According to the data from the 2009–2011 period by the Korea Statistical Office, in 2012, the incidence of infant deaths under 1 year of age was 3.0 per 1000 live births, the maternal mortality rate was 17.2 per 100,000 live births, and the perinatal mortality rate was 3.1 per 1000 live births for neonates who were born over 28 weeks’ gestational age and who were less than 7 days old . These data encompassing the present study period included 1677 deaths among 7498 victims of ILD caused by HD exposure, with a mortality rate of 22.4% . In the present study, 17 neonates (14.3%) and 27 mothers (55.1%) died among 49 mothers who used HDs during pregnancy. The observed high mortality rate among the pregnant women in the present study may be attributed to specific immunological changes during pregnancy. There are several effects of HDs on the fetus during pregnancy: 1) increase in maternal blood concentration of the medication which can directly affect the fetus given that the medication can pass through the placenta ; 2) metabolites that accumulate when medication concentrations increase in the mother’s body which can impact the fetus via inflammatory mediators , hormones , and toxins ; 3) deterioration of the maternal physical condition caused by the medication (repair or damage to several organs) which can affect the fetus; and 4) disruption of implantation due to medication effects .
The placenta, through which medications pass and are delivered to the fetus, also serves to filter the substances that pass through. The placenta is a metabolically active tissue that responds to the maternal environment, including perturbations during pregnancy, by regulating the fetal supply of nutrients and oxygen and the secretion of hormones into the maternal and fetal circulation . Importantly, there might be differences in the transplacental transfer of medications due to significant functional differences of the placenta between the first two months of pregnancy (histiotrophic nutrition) and later in pregnancy (hemotrophic nutrition) . In some cases, inflammatory mediators secreted from the mother can cross the placenta and affect the fetus . Inflammatory processes in mothers can cause premature birth  and fetal damage regardless of preterm birth . One study investigating the effects of persistent inhalation of chemicals by mothers reported that birthweight decreased with increasing exposure to contaminants , which is in agreement with the results of the subgroup analysis based on fetal survival performed in the present study. Our findings suggest that both pregnant women and neonates in the present study experienced not only direct lung damage but also systemic adverse effects caused by HDs through inhalation.
The analysis of pregnant women with their fetuses categorized according to maternal survival revealed that survival was related to the total duration of HD use, especially the duration of pre pregnancy HD use. These results may be associated with not only the direct effects of HDs but also rapid worsening of symptoms due to the progression of damage to various maternal organs, especially the lungs, with continuous exposure. Longer duration of HD use was associated with decreased maternal-fetal survival, consistent with studies reporting that HD use exacerbates HDLI in a dose-dependent manner .
Regarding immune tolerance that occurs during pregnancy, according to the “evolutionary non-self model,” the presence of fetal antigens at the maternal-fetal interface does not necessarily activate the immune system. “Danger” and related models assert that danger signals are not expressed as long as the fetus is growing and developing normally and that the immune system is not activated to become harmful to the fetus. In the present study, the subgroup analysis based on maternal survival revealed that the onset of clinical symptoms after childbirth was associated with survival. In addition, the subgroup analysis based on fetal survival indicated that chances of maternal survival increased as time from the onset of clinical symptoms to birth diminished. However, maternal mortality increased in cases where the symptoms occurred before childbirth, indicating that the receptor-mediated immune response is activated in the presence of infection to protect the mother. Eventually, the change in the immune status of the mother due to HD use means that exceeding the threshold for immune tolerance is recognized as a “danger” state, leading to the deployment of a rapid immune response .
In mothers exposed to hazardous chemical material, the fetus may not be implanted or the neonate might have a lower birth weight . In the present study, we performed subgroup analysis to determine the effect of HD exposure on trimester-specific survival rates. To this end, we grouped prepregnancy with the first trimester and the second trimester with the third trimester to evaluate exposure duration because the first trimester of pregnancy is considered to be a vulnerable period for implantation and fetal organ formation. In the first trimester, various issues, including abnormalities in the endocrine system, can have a critical impact on fetal development after fetal exposure to hazardous substances . However, in the current study cohort, there were no cases of exposure in the first or third trimester in the subgroup with fetal and maternal death; therefore, statistical analysis could not be conducted. It is possible that exposure might lead to implantation difficulties in the first trimester. Additionally, the symptoms of mothers appeared before the 27th week in the group with both fetal and maternal death; therefore, there was no HD use in the third trimester in this group.
In Korea, summer is humid whereas spring, autumn, and winter are dry. Thus, we determined the survival rates specifically in summer and non-summer seasons and found that the proportion of mothers who became pregnant was higher in the spring and summer when HD use began to decline than in autumn and winter when HD use began to increase. One possibility is that an implantation disruption may occur when pregnancy starts in the autumn and winter during which HD use is relatively higher .
The current study has several limitations. First, the exact concentration and capacity of HD use and total seasonal consumption could not be confirmed. The information on HD use was obtained from blinded medical records and retrospectively reviewed; therefore, data to estimate HD concentrations, such as room size, average humidifier usage period, season of use, ventilation status, could not be obtained. To compensate for this limitation, converted dates were used, such as the date from the start of each event, seasonal classification, and trimester of exposure during pregnancy. Second, while we aimed to use objective data from the collected information, we cannot rule out recall bias over time. Third, the specific link between the effects of the maternal condition, such as hypoxia, hormones, inflammatory factors, abnormalities in metabolic processes, on fetal growth are unknown. Fourth, it is difficult to confirm the long-term consequences of HD exposure during the fetal period and to determine whether HD exposure affects the future growth and development of neonates, even those with no abnormalities at birth. Fifth, in mothers who are exposed to HDs, it is necessary to consider the individual differences in maternal reactions. Sixth, regarding premature babies, the differences in medical technology and development over the past 10 years might have affected mortality. Finally, we were not able to compare pregnant women who used HD with age-matched non-pregnant women who used HD or with age-matched pregnant women who did not use HD because women with no clinical symptoms did not use medical services or give specific information about their HD use. Because of this limitation, we analyzed the data as a nested case-control study including subjects who used HD during pregnancy.
Despite these limitations, the current study investigated the rarely considered relationship between maternal and fetal survival in response to HD exposure, specifically including data on fetal survival in response to maternal inhalation exposure to small amounts of chemically hazardous substances with definitive maternal adverse effects. HDs do not generally have hazardous effects in humans; a large population throughout Korea has been exposed to HDs for a long duration. The present study included patients with clear respiratory symptoms. Because of various ethical and moral concerns, it is difficult to determine the effect of HD use in pregnant women. As a major strength, this is the first study investigating the survival of neonates born to mothers who were exposed to HDs during pregnancy.