exits through the mouthpiece during puffing. The number of compounds emitted in tobacco smoke may actually exceed 100,000 [45]. This toxin exposure may cause direct damage to fetal genetic material. One study compared the chromosomal instability of amniocytes from pregnant persons who smoked and did not smoke and noted an increased incidence of structural chromosomal abnormalities among those who smoked regularly (12 versus 3.5 percent, respectively) [46]. Most of these abnormalities were the result of deletions or translocations, and many were localized to the 11q23 region, which is also associated with several hematologic malignancies.

●Increased sympathetic activation – Finally, exposure to nicotine results in sympathetic activation leading to acceleration of fetal heart rate and a reduction in fetal breathing movement. While the consequences of these changes are not well understood, both of these parameters are used as indicators of fetal well-being in antenatal fetal assessment tests.

Genetic susceptibility — Maternal genotype may modify the risk of low birth weight (LBW) in pregnant individuals who smoke [47]. A study of 741 mothers (174 self-reported ever smokers, 567 never smokers) who delivered singleton infants confirmed a reduction in birth weight and length of gestation in those with any smoking (280 grams lower and 0.8 weeks shorter, respectively). In addition, continuous smoking by those whose genotypes were CYP1A1 Aa/aa (heterozygous and homozygous variants) and GSTT1 (del) had significantly greater reductions in infant birth weight than those with CYP1A1 AA (homozygous wild) or GSTT1 present genotypes (520 versus 252 grams for CYP1A1; 642 versus 285 grams for GSTT1). Another study reported that fetal GSTT1 (del) also significantly reduced gestational age-adjusted birth weight in offspring of mothers who smoked [48].

In a third study, maternal oxidative stress levels increased significantly as the maternal cotinine levels increased in mothers with null-type GSTM1 (glutathione S-transferase M1) or wild-type GSTT1 [49]. In this study, fetal cotinine levels were significantly associated with maternal cotinine levels, and fetal oxidative stress was associated with fetal cotinine levels.

A case control study of 910 Chinese pregnant women evaluated the effects of prenatal exposure to "environmental" tobacco (maternal passive smoking) and reported that, regardless of genotype, prenatal exposure to tobacco significantly increased the risk of LBW at term [50]. Those with the CYP1A1 variant or GSTT1-null genotype had higher prevalence of LBW, and women with both CYP1A1 variant and GSTT1-null genotype had higher rates. While the genotype appeared to have an influence on LBW in women exposed to tobacco, this effect on LBW was not observed in the nonexposed women [50].

The CYP1A1, GSTM1, and GSTT1 genes were studied because they encode enzymes (eg, aryl hydrocarbon hydroxylase, glutathione S-transferases) active in the body's metabolism and elimination of toxic substances contained in cigarette smoke. These studies suggest that maternal genetic polymorphisms that influence the activity of these enzymes increase maternal/fetal susceptibility to the adverse effects of environmental substances.

Impact of smoking on offspring genetics — Specific epigenetic changes, measured as alterations in genome-wide DNA methylation patterns, have been identified in offspring of mothers who smoke [51]. Additionally, epigenomic changes, including placental methylation and miRNA expression, have been identified in the placentas of mothers who smoke [52]. A review of studies assessing the impact of intrauterine smoking on offspring DNA methylation reported that multiple strong, highly replicated methylation signatures have been identified at CpG sites in gene regions AHRR, CYP1A1, MYO1G, CNTNAP2, GFI1, and FRMD4A [53]. Changes in gene expression in response to smoke exposure have also been consistently identified. Similarly, a number of differentially methylated placental genes have been reported in placentas of mothers who smoke [54]. It is not yet known if smokeless tobacco and e-cigarettes result in similar genetic changes.

In an ongoing cohort study assessing the effects of the prenatal environment and adiposity, cigarette smoking before and during pregnancy was associated with lower birth weight and body mass index (BMI) at birth [55]. Neonatal methylation levels at three of the seven loci studied were significantly associated with the prenatal environment. Methylation levels at cg25685359 (MIRLET7BHG) showed a significant positive association with maternal smoking before pregnancy and a negative association with birth weight. Methylation levels at this loci also showed a suggestive association with BMI change in early childhood (up to 48 months).

The clinical significance of these gene methylation and expression changes is not yet understood but likely contribute to the adverse obstetric and neonatal effects of maternal tobacco use as well as to long term effects beyond the womb.

ADVERSE OUTCOMES — Tobacco use negatively impacts maternal and fetal health and carries over into the postnatal period. The majority of the available data are based on maternal cigarette smoking.

Maternal

Subfertility — As much as 13 percent of subfertility and delay in time to conception has been attributed to smoking [56]. Chemicals in cigarette smoke, including heavy metals, polycyclic hydrocarbons, nitrosamines, and aromatic amines, appear to accelerate follicular depletion and may impede gametogenesis [57-59]. (See "Female infertility: Causes", section on 'Oocyte aging'.)

A meta-analysis of 12 studies reported the overall odds ratio (OR) for risk of infertility in females who smoked versus those who did not was 1.60 (95% CI 1.34-1.91) [60]. Studies of subfertile women undergoing in vitro fertilization (IVF) treatment also showed a reduction in fecundity among those who smoked. The odds of pregnancy per number of IVF-treated cycles were significantly lower in females who smoked versus those who did not: OR 0.66 (95% CI 0.49-0.88). Lastly, compared with oocytes of nonsmoking women, oocytes harvested from females who smoke and are undergoing IVF have a greater percentage of immature oocytes, increased thickness of the zona pellucida, and higher levels of markers of oxidative stress [58,61,62]. (See "Natural fertility and impact of lifestyle factors", section on 'Tobacco'.)

The range of negative general health outcomes from smoking and the benefits of smoking cessation are discussed in detail elsewhere. (See "Benefits and consequences of smoking cessation".)

Other — As women have delayed childbearing and smoking rates among young women have increased, there is the additional risk of coexisting smoking-related conditions such as lung cancer, hypertension, and asthma that could impact pregnancy. The attributable risk for smoking in pregnant women with coexisting smoking-related disorders are difficult to tease out from the available literature.

Lung cancer during pregnancy is rare, but it is the second leading cause of mortality in women of reproductive age (25 to 39 years) and thought to be increasing due to the aforementioned factors. However, not all of the lung cancers diagnosed during pregnancy are smoking related. In one series of 2422 women diagnosed with nonsmall cell lung cancer (NSCLC), 160 were of reproductive age and, in 8 of these 160 women (5 percent), NSCLC was diagnosed during pregnancy. All of the patients in this series were either did not smoke or smoked lightly [63]. Metastases to the placenta and fetus have also been reported. Other studies have suggested a larger contribution of smoking in lung cancers diagnosed during pregnancy. However, the available reported cases are small and meaningful conclusions cannot be made on the precise contribution of tobacco exposure (including passive smoking) on lung cancers diagnosed during pregnancy. There are also no data to suggest that pregnancy changes the biology of lung cancer [64].

Other smoking-related conditions, such as hypertension, can coexist during pregnancy and are associated with significant fetal and maternal mortality. Ideally, all reproductive aged women should receive preconception-specific messaging or formal consultation that includes the known risks of smoking and options for smoking cessation. By doing so, we can prevent or reduce pregnancy complications that are directly or indirectly attributable to smoking. The benefits of smoking cessation in nonpregnant women are discussed separately. (See "Benefits and consequences of smoking cessation", section on 'Benefits of smoking cessation'.)

Pregnancy

Summary — Cigarette smoking has been associated with numerous adverse pregnancy outcomes, including placental abruption, preterm premature rupture of membranes (PPROM), placenta previa, preterm labor and delivery, low birth weight (LBW), and ectopic pregnancy [1]. While the pathophysiology is not completely understood, several possible mechanisms related to impaired gas exchange, direct toxicity, and sympathetic activation have been proposed. (See 'Pathophysiologic effects of smoking on pregnancy' above.)

Pregnancy loss (miscarriage) — Cigarette smoking during pregnancy may have a modest effect on pregnancy loss [65]. In a 2014 systematic review and meta-analysis, any active smoking was associated with increased risk of pregnancy loss (summary relative risk [RR] ratio 1.23, 95% CI 1.16-1.30; n = 50 studies) and a dose effect was observed (1 percent increase in RR per cigarette smoked per day) [66]. However, there are many limitations to these data, most importantly, lack of ascertainment of smoking status at various times during pregnancy and variations in study designs. Cigarette smoking has been associated with early pregnancy loss after assisted reproductive technology treatment [67].

Passive smoke exposure through partner smoking has also been associated with increased risk of miscarriage [68,69]. In a retrospective population study of over 5.7 million rural nonsmoking Chinese women, partner smoking increased the risk of miscarriage by 17 percent in adjusted analysis (adjusted OR 1.17, 95% CI 1.16-1.19) [69].

Stillbirth and neonatal death — In a meta-analysis of 142 studies, any active maternal smoking increased the risk of stillbirth by nearly 50 percent (summary RR 1.46, 95% CI 1.38-1.54) and the risk of neonatal death by over 20 percent (summary RR 1.22, 95% CI 1.14-1.30) [70]. A Danish cohort study of over 840,000 women that was not included in the meta-analysis reported increased stillbirth risks of 38 percent for antepartum stillbirth and 50 percent for intrapartum events [71]. Importantly, women who quit smoking by the beginning of the second trimester had the same risk of stillbirth as women who did not smoke at all. A dose-response curve has been reported for stillbirth, with those who smoked heavily having the greatest risk [72-74]. In addition, a prospective study suggested that nonsmoking women passively exposed to secondhand smoke may be at higher risk of intrauterine death than nonexposed women (RR 1.53, 95% CI 0.98-2.38) [75]. This trend could not be explained by age, previous spontaneous abortion, educational level, planning of pregnancy, or alcohol use. However, most of this risk due to passive smoking was confined to first-trimester fetal loss (RR 2.16, 95% CI 1.23-3.81), whereas active smoking was associated with intrauterine death later in pregnancy. Studies additionally report that combined use of alcohol and tobacco products appears to increase the risk of stillbirth beyond that of exposure to either substance alone [76].

Preterm premature rupture of membranes — There is a consistent increase in risk of PPROM among those who smoke, with relative risks ranging from 1.9 to 4.2 [77-81]. The risk persists when controlled for other known risk factors for PPROM, including intrauterine or genitourinary infection. In a retrospective cohort study of nearly 18,000 births, heavy smoking (>10 cigarettes per day) was associated with a fivefold increased risk of PPROM at <28 week, over double the risk of PPROM and <32 weeks, and over three times the risk at >37 weeks of gestation [82]. Of note, smoking 1 to 10 cigarettes per day was not associated with an increased risk of PPROM at any of the gestational ages. (See "Preterm prelabor rupture of membranes: Clinical manifestations and diagnosis".)

Reduction in birth weight — LBW (ie, <2500 grams) is the best-studied complication of smoking and/or being exposed to secondhand smoke during pregnancy. Women who smoke and/or use e-cigarettes are 1.5 to 3.5 times more likely to have a LBW infant [83-92]. The risk increases with increasing cigarette consumption and decreases with smoking cessation earlier in pregnancy [93-95]. Birth weight is influenced greatly by gestational age at delivery, and smoking modestly increases the risk of preterm birth. However, the effect of smoking on birth weight cannot be explained solely by earlier gestational age at delivery. Those who smoke have an increased risk of a small for gestational age (SGA) infant with relative risks ranging from 1.3 to 10.0 [83-85,96]. It has been estimated that at least 20 percent of LBW and SGA infants are attributable to tobacco exposure during pregnancy [83], and, if smoking were eliminated in pregnant women, the number of SGA infants would be reduced by 12 percent [97]. In observational studies, smoking cessation in the first trimester lowers the rate of SGA births to the level of those who do not smoke [98-100].

Supplementation with higher doses of folic acid is another intervention to potentially reduce the incidence of SGA and LBW infants. One trial reported that supplementing mothers who smoked with higher doses of folic acid (4.0 mg versus 0.8 mg), in addition to a smoking cessation program, was associated with a 140 gram mean higher birth weight and approximately 30 percent reduced risk of having an SGA or fetal growth-restricted infant [101]. Although there is biological plausibility for this finding given that smoking has been associated with lower folate levels [102,103], the precise mechanism is unknown. In one study of 80 pregnant women (40 smokers and 40 nonsmokers), pregnant women who smoked had lower levels of serum folate compared with the pregnant nonsmoking women [103]. The lower folate levels were noted in those who smoke regardless of MTHFR genotype. There were also no differences in homocysteine levels between smoking and nonsmoking pregnant women. Nevertheless, supplementation with higher doses of folic acid is a promising intervention with the potential to have a significant public health impact if the results can be replicated. (See "Infants with fetal (intrauterine) growth restriction".)

For non-LBW infants, the birth weight deficit associated with smoking is 100 to 300 grams, depending on the number of cigarettes smoked [83,104-106]. Smoking during the third trimester appears to have the greatest impact on birth weight, and pregnant patients who quit smoking by the third trimester have infants with higher birth weights and birth weights similar to those of pregnant persons who do not smoke [84,107-109]. A case-control study conducted among Italian pregnant women with term deliveries reported that both self-reported active smoking during pregnancy and environmental tobacco smoke exposure were associated with a birth weight less than the 5^th percentile [110]. Similar to other studies, a dose-response relationship was observed. The effect of smoking on birth weight seems to be more marked among older women [83]. Male fetuses may be more affected [111], but this has not been a consistent finding.

Placental abruption/placenta previa — Cigarette smoking increases the risk of placental abruption, with reported adjusted relative risks of up to 3.5 [112]. Dose-response curve analysis has consistently revealed that the risk of abruption is greatest among pregnant individuals who smoke heavily [113-115]. Because PPROM is associated with both cigarette smoking and placental abruption, the relationship between cigarette smoking and abruption may be partially explained by the increased risk of PPROM. However, cigarette smoking appears to be a risk factor for placental abruption, independent of PPROM.

Cigarette smoking has also been consistently associated with placenta previa, with reported relative risks ranging from 1.4 to 4.4 [115-121]. A dose-response curve for this complication has not been consistently replicated.

Preterm birth — Preterm birth (PTB; <37 weeks of gestation) is a complex variable to study because it represents the final common pathway for numerous conditions during pregnancy. Preterm birth may be the consequence of idiopathic premature labor or may be indicated due to complications of pregnancy such as preeclampsia, PPROM, chorioamnionitis, or placental abruption, and may be iatrogenic (ie, indicated preterm birth). (See "Spontaneous preterm birth: Pathogenesis".)

Individuals who smoke are 1.3 to 2.5 times more likely to have a preterm birth, particularly one prior to 32 weeks of gestation [86,122-128]. In a population-based cohort study of self-reported maternal tobacco use (smoking or snuff) and PTB, women who used tobacco were 1.6 to 1.9 times more likely to have an extremely PTB (birth less than 28 weeks of gestation) [129]. Maternal smoking in early pregnancy was associated with increased risks of both spontaneous and medically indicated PTB, while snuff use was associated with an increase in medically indicated PTB. In at least one study, the RR of PTB associated with smoking was highest among women with no known risk factors [122]. Even small amounts of smoking appear to increase the preterm birth rate. A different population-based study that utilized self-reported information on smoking reported that smoking one to two cigarettes per day was associated with a 30 percent increased risk of preterm birth compared with individuals who did not smoke (adjusted OR 1.31, 95% CI 1.29-1.33) [128].

Most importantly, cigarette smoking and drug use are often the only potentially modifiable risk factors associated with PTB. There is evidence from observational studies that smoking cessation in the first trimester lowers the rate of PTB to near that of pregnant individuals who do not smoke [98,99,127,130,131]. In the above cohort study, when mothers stopped tobacco use in early pregnancy, there was no increased risk of PTB [129].

Congenital malformations — Although the overall rate of congenital malformations does not appear to be higher among infants born to pregnant individuals who smoke [132-136], smoking may increase the risk of specific anomalies. Studies have reported links between maternal smoking and the development of cleft lip with or without cleft palate [135,137-144], gastroschisis [145,146], anal atresia [147], transverse limb reduction defects [146,148,149], cardiac defects [150-152], digital anomalies (polydactyly, syndactyly, or adactyly) [153], and bilateral renal agenesis or hypoplasia [154].

The timing of exposure, amount of exposure, and maternal age can impact the risk of developing a congenital malformation in response to cigarette smoke, which highlights the complexity of studying this relationship. As an example, in a case-control study comparing over 14,000 infants born with a congenital heart defect (CHD) with over 60,000 unaffected infants, an increased risk of specific cardiac malformations was reported for infants exposed to cigarette smoke during the first trimester of pregnancy [151]. The cardiac malformations included pulmonary artery anomalies, pulmonary valve abnormalities, and isolated atrial septal defects. While the risk of these specific anomalies was increased, the adjusted risk of having any CHD was similar to previously reported results [150]. A dose-response relationship was also reported; the risk of fetal CHD increased as daily maternal cigarette use increased during the first trimester [151]. Lastly, the study reported a significant increased risk of a CHD in infants born to mothers age 35 or older who smoked compared with younger mothers who smoked. The results did not change when adjusted for body mass index (BMI), diabetes, and alcohol consumption.

The assessment of cigarette smoking on the development of congenital malformations is further confounded by evolving evidence suggesting that genetic factors may modify the risk of developing congenital anomalies related to smoking. Smoking may increase the risk only in individuals who are carriers of specific genotypes, including polymorphisms of the transforming growth factor-alpha locus [83,136,140]. However, regardless of genetic susceptibility, smoking cessation should be strongly encouraged for all who are planning a pregnancy, as both active and passive smoking have been implicated in increased risk of cardiac malformations in offspring [152].

Preeclampsia — Meta-analysis has shown that maternal cigarette smoking is associated with a significant reduction in the risk of preeclampsia (OR 0.51, 95% CI 0.37-0.63) [155]. The reduction occurs in all maternal BMI categories [156]. This benefit does not outweigh the multiple medical and obstetric risks associated with smoking during pregnancy. Based on an in vitro experiment, the mechanism may be that cigarette smoke reduces fms-like tyrosine kinase-1 (sFlt-1) and increases placental growth factor (PlGF), which is the opposite of the changes observed in women who develop preeclampsia [157]. (See "Preeclampsia: Pathogenesis".)

Gestational diabetes — At least one observational study has suggested an increased risk of gestational diabetes mellitus (GDM) in pregnant individuals who continue to smoke during pregnancy. In a secondary analysis of data from the Pregnancy Risk Assessment Monitoring System (PRAMS), patients who continued to smoke increased their risk of GDM compared with those who quit smoking or never smoked, even after controlling for maternal age, race/ethnicity, prepregnancy body mass index, and gestational weight gain [158]. However, a 2020 meta-analysis did not support this association [159]. Until this association is confirmed, pregnant individuals should be screened for GDM according to established guidelines. (See "Gestational diabetes mellitus: Screening, diagnosis, and prevention".)

Postnatal — Postnatal morbidities that have been associated with maternal smoking include sudden infant death syndrome (SIDS), respiratory infections (eg, bronchitis, pneumonia), asthma, atopy, otitis media, infantile colic, bronchiolitis, short stature, lower reading and spelling scores, shorter attention spans, hyperactivity, childhood obesity, and decreased school performance [160-168]. However, it is difficult to separate the impact of maternal smoking and other confounders. Studies that have adjusted for measured and unmeasured confounders have often found these adverse outcomes are not present or are related to familial or environmental factors associated with maternal smoking [169-172]. (See "Secondhand smoke exposure: Effects in children".)

Neonatal effects — Prenatal nicotine appears to have a dose-response effect on the neonate (from birth to 28 days of age) as demonstrated by the following studies:

●In two prospective studies, infants exposed to tobacco had increased signs of stress, hypertonicity, and excitability compared with the nontobacco-exposed group [173,174]. A dose-response relationship was demonstrated with higher maternal salivary cotinine values associated with neonatal signs of increased stress and excitability [173].

●A prospective cohort study of over 1700 mother-newborn dyads reported decreased high-frequency electroencephalographic patterns in neonates with prenatal tobacco exposure; the decrease in response was inversely proportional to the amount of tobacco exposure [175].

●In a large community-based prospective study, maternal smoking was associated with increased irritability and hypertonicity in neonates assessed by the Graham-Rosenblith Behavioral Examination of the Neonate [176]. Infants of mothers who smoked heavily (defined as one or more packs per day) had the greatest degree of irritability and increased muscle tone.

●In another study, evaluation of neurobehavior at 10 to 27 days demonstrated that neonates exposed to in-utero maternal smoking compared with matched unexposed controls were more likely to require increased handling and had poorer self-regulation [177]. These results suggest that postnatal effects of maternal smoking may be subtle and further studies are required to better understand the neonatal impact of maternal smoking during pregnancy.

●A prospective Finnish study of very low birth weight (birth weight below 1500 g) infants born between 2001 and 2006 demonstrated neonates with prenatal exposure to maternal smoking compared with those without in-uterine exposure had smaller frontal lobe and cerebellar volumes based on magnetic resonance imaging of the brain at term-corrected age [178]. Involvement of these areas is consistent with reports of prenatal smoking exposure and impairment of functions associated with the frontal lobe and cerebellar, such as emotion, impulse control, and attention [179,180].

However, there is no convincing evidence that prenatal nicotine exposure is associated with a neonatal withdrawal syndrome.

Long-term effects — Several postnatal morbidities of maternal smoking during pregnancy have been reported. There is a well-documented association between prenatal tobacco exposure and SIDS, but with the other following conditions, the relationship is less certain.

●Sudden unexpected infant death (SUID)/SIDS – Smoking is a risk factor for SUID, defined as infant death <1 year of age. In a birth cohort study conducted in the United States that evaluated self-reported smoking, any maternal smoking more than doubled the risk of SUID (adjusted OR 2.44, 95% CI 2.31-2.57) [181]. Smoking just one cigarette a day throughout pregnancy, compared with none, resulted in a twofold increased risk (adjusted OR 1.98, 95% CI 1.73-2.28). Women who reduced their smoking or quit during pregnancy decreased their risk of SUID by 12 to 21 percent, respectively; nearly one-quarter of women who smoked prepregnancy quit before the first trimester. This study is consistent earlier case-control data from multiple countries [182-185]. An observational national registry study reported elevated risks of SUID and SIDS with maternal snuff (non-combustible tobacco) use as well [186].

Similar to the risk of stillbirth, there appears to be a dose-response curve for SUID. In the previously cited United States birth cohort study, the probability of SUID increased linearly, by 0.07 odds per cigarette, in women who smoked 1 to 20 cigarettes per day; the risk plateaued for women who smoked more than 20 cigarettes per day [181]. (See "Stillbirth: Incidence, risk factors, etiology, and prevention".)

●Diabetes mellitus – Maternal smoking during pregnancy has been associated with an increased risk of type 2 diabetes. A study based on data from the British National Child Development Study reported that patients exposed to prenatal episodes of heavy maternal smoking (>10 cigarettes per day) had a fourfold increased risk of diabetes mellitus as young adults (16 to 33 years of age) compared with those without prenatal tobacco exposure [187].

●Cognitive ability – The impact of smoking on cognitive development is unclear, in part because cognitive development is a broad construct that is difficult to measure without long-term studies. Changes in cognitive function may not be apparent until years later. Furthermore, methods to assess tobacco exposure are often indirect, and there are multiple potential confounders such as polysubstance use and concurrent anxiety or use of psychoactive medications. Several cohort studies have reported an inverse association between maternal smoking during pregnancy and offspring cognitive ability [188-190]. However, in many of these studies, confounding variables (particularly maternal characteristics such as socioeconomic status, use of other drugs of abuse, and maternal cognitive ability) were not well controlled.

To address this issue, a study analyzed data from the United States National Longitudinal Survey of Youth 1979, which includes information on a wide range of potentially confounding maternal characteristics including maternal cognitive testing [191]. In an unadjusted analysis, intelligence quotient (IQ) scores were 2.9 points lower in children whose mothers smoked >1 pack of cigarettes during pregnancy compared with children whose mothers did not smoke. However, when maternal IQ and educational levels were controlled, there was no difference in IQ scores between the two groups of children. In contrast, in a different prospective study that followed 131 individuals to age 16 to 18, intrauterine tobacco exposure was associated with lower late-adolescent executive function after controlling for multiple confounders including demographics; intrauterine cocaine, marijuana, and alcohol exposures; early childhood lead exposures; and violence exposures [192].

●Behavioral problems – There have been several studies suggesting an increased rate of behavioral problems in children exposed to prenatal maternal smoking independent of postnatal maternal smoking and use of other drugs during pregnancy [193]. These findings include increased rates of conduct disorders in boys [160,161], adolescent-onset drug dependency in girls [160], and attention deficit hyperactivity disorder (ADHD) [179,180]. A meta-analysis of 20 studies (15 cohort and 5 case-control studies) reported a 60 percent increased risk of offspring ADHD in women who smoked (OR 1.60, 95% CI 1.45-1.76) [194]. While the meta-analysis confirms association, it does not explain causality as there are multiple potential confounding risk factors. A subsequent population-based study of over 1000 patients born between 1998 and 1999 and diagnosed with ADHD reported a dose-response relationship between risk of offspring ADHD and increasing deciles of maternal cotinine [195]. Another study of 1000 mother-child pairs reported that prenatal maternal smoking selectively increased the probability that female offspring would smoke [196].

●Pulmonary function

•Asthma risk – Maternal smoking has been associated with increased incidence of asthma in offspring [197-200].

•Potential epigenetic changes associated with maternal smoking – A study of 16 mother-child pairs in which the mother smoked during pregnancy reported genome-wide DNA methylation changes that differed between mother and child, maintenance of those DNA changes in the child over years of life, and association of these changes with regions that contribute to pulmonary function [201]. Thus, maternal smoking may result in epigenetic changes in the offspring that contribute to pulmonary disease. These epigenetic changes may be carried through generations, as suggested by a generational cohort study from the Netherlands that reported an association between grandmaternal smoking and increased asthma risk in male grandchildren [202].

•Potential mediation of smoking's effects with maternal vitamin C use – In a US multi-center trial comparing pulmonary function in children of pregnant patients who smoked and received either vitamin C supplementation or placebo, children in the vitamin C group had improved pulmonary function and less wheeze at five years of age [203]. Specifically, children of vitamin C recipients had 17 percent higher mean forced expiratory flow (FEF) 25-75 (1.45 versus 1.24 L/s; adjusted mean difference, 0.21, 95% CI 0.13-0.30), 4 percent increased FEV1 (1.13 versus 1.09 L, adjusted mean difference 0.05, 95% CI 0.01-0.09), and a 40 percent reduction in wheeze (28 versus 47 percent, estimated odds ratio 0.41, 95% CI 0.23-0.74).

●Schizophrenia – It remains unclear whether smoking during pregnancy is an independent risk factor mental health illness in offspring. A large nested case-control study conducted in Finland reported a higher maternal cotinine level, measured as a continuous variable, was associated with a greater than threefold increased odds (OR 3.41, 95% CI 1.86-6.24) of schizophrenia in their offspring [204]. Cotinine levels were measured from archived samples collected as part of the Finnish Maternity Cohort study, which had over 98 percent participation. There was also a dose-response with individuals with heavy exposure having the highest odds. This relationship remained significant after adjusting for potential confounders including parental mental health illness.

In contrast, a subsequent Swedish population-based study that adjusted for familial confounding by including data on siblings reported that the association between maternal smoking and severe mental illness was nonsignificant at both moderate and high levels of maternal smoking [205]. This study suggested that familial factors, and not maternal smoking, may be more responsible for the excess risk of mental illness. However, for purposes of this analysis, the study relied on maternal report of daily cigarette smoking quantity, which was typically recorded in the first trimester, and did not use cotinine levels. The authors justified this approach noting that in a separate validation study of antenatal visits, only 6 percent of those who denied smoking had cotinine levels consistent with active smoking. It is difficult to use these findings alone to dismiss the findings of the Finnish study.

●Neurologic disorders – Adjusted analysis of over 73,000 singleton pregnancies from the Danish National Birth Cohort reported a 66 percent increased risk of Tourette Syndrome (TS) and chronic tic disorders (CT) in children born to mothers who smoked 10 or more cigarettes daily while pregnant (ie, heavy smoking) [206]. Heavy prenatal smoking was also associated with a twofold increased risk of TS/CT with ADHD. Both light and heavy prenatal smoking were associated with a twofold increased risk of TS/CT with non-ADHD psychiatric comorbidity.

●Other effects – Other reported effects of prenatal maternal smoking include the following:

•Decreased sperm volume and count in adult male offspring [207].

•Earlier reproductive maturation and reduced fertility in prenatally exposed females [208-212].

•Decreased neonatal serum parathyroid hormone and 25-hydroxyvitamin D (25OHD) and increased serum phosphorus [213]. In contrast, 1,25-dihydroxyvitamin D was normal in exposed neonates.

•Sleep problems [214].

•Increased risk of offspring tobacco use in later life, independent of postnatal exposure to secondhand smoke [215,216]. Animal models support the biologic plausibility of this association and indicate that in utero exposure to maternal smoking can have a long-lasting impact on the neural pathways that affect lifetime sensitivity to nicotine [39].

•Increased risk of developing polycystic ovary syndrome in female offspring [217].

•Childhood hearing loss in cross-sectional and large cohort studies [218].

•Increased risk of bone fractures in offspring up to one year of age [219].

Breastfeeding — Cigarette smoking is associated with decreased milk volume production, lower milk fat concentration, and consequently, shorter duration of lactation [220-226]. Breastfed infants of smoking mothers slept less when fed after the mothers smoked recently than when they had abstained [227]. These infants have urinary cotinine levels up to 10-fold higher than bottle-fed infants of smoking mothers, and up to 50 times higher than infants of nonsmoking mothers [228]. (See "Secondhand smoke exposure: Effects in children".)

EFFECTS OF SECONDHAND SMOKE — Exposure to secondhand smoke during pregnancy also appears to have adverse effects on the fetus, child, and adult [229-232].

●In a 2011 meta-analysis of 19 studies that assessed the effects of secondhand smoke exposure on nonsmoking pregnant women, exposure to cigarette smoke significantly increased the risk of stillbirth (odds ratio [OR] 1.23, 95% CI 1.09-1.38; four studies), and congenital malformations (OR 1.13, 95% CI 1.01-1.26; seven studies), although none of the associations with specific congenital abnormalities were individually significant [229]. Secondhand smoke exposure had no significant effect on risk of miscarriage or perinatal or neonatal death.

●In a 2008 meta-analysis by the same authors, secondhand smoke exposure in nonsmoking pregnant women reduced mean birth weight by 33 g or more and increased the risk of birth weight below 2500 g by 22 percent, but had no clear effect on gestation or the risk of being small for gestational age (SGA) [232].

Although a study of the incidence of preterm birth in the Belgian population after implementation of smoke-free legislation in 2006, 2007, and 2010 noted a significant reduction in preterm birth after the introduction of each phase of the smoking ban, this finding was likely due to chance or confounders since the smoking bans had no significant effect on birth weight (mean birth weight, low birth weight, or SGA infant), which is more strongly correlated with smoking than preterm birth [233].

Data on the effect of exposure to secondhand smoke on fecundability are mixed. A prospective study and review suggested that any reduction is likely to be small [234].The effects of secondhand smoke on children and adults are discussed separately. (See "Secondhand smoke exposure: Effects in children" and "Secondhand smoke exposure: Effects in adults" and "Control of secondhand smoke exposure".)

RESOURCES FOR PATIENTS AND CLINICIANS

●The American College of Obstetricians and Gynecologists offers an online Frequently Asked Questions infographic on Tobacco and Pregnancy, available in both English and Spanish, free of charge.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Smoking cessation, e-cigarettes, and tobacco control" and "Society guideline links: Substance misuse in pregnancy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Smoking in pregnancy (The Basics)" and "Patient education: Secondhand smoke and children (The Basics)")

●Beyond the Basics topics (see "Patient education: Quitting smoking (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Although use of tobacco products, particularly cigarettes, has declined in general, pregnant individuals continue to smoke and use tobacco products. The true prevalence of tobacco use during pregnancy is difficult to discern, not only because of incomplete records, but also because most studies rely on self-reported tobacco-use behavior and are therefore subject to underreporting. (See 'Epidemiology' above.)

●Identifying maternal tobacco use – Identifying maternal tobacco product use allows for targeted interventions to prevent adverse pregnancy outcomes. All pregnant persons should be asked regularly about tobacco use. The strong social norms discouraging smoking while pregnant lead some individuals to fail to disclose their true smoking status, as detected by measurement of urine cotinine, a nicotine metabolite. (See 'Identifying maternal tobacco use' above.)

●Mechanisms of adverse pregnancy outcomes related to tobacco use – Mechanisms, observed and proposed, to explain the adverse pregnancy outcomes associated with maternal smoking include impaired fetal oxygenation, altered fetal development and physiologic response, toxin exposure, maternal genetic susceptibility, and fetal and placental epigenomic methylation changes. (See 'Pathophysiologic effects of smoking on pregnancy' above.)

•Adverse pregnancy outcomes – Cigarette smoking has been associated with numerous adverse pregnancy outcomes, including spontaneous pregnancy loss, placental abruption, preterm premature rupture of membranes, placenta previa, preterm labor and delivery, low birth weight (LBW), and ectopic pregnancy. (See 'Pregnancy' above.)

•Increase in smoking-related conditions – In addition to increasing the risk of subfertility, cigarette smoking may increase the rate of smoking-related conditions that are diagnosed or managed during pregnancy (eg, lung cancer, hypertension, asthma). (See 'Maternal' above.)

●Impact on child – Postnatal morbidities that have been associated with maternal smoking include sudden infant death syndrome, respiratory infections (eg, bronchitis, pneumonia), asthma, atopy, otitis media, infantile colic, bronchiolitis, short stature, lower reading and spelling scores, shorter attention spans, hyperactivity, childhood obesity, and decreased school performance [160-168]. A possible association has been reported with severe mental illness in the offspring, but the data are inconsistent. It is difficult to separate the impact of maternal smoking and other confounders. (See 'Postnatal' above.)

●Impact of secondhand smoke – Secondhand smoke exposure is associated with stillbirth and LBW. The effects of secondhand smoke on preterm birth and congenital anomalies are unclear. (See 'Effects of secondhand smoke' above.)