Fetal growth and development disorders in smoking pregnant women

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BACKGROUND

Studies have revealed that the most studied fetal complication of smoking during pregnancy is the low birth weight in newborns [1–5]. If impaired physical development is present, slow growth and malnutrition of the fetus (P05) are diagnosed in accordance with the International Classification of Diseases, 10^th Edition (ICD-10).

P05.0 Small fetus for gestational age. This usually refers to a condition when the body weight is less and the body height is greater than the 10^th percentile for gestational age. Low birth weight is used for the calculated term.

P05.1 Small fetus for gestational age. This usually refers to a condition when the body weight and height are less than the 10^th percentile for the gestational age. Small fetus is used for the calculated term.

P05.9 Unspecified fetal growth retardation and delayed growth (height) of the fetus not otherwise specified.

According to Suhag and Berghella (2013), fetal growth retardation (FGR) is established when the estimated fetal weight, calculated by biometric measurements, is less than the 10^th percentile for gestational age, that is, the starting point in assessing fetal development is the estimated weight [6]. In the clinical guidelines for obstetrics and gynecology [7], the term “FGR syndrome” is adopted if the estimated weight is less than the 10^th percentile for the gestational age. This group is heterogeneous. According to the clinical practice guideline on “fetal growth restriction” (2014), fetuses with developmental delay and an estimated fetal weight less than the 10^th percentile are divided into two subgroups, namely, low weight for gestational age (LWGA) and intrauterine growth retardation (IUGR). LWGA is characterized with a normal amount of amniotic fluid and normal indicators of dopplerometry in the umbilical cord arteries, while IUGR is characterized with oligohydramnios and/or pathological indicators of dopplerometry in the umbilical artery or when the estimated fetal weight is less than the 5^th percentile [8]. This terminology is supported by several researchers [6, 9, 10]. According to Suhag and Berghella (2013), the LWGA population is present in 40% of cases with constitutionally small fetuses, in 20% with genetic diseases or toxic effects (including maternal smoking), and in 40% of cases with disorders of the placentofetal blood flow or oligohydramnios, which enable diagnosis of IUGR in this group of fetuses with an estimated weight within the 5^th–10^th percentile [6].

Fetuses with FGR are divided into two groups:

1. With symmetric developmental delay, proportional delay in fetometric parameters of the fetus, and abdominal circumference (AC) and head circumference (HC) parameters less than the 5^th This develops at the end of the first trimester and early period of the second trimester of pregnancy.
2. With an asymmetric developmental delay, disproportionate disorders of fetometric indicators, and a deficit in the growth of AC with normal indicators of HC. This develops in third trimester [7, 11–13].

Lee et al. (2003) propose to divide fetuses with LWGA into three groups: 1) small for gestational age by weight (mass), 2) small for gestational age by height, and 3) small for gestational age by height and weight [4]. In the ICD-10 P05.9 section “Slow growth and lack of nutrition of the fetus,” change in only one anthropometric indicator, the height of the newborn, is envisaged. Thus, we consider it necessary to distinguish fetuses with delayed bone growth who mothers were smoking during pregnancy.

This study aimed to identify abnormalities in the growth and development of the fetus of pregnant women, who were smoking during pregnancy, at 30–34 weeks of gestation through three ultrasound screening sessions.

MATERIALS AND METHODS

Study design

Pregnant women, who consulted in the N.A. Semashko Northern Medical Clinical Center of the Federal Medical and Biological Agency of Russia, were examined during ultrasound screening. Screening of pregnant women was performed in accordance with the Order of the Ministry of Health of the Russian Federation No. 457 dated December 28, 2000, with additions from the Order of the Ministry of Health of the Russian Federation No. 808n dated October 2, 2009. A continuous examination of pregnant women was performed with three ultrasound screenings. Three screenings were performed in 1048 pregnant women.

Following the implementation of the inclusion and exclusion criteria, an examination cohort of 120 patients was formed. The nonsmoking group (group 1) 40 nonsmoking pregnant women, and the smoking group (group 2) included 80 pregnant women with tobacco addiction according to the Fagerström test “smoking pregnant women.” Since the “window of vulnerability” for exposure to tobacco smoke occurs during the pre- and peri-implantation period [14], the indicators of fetal development in the smoking group were compared in two subgroups, namely, subgroup 2a of women smoking only in the first trimester (embryonic period) and subgroup 2b of women smoking throughout pregnancy. All pregnant women signed an informed consent. The study followed a cross-sectional design.

Compliance criteria

The inclusion criteria were a singleton pregnancy, cephalic presentation of the fetus, presence or absence of smoking during pregnancy, and voluntary consent of the pregnant women for examination.

The exclusion criteria were alcohol abuse, intake of psychoactive substances, severe extragenital pathology, in vitro fertilization, and refusal to participate in the study.

Description of the medical intervention

In all pregnant women of the examined groups, the gestational age was calculated from day 1 of the last menstruation and correlated with the gestational age established at the first ultrasound screening. The screening protocol for ultrasound study followed the Order of the Ministry of Health of the Russian Federation No. 457, dated December 28, 2000 [15]. Values of the measured parameters were correlated with the biometric diagrams and tables of Merz [11] in accordance with the gestational age, indicating values in the 5^th–95^th percentile interval as normal, below the 5^th percentile as low, and above the 95^th percentile as high. In neonatology, birth weight less than the 10^th percentile for gestational age was considered low, and estimated fetal weight less than the 10^th percentile was regarded as low [11].

Main study outcome

The anthropometric data of newborns of the examined groups were assessed.

Statistical analysis

Statistical data analysis was performed using the SPSS 22.0 statistical software package for Windows. Quantitative characters are presented as the median (Me) and the first and third quartiles (Q₁; Q₃). Quantitative differences between the groups were assessed using the nonparametric Mann–Whitney test; Pearson’s χ² test was used to detect a relationship between two nominal variables. The level of critical significance was p ≤ 0.05.

RESULTS

A computer program was used to calculate the estimated fetal weight using the formula: Log10W = −1.7492 + 0.166 × × biparietal diameter + 0.046 ∙ AC – 2.646 (AC ∙ biparietal diameter)/1000 (cm, kg) [16], and fetometric parameters of the fetus were analyzed (Table 1).

 

Table 1. Fetometric parameters of the fetus in the nonsmoking and smoking groups of pregnant women

Indicators	Pregnant women, n (%)		р-level
	Group 1, n = 40	Group 2, n = 80
Biparietal diameter – normal – low – above normal	33 (82.5) 7 (17.5) 0 (0.0)	46 (57.5) 34 (42.5) 0 (0.0)	0.006
Frontal–occipital circumference – normal – low – above normal	36 (90.0) 2 (5.0) 2 (5.0)	70 (87.5) 9 (11.2) 1 (1.3)	0.265
Head circumference – normal – low – above normal	32 (80.0) 8 (20.0) 0 (0.0)	40 (50.0) 40 (50.0) 0 (0.0)	0.002
Abdominal circumference – normal – low – above normal	32 (80.0) 1 (2.5) 7 (17.5)	71 (88.8) 5 (6.2) 4 (5.0)	0.063
Femoral bone – normal – low – above normal	39 (97.5) 1 (2.5) 0 (0.0)	64 (80.0) 16 (20.0) 0 (0.0)	0.010
Shin bones – normal – low – above normal	39 (97.5) 0 (0.0) 1 (2.5)	71 (88.8) 9 (11.2) 0 (0.0)	0.035
Shoulder – normal – low – above normal	40 (100.0) 0 (0.0) 0 (0.0)	67 (83.8) 13 (16.2) 0 (0.0)	0.004
Forearm – normal – low – above normal	40 (100.0) 0 (0.0) 0 (00.0)	76 (95.0) 4 (5.0) 0 (0.0)	0.300

Note: p was calculated using the Pearson Chi-square test.

 

A significant difference in the smoking and nonsmoking groups of pregnant women was revealed in fetuses in terms of biparietal head size, HC, femoral bone length, leg bone length, and shoulder bone length. Fetometry disorders may be associated with FGR. Since the third screening is performed at 30–34 weeks of gestation, the estimated fetal weight in the smoking and nonsmoking groups of pregnant women was determined in accordance with the gestational age (Table 2).

 

Table 2. Estimated fetal weight in the nonsmoking and smoking groups of pregnant women

Fetal weight	Pregnant women, n (%)		р-level
	Group 1, n = 40	Group 2, n = 80
Normal Low Above normal	36 (90.0) 0 (0.0) 4 (10.0)	70 (87.5) 10 (12.5) 0 (0.0)	0.001

Note: p was calculated using the Pearson Chi-square test.

 

Fetal weight values over the 95^th percentile for gestational age were recorded only in the nonsmoking group. The estimated fetal weight less than the 10^th percentile for gestational age was recorded only in the smoking group (p = 0.001). In these 10 fetuses, based on the combination of low weight and low rates of fetal bone growth, a small fetal size for gestational age was established.

A comparative assessment of the weight of fetuses in groups of women who stopped smoking in the first trimester and those who were smoking throughout pregnancy was performed. Data are presented in Table 3.

 

Table 3. Estimated fetal weight in groups of women who stopped smoking in trimester I and those smoking throughout the pregnancy

Fetal weight	Pregnant women, n (%)		р-level
	Subgroup 2а, n = 40	Subgroup 2b, n = 40
Norm Low	36 (90.0) 4 (10.0)	34 (85.0) 6 (15.0)	0.499

Note: p was calculated using the Pearson Chi-square test.

 

Fetal weights below the 10^th percentile for gestational age were registered with nearly the same frequency in the two subgroups. This confirms the early symmetrical development of fetal disorder [7, 11].

The main fetometric parameters were assessed in fetuses without growth retardation of the long bones of the fetus to clarify the role of the toxic effect of tobacco smoke products on individual fetometric parameters. The results are presented in Table 4.

 

Table 4. Fetometric parameters in fetuses with no signs of bone growth retardation in the nonsmoking and smoking groups of pregnant women

Indicator	No signs of bone growth retardation according to ultrasound examination data, n (%)
	Nonsmoking, n = 35	Smoking, n = 47	р-level
Biparietal diameter – norm – low	32 (91.4) 3 (8.6)	38 (80.9) 9 (19.1)	0.180
Frontal–occipital circumference – norm – low – above normal	33 (94.3) 0 (0.0 2 (5.7)	45 (95.8) 1 (2.1) 1 (2.1)	0.483
Head circumference – norm – low	32 (91.4) 3 (8.6)	33 (70.2) 14 (29.8)	0.027
Abdominal circumference – norm – low – above normal	28 (80.0) 0 (0.0) 7 (20.0)	43 (91.5) 0 (0.0) 4 (8.5)	0.191

Note: p was calculated using the Pearson Chi-square test.

 

As shown in Table 4, in the absence of signs of fetal bone growth retardation in the smoking group of pregnant women, low HC values (<5^th percentile) were registered in fetuses significantly more often, which is consistent with the data of Ekblad et al. (2013), who demonstrated a dynamic decrease in the fetal HC growth rate in women smoking during pregnancy [10].

The anthropometric indicators of newborns in case of term delivery in the study groups were assessed (Table 5).

 

Table 5. Anthropometric indicators of newborns in nonsmoking and smoking groups of women during term delivery

Признак	Women, Me (Q1; Q3)		р-level
	Group 1, n = 38	Group 2, n = 75
Weight, g	3500 (3327.5; 3990)	3390 (3080; 3598)	0.087
Height, cm	53.0 (51.3; 54.0)	51.5 (50.0; 53.0)	0.040

Note: p was calculated using the Mann–Whitney test.

 

As shown in Table 5, the median weight of full-term newborns of smoking mothers was 110 g lower than that of nonsmoking mothers, but the differences were insignificant. The height of full-term newborns of the smoking group was significantly less (p = 0.040), which corresponds to the literature data [12].

DISCUSSION

The results of this study revealed that disorders in the growth and development of the fetus at 30–34 weeks of gestation in the smoking group are mainly manifested by a low estimated fetal weight for gestational age, low values of the length of tubular bones for gestational age, and low HC values for gestational age. Many researchers agree that smoking during pregnancy increases significantly the resistance of placental blood flow, which leads to FGR [17, 18]. The assumption was that FGR is the result of the influence of nicotine that causes vasospasm. However, Sastry believes that FGR is facilitated by a decrease in transplacental transfer of amino acids, since nicotine blocks cholinergic receptors and disrupts the transport of amino acids to the fetus [19].

Low estimated fetal weight for gestational age was revealed in 10 pregnant smokers, namely, four women stopped smoking in the first trimester and six women were smoking throughout the pregnancy. Low tobacco dependence (according to the Fagerström test) was noted in nine pregnant women, and only one patient had a strong degree of tobacco dependence. All pregnant women indicated that they smoked ≤10 cigarettes per day. Jaddoe et al. showed that when comparing groups of pregnant women who stopped smoking in the first trimester and those who continued to smoke 10 cigarettes per day, no significant difference was found in the risk of low birth weight in the children, which was consistent with our data [20].

In three pregnant smokers, the estimated fetal weight was below the 5^th percentile, which is the criterion for IUGR. In seven pregnant smokers, the estimated fetal weight was within the 5^th–10^th percentile interval, which was the basis for their inclusion in the FGR group. Three of these seven fetuses had impaired placentofetal blood flow, which allows them to be diagnosed with IUGR. In four patients, no disorders and signs of oligohydramnios were detected by Doppler examination, but since pregnant women were a high-risk (smoking) population, tobacco smoke products may have toxic effect on the fetus such as LWGA [10, 21, 22]. In this group, fetal congenital malformations were also found (agenesia of the left kidney). Thus, in the FGR group of fetuses, IUGR was diagnosed in six cases; therefore, case follow-up is required to predict the time of delivery, and LWGA was detected in four cases caused by the toxic effects of tobacco smoke products. Thus, it is necessary to study the curves of fetal weight and growth over time [11, 23, 24].

In an experimental study, Esposito et al. (2008) exposed pregnant mice to cigarette smoke during three different developmental periods, namely, pre-/peri-implantation period, post-implantation period, and entire gestation period. Intrauterine exposure to cigarette smoke during the pre-/peri-implantation period of mouse pregnancy inhibits fetal growth and results in significant weight loss at term pregnancy. Moreover, exposure to cigarette smoke during the post-implantation period of intrauterine development causes a decrease in the crown–rump length of the fetus and does not exert a significant effect on the fetal weight. In contrast to mass indicators, the crown–rump length decreased equally regardless of the period of exposure to tobacco smoke. Intrauterine exposure to tobacco smoke possibly induces a delay in intrauterine osteogenesis, which contributes to a delay in the intrauterine growth (height) of the fetus. Regardless of the period of exposure to tobacco smoke, minor ossification defects were detected. In our study, 16 fetuses of pregnant smokers had a retardation in the growth of the femoral bones (length <5^th percentile), six of them showed impaired growth of the femoral bones with an assumed weight of the fetus of more than the 10^th percentile, and three fetuses had retardation in the growth of femoral and humeral bones (length <5^th percentile). Since bone growth retardation in these six fetuses was not accompanied by low estimated fetal weight, isolated fetal bone growth retardation is probable. Prabhu et al. (2010) demonstrated a linear dose–response relationship between exposure to tobacco smoke in the first trimester and slowed growth of the femoral bone in the second trimester of pregnancy.

Mukhopadhyay et al. (2010) revealed significant changes in the gene expression in brain tissues in mice exposed to tobacco smoke. Tobacco smoke influenced changes in the expression of a number of genes that regulate key processes in the hippocampus, such as synaptic function, axonal control, neurogenesis, and apoptosis. In the absence of small weight and height for gestational age, significant changes in the expression of genes associated with the development and function of the hippocampus were noted [25]. These findings are consistent with other studies showing changes in the fetal brain development after prenatal exposure to tobacco, even in the absence of LWGA [26]. In our study, all fetuses with a low presumed weight had HC less than the 5^th percentile. Low indices of the HC are combined with low indices of the size of bones and abdomen and indicated a symmetrical type of FGR, which is combined with a normal AC/HC ratio in nine fetuses. In one fetus, whose mother smoked during the entire pregnancy, Doppler examination revealed AC/HC ratios of more than the 95^th percentile, which indicates the risk of fetal microcephaly [10, 11].

In the smoking group of pregnant women whose 14 fetuses do not have signs of bone growth retardation and with an estimated fetal weight more than the 10^th percentile, the HC values were less than the 5^th percentile with AC/HC ratios more than the 95^th percentile. This allows us to suspect growth retardation of the fetal head [7]. Our data are consistent with literature data, as Marroun et al. [27] revealed that cigarette smoking by mothers can lead to a decrease in the volumes of the brain, cortical gray matter, and white matter in children; Roza et al. showed that smoking during pregnancy can negatively affect fetal head growth [28].

Currently, many studies have confirmed that smoking during pregnancy causes fetal damage, and its molecular mechanism remains unclear [25, 29]. Several scientific works provide evidence that it is associated with aberrant epigenetic modifications [30, 31]. Owing to the widespread use of tobacco and the harmful effects of tobacco smoke products, measures should be taken to create a smoke-free environment for pregnant women. Providing education about the danger of smoking during pregnancy is necessary, and women of reproductive age should be motivated to quit smoking at the stage of pregnancy planning.

CONCLUSIONS

1. Low estimated fetal weight (less than the 10^th percentile) for gestational age was recorded only in the smoking group of pregnant women (p = 0.001) and in 90.0% of cases with low tobacco dependence. It was accompanied by low bone sizes and was found in 10.0% in the group of women who stopped smoking in the first trimester and in 15.0% in the group of women who were smoking throughout the pregnancy, which confirms the early formation of symmetric FGR.
2. In the smoking group, at 30–34 weeks of gestation, low (less than the 5^th percentile) values of fetometric parameters of bone growth were significantly more frequent, namely, length of the femoral bones (p = 0.01), length of the shin bones (p = 0.035), length of the shoulder bones (p = 0.004), biparietal diameter of the head (p = 0.006), and HC (p = 0.002).
3. In the absence of signs of fetal bone growth retardation and the estimated weight of the fetus is within the 10^th–95^th percentile, low HC values for gestational age (less than the 5^th percentile) were recorded significantly more often in the smoking group (p = 0.027) than in the nonsmoking group, that is, in 29.8% of cases, and the fetuses of these women had high AC/HC ratios that indicated retardation in fetal head growth.
4. Fetometry data are confirmed by anthropometric indicators of newborns at term delivery, that is, the height of full-term newborns born from smoking mothers is significantly low (p = 0.040).

ADDITIONAL INFORMATION

Funding. The work was performed within the Russian Humanitarian Science Foundation grant No. 14-16-29002: “A systematic approach to the prevention of the consumption of legal psychoactive substances (tobacco and alcohol) in pregnant women.”

Ethical considerations. Permission No. 06/6-12, dated June 13, 2012, was received to conduct a study from the independent ethical committee of the Saratov State Medical University.

Conflict of interest. The authors declare no conflict of interest.

About the authors

Ekaterina M. Gryzunova

Northern Medical Clinical Center named after N.A. Semashko

Email: gryzunova.ekaterina@yandex.ru
Russian Federation, Arkhangelsk

Alexey N. Baranov

Northern State Medical University

Author for correspondence.
Email: a.n.baranov2011@yandex.ru

MD, Dr. Sci. (Med.), Professor

Russian Federation, Arkhangelsk

Andrey G. Solovyov

Northern State Medical University

Email: asoloviev1@yandex.ru

MD, Dr. Sci. (Med.), Professor

Russian Federation, Arkhangelsk

Elena V. Kazakevich

Northern Medical Clinical Center named after N.A. Semashko

Email: secretary@nmcs.ru

MD, Dr. Sci. (Med.), Professor

Russian Federation, Arkhangelsk

Galina N. Chumakova

Northern State Medical University

Email: zelchum-neo@yandex.ru

MD, Dr. Sci. (Med.), Professor

Russian Federation, Arkhangelsk

Larisa G. Kiselyova

Northern State Medical University

Email: kis272@yandex.ru

MD, Cand. Sci. (Med.), Assistant Professor

Russian Federation, Arkhangelsk

References

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