Discussion

Substances included in tobacco smoke have highly toxic properties. Their presence in the human organism may affect placental and fetal cell proliferation and differentiation. Thus, cigarette smoking raises the risk of miscarriage, fetal growth restriction, preterm births, and placental abruption. ^{Reference Jauniaux and Burton16} Cigarette smoke induces premature aging of the placenta as well as degenerative changes. The latter are accompanied by a large quantity of collagen in chorionic villi, greater thickness of the subtrophoblastic basement membrane, and reduced vascularization. Premature aging is caused by the increased number of syncytial buds and a higher rate of apoptosis. Both, premature aging and degenerative changes may reduce the functional component of placenta and result in an unsuccessful pregnancy outcome. ^{Reference Ashfaq, Janjua and Nawaz17} A significant loss of trophoblasts and syncytial buds due to apoptosis among smoking women may disrupt their hormonal balance, leading to premature labor and preterm births.

Based on the abovementioned data, we conclude that smoking during pregnancy is a risk factor for preterm birth. In the present study, nearly 14% of women smoked during their pregnancy. The rates of preterm births were directly proportional to the severity of smoking. Nonsmoking women had a preterm delivery rate of 6.8%, whereas women who were very heavy smokers (≥22 cigarettes/day) had a preterm delivery rate of 13.2% The largest increase was noted between nonsmokers and mild smokers (1–7 cigarettes/day), and between moderate (8–14 cigarettes/day) and heavy (15–21 cigarettes/day) smokers. In other words, even a low rate of maternal smoking has a marked effect on preterm birth rates. Very heavy smoking (≥22 cigarettes/day) had a major impact on extremely preterm births (<28 weeks of gestation) and very preterm births (28–31 weeks of gestation).

Fetal gender was also correlated with preterm births. Preterm infants were more frequently boys than girls, with the exception of the infants of very heavy smokers. Although the percentages were not very high, the analysis yielded statistical significance because of the large number of births included in the study.

A number of study groups have addressed the relationship between smoking and preterm birth. A Swedish population-based cohort study analyzed 1,372,274 singleton births between 1999 and 2012. The risk of preterm birth was determined among women who used snuff and smoked. The use of Swedish snuff or smoking during pregnancy was specifically associated with a high risk of extremely preterm birth (<28 weeks of gestation). Maternal smoking during early pregnancy was associated with a higher risk of all categories of preterm birth. The risk was inversely proportional to gestational age, and the association was dose dependent. ^{Reference Dahlin, Gunnerbeck, Wikström, Cnattingius and Edstedt Bonamy3}

The abovementioned data are nearly consistent with the findings of the present study. However, among smokers, we noted a higher rate of moderately preterm births (32–36 weeks of gestation) compared to extremely and very preterm births. Among very heavy smokers (≥22 cigarettes/day), we noted a higher rate of extremely and very preterm deliveries. These differences between the Swedish study and ours might be explained by the different numbers of cases. The Swedish study comprised nearly sixfold higher numbers of cases than ours, and yielded a larger number of extremely and very preterm infants.

Another study from the Netherlands consisting of 7098 pregnant women analyzed the effect of active and passive maternal smoking during pregnancy, and the risks of low birth weight and preterm birth. ^{Reference Jaddoe, Troe and Hofman18} Active smoking until pregnancy was apparently not associated with low birth weight and preterm birth. However, ongoing active smoking even in late pregnancy was associated with low birth weight (adjusted OR 1.75 (adjusted OR 1.75; 95% CI 1.20, 2.56) and preterm births (adjusted OR 1.36; 95% CI 1.04, 1.78). These data show that smoking exerts a negative effect when the noxious agents are inhaled during pregnancy. The long-term effects of smoking on the cardiovascular system and the risk of bronchial carcinoma are undisputed, but smoking does not appear to exert a harmful effect on pregnancy when the women cease to smoke at the very start of their pregnancy. Smokers should therefore be encouraged to stop smoking in the first trimester, or better still when planning a pregnancy.

This conclusion has been endorsed by several authors who reported that maternal smoking is an important risk factor for preterm delivery, but the risk can be reduced by the cessation of smoking before or at least in the early weeks of pregnancy. ^{Reference Dahlin, Gunnerbeck, Wikström, Cnattingius and Edstedt Bonamy3,Reference Shah and Bracken19,Reference McCowan, Dekker and Chan20}

Furthermore, preterm births constitute an economic problem because the infants must necessarily undergo treatment in neonatal intensive care units.

In a study conducted by a German statutory health insurance, the average costs of medication, hospital treatment, outpatient treatment, and nonmedical remedies during the first 3 years after birth were analyzed for early preterm, late preterm, and full-term births. As expected, higher costs were incurred for preterm infants than for those born at term. The highest costs were registered for the hospital treatment of early preterm births. The differences in costs tended to fall in the second and third years after birth, except for ambulatory treatment costs; the latter were consistently high especially for early preterm births. ^{Reference Jacob, Lehne, Mischker, Klinger, Zickermann and Walker21}

Another study from the USA ^{Reference St John, Nelson, Cliver, Bishnoi and Goldenberg22} analyzed the costs of initial hospital care for newborn infants according to gestational age. The retrospective review included all infants born ≤32 weeks of gestation between 1989 and 1992. A cohort of term and near-term infants was selected at random. The total cost of initial care for the US population of neonates was estimated at $10.2 billion annually: 11.9% was spent on infants born between 24 and 26 weeks of gestation and 42.7% were spent on those born at ≥37 weeks’ gestation. Thus, 45.4% of the costs are distributed among those newborns born between 27 and 36 weeks of gestation. Although the costs for an extremely premature newborn are very high, the costs for extremely low gestational age infants are a small component of total neonatal care costs because so few infants are born at these early gestational ages. ^{Reference St John, Nelson, Cliver, Bishnoi and Goldenberg22}

Clements et al. ^{Reference Clements, Barfield, Ayadi and Wilber23} have also investigated the costs of preterm infants as a function of gestational age: 14,033 of 76,901 surviving infants received early intervention. The total sum was almost $66 million, with a mean cost per surviving infant of $857. Mean cost per infant was highest for children who were 24–31 weeks’ gestational age ($5393) and higher for infants who were 32–36 weeks’ gestational age ($1578) compared with those who were born at term ($725). ^{Reference Clements, Barfield, Ayadi and Wilber23} Premature newborns have higher treatment costs compared to term-born infants. The cost per surviving infant generally decreased with increasing gestational age.

Considering the abovementioned numbers, the aim should be – not only against the economic background but also with regard to morbidity and mortality – to prolong the pregnancy as far as possible in every phase of preterm birth.

In addition to the risk of premature birth as a result of maternal smoking, the latter had an effect on fetal gender: preterm infants were more often boys than girls.

The greater mortality risk for males during pregnancy and infancy are well known. Male preterm infants have higher rates of neonatal mortality and are more vulnerable to long-term neurological and motor impairment after birth. ^{Reference Verloove-Vanhorick, Veen, Ens-Dokkum, Schreuder, Brand and Ruys24-Reference Stevenson, Verter and Fanaroff26} A study group from the Netherlands analyzed the relationship between gender and disabilities or handicaps at 5 years of age in children born before 32 weeks of gestation. ^{Reference Verloove-Vanhorick, Veen, Ens-Dokkum, Schreuder, Brand and Ruys24} The study comprised 648 infants, of whom 345 were boys. The prevalence of handicaps was three times higher among boys than girls (21% vs. 7%, OR 3.2). Adjustment for gestational age and birth weight (logistic regression analysis) did not alter the results (OR 3.5).

On the basis of large datasets, the numbers of boys among preterm infants versus infants born at term were analyzed in several studies; ^{Reference Zeitlin, Saurel-Cubizolles and de Mouzon10,Reference Astolfi and Zonta27} a predominance of males was noted among preterm births. Several explanations have been proposed for this phenomenon: (a) higher average maternal body weight, which increases the probability of preterm labor, ^{Reference Hall and Carr-Hill28,Reference McGregor, Leff, Orleans and Baron29} (b) greater sensitivity to certain medical complications associated with preterm birth, such as pregnancy-induced hypertension or infection, ^{Reference MacGillivray and Davey30} (c) different biochemical processes in male and female fetuses, which favor preterm labor in the case of male infants. ^{Reference Cooperstock and Campbell31} Placental or chorion trophoblast cells from pregnancies with a male fetus seem to produce more pro-inflammatory TNFα and less anti-inflammatory IL-10 and granulocyte colony-stimulating factor (G-CSF) than cells from pregnancies with a female fetus, more prostaglandin synthase (PTGS-2) and less prostaglandin dehydrogenase (PGDH). These results suggest that in the presence of a male fetus the trophoblast has the potential to generate a more pro-inflammatory environment leading to preterm birth ^{Reference Challis, Newnham, Petraglia, Yeganegi and Bocking32} and (d) boys are more likely conceived at the beginning of the fertile period in contrast to girls, who are conceived in the middle of the cycle. ^{Reference James33,Reference James34}

This last mentioned hypothesis was refuted by a French study, which only recruited children after IVF and was thus able to clearly determine the time of conception. The association between preterm birth and the male sex was somewhat less pronounced, but still present. ^{Reference Astolfi and Zonta27}

Despite these explanatory approaches concerning gender-specific preterm delivery, the pathomechanism is not really understood. A higher body weight or early conception in the menstrual cycle does not appear to adequately explain the higher rate of preterm delivery at 6 weeks before, or even earlier than, the calculated day of delivery.

A large study from the Netherlands Perinatal Registry consisting of 1,736,615 singleton pregnancies from 1999 to 2010 ^{Reference Peelen, Kazemier and Ravell9} analyzed the gender-related risk of preterm birth. The authors found that male fetuses were at higher risk of preterm birth with intact membranes compared to female fetuses; the peak was noted between 27 and 31 weeks of gestation (relative risk (RR) 1.5; 95% CI 1.4–1.6). Furthermore, male fetuses were associated with a higher risk of premature rupture of membranes between 27 and 37 weeks of gestation (RR 1.2; 95% CI 1.16–1.23). No remarkable gender difference was registered among medically indicated preterm births. ^{Reference Peelen, Kazemier and Ravell9}

Zeitlin et al. ^{Reference Zeitlin, Saurel-Cubizolles and de Mouzon10} analyzed one European and three French data sources, as well as data extracted from published articles, to explore the gender distribution of preterm versus term births. Male infants are subject to a higher risk of preterm birth in a wide range of populations, regardless of geographical conditions and over a long period of time. The ORs associated with the male gender were between 1.09 and 1.24 in 21 of the 24 populations. ^{Reference Zeitlin, Saurel-Cubizolles and de Mouzon10}

In another investigation, the same study group ^{Reference Zeitlin, Ancel, Larroque and Kaminski35} analyzed the association between fetal gender, mode of onset of labor, and the principal cause of very preterm birth. Two-thousand and six twenty-four very preterm singleton births born at less than 33 weeks’ gestation in 9 French regions in 1997 were included in the study. Spontaneous preterm births were registered for 57% of male fetuses and 50.8% of infants were born prematurely due to medical indications. These data show that male infants have a higher risk of preterm birth resulting from spontaneous labor. ^{Reference Zeitlin, Ancel, Larroque and Kaminski35}

In the present study, we focused on smoking and gender-related preterm delivery (≤36 weeks of gestation), but did not differentiate between the weeks of gestation. Nevertheless, our results confirm the previously reported data. A significantly larger number of preterm infants were male among nonsmokers and nearly all smoking groups, except for very heavy smokers (≥22 cigarettes/day). Preterm deliveries were highest in the latter group but the numbers were independent of gender. This might be explained by massive placental alterations, which may raise the number of preterm deliveries regardless of the child’s gender. The placenta itself could be an important, yet not fully investigated parameter, and may well be a factor involved in the fetal gender-related outcome. The beginning of labor is known to be associated with the production of placental corticotropin-releasing hormone and corticotropin-releasing hormone-binding proteins, and inflammatory processes or interactions between these different mechanisms. ^{Reference Kim, Shim and Sung36,Reference Muglia and Katz37} Interestingly, increased levels of inflammatory markers were found more often in the placenta of male infants than female infants. ^{Reference Peelen, Kazemier and Ravell9,Reference Ghidini and Salafia38,Reference Clifton39} Furthermore, the placenta of female fetuses appear to react differently and is possibly more resistant to adverse events. ^{Reference Peelen, Kazemier and Ravell9,Reference Clifton39} The role of placenta and gender must be addressed in future investigations.

Preterm labor leading to preterm delivery is a multifactorial problem. Clinicians should give greater attention to women carrying a male fetus. This additional risk factor should be taken into account when dealing with high-risk pregnant women, and may help in decision-making processes such as tocolysis or antenatal steroid prophylaxis. This approach is further justified by the higher mortality rates noted in male fetuses.