From the Division of Research, Kaiser Foundation Research Institute, Kaiser Permanente, Oakland, CA.
Received for publication August 20, 2002; accepted for publication April 3, 2003.
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ABSTRACT |
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abortion, spontaneous; baths; cohort studies; epidemiologic studies
Abbreviations: Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval; KPMCP, Kaiser Permanente Medical Care Program.
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INTRODUCTION |
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Although experimental studies in animals have demonstrated that a body temperature elevated above normal (hyperthermia) results in resorption, abortion, and fetal death (14), the effect of hyperthermia on the risk of miscarriage in humans remains largely unknown. Of the limited number of studies of the effect of hyperthermia on human pregnancy outcomes, the majority focused on malformations (514). In addition, hyperthermia in those studies was, in most cases, due to fever usually induced by febrile infections (614). Therefore, it was often difficult to separate the effect of febrile infections from that of the resultant hyperthermia. Consequently, despite the evidence from animal studies, physicians still lack the data from human studies to advise pregnant women regarding the risk of hyperthermia due to the elevated temperature of external sources, such as hot tubs or Jacuzzis (any type of whirlpool bath; Jacuzzi Brands, Inc., West Palm Beach, Florida).
We sought to examine the effect of exposure to external heat sources on the risk of miscarriage in a population-based prospective cohort study. Specifically, we examined whether exposure to hot tubs or Jacuzzis during pregnancy increases the risk of miscarriage.
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MATERIALS AND METHODS |
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Of 2,729 eligible women, 164 (6 percent) were contacted too far along in their pregnancy (>15 weeks) for interview; 317 initially agreed to participate but were unable to schedule an interview; 1,185 (43.4 percent) refused to participate; and, ultimately, 1,063 (39 percent) completed the interview. "Too stressful" or "too busy" was cited most frequently as the reason for refusal (47.9 percent). In addition, the main exposure of interest was to magnetic fields, which required women to wear a meter that captured their exposure to magnetic fields. Some women were unwilling to do so (6.2 percent), or their husbands objected to their participation (11.1 percent). Miscellaneous reasons or no reasons given accounted for the remaining 34.6 percent of refusals. A more detailed description of the study design and methods can be found elsewhere (15).
Information on exposure to hot tub or Jacuzzi use during pregnancy was obtained during an in-person interview conducted soon after a womans pregnancy was confirmed (the median gestational age at interview was 71 days). The timing of initial use after the last menstrual period, the frequency of use, and the usual temperature setting for hot tubs or Jacuzzis were also ascertained, as was information on reproductive history, known or potential risk factors for miscarriage, and sociodemographic characteristics.
Pregnancy outcomes up to 20 weeks of gestation were determined for all participants through the following three methods: 1) searching the KPMCP inpatient or outpatient databases, 2) reviewing medical records, and 3) contacting participants whose outcomes could not be determined by using the previous two methods. Because, by definition, no miscarriage occurs after 20 weeks of gestation, pregnancy status was censored at 20 weeks of gestation for those pregnancies that continued beyond 20 weeks. We had information on pregnancy outcomes for every participant up to 20 weeks of gestation. More than 95 percent of miscarriages in our study population occurred before 15 weeks of gestation.
Because we recruited pregnant women during early gestation (median, 40 days), 103 of the 170 women who experienced miscarriages had already miscarried before the in-person interview was conducted. Those women were still included in the study although the information on their exposures, including use of hot tubs or Jacuzzis, was ascertained up to the time of miscarriage only. The median gestational age at miscarriage for all women who had a miscarriage was 64 days.
Cox proportional hazards regression was used to take into account possible different gestational ages at study entry between exposed (users of a hot tub or Jacuzzi) and unexposed (nonusers) participants (16, 17). Since miscarriage rates change with gestational age (higher during early gestation), not taking into account the variation in gestational ages at entry between the exposed and unexposed groups could have produced a spurious association between hot tub or Jacuzzi use and miscarriage. By using the Cox model with left truncation, we examined the association between exposure to hot tubs or Jacuzzis and the risk of miscarriage at any specific gestational age for only those women who had entered into the study and remained pregnant at that specific gestational age. Rather than assuming that all participants entered the study as soon as they conceived (gestational age = 0), as would have been the case if logistic regression had been used, the Cox model started to accumulate follow-up time only at the gestational age when a participant entered into the study (at her positive pregnancy test). In other words, the interval between conception and study entry was truncated in this case (i.e., treated as missing follow-up time). Using the Cox model also enabled us to easily assess whether the effect of the exposure to hot tubs or Jacuzzis on the risk of miscarriage changed with gestational age. Entry time was defined as gestational age at the positive pregnancy test because we started to follow a womans pregnancy at her positive pregnancy test. The median gestational age at entry for the entire cohort was 40 days. The follow-up time was gestational age in days. Gestational age was determined by ultrasound (16.4 percent), an obstetrician (50.9 percent), or the last menstrual period (32.7 percent).
The numbers of pregnancies for the initial risk sets were as follows: eight in the first risk set, 58 in the second risk set, 145 in the third risk set, 330 in the fourth risk set, 381 in the fifth risk set, and 432 in the sixth risk set. All participants were followed until 1) miscarriage, 2) termination of pregnancy due to other causes (e.g., ectopic pregnancy or induced abortion), or 3) 20 weeks of gestation.
Hot tub or Jacuzzi use was introduced into the Cox proportional hazards model as a time-dependent variable depending on the timing of initial use during pregnancy. A woman was considered exposed during the follow-up time after her initial use of a hot tub or Jacuzzi. The womans follow-up time between entry into the study and initial use was considered unexposed. Variables included in the model were confounders (changing hazard ratios by more than 20 percent) and known risk factors for miscarriage as well as common socioeconomic and demographic variables. Variables associated with only hot tub or Jacuzzi use but not the risk of miscarriage were not qualified as confounders and did not affect the estimates. Consequently, they were not included in the final model.
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RESULTS |
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After adjustment for the same variables, a maternal fever of 100°F (37.8°C) or higher during pregnancy was not associated with the risk of miscarriage (aHR = 1.0, 95 percent CI: 0.5, 2.1) in our study population.
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DISCUSSION |
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Second, the information on hot tub or Jacuzzi use was based on self-reporting; one could argue that inaccuracy due to self-reporting may lead to misclassification of the exposure. To assess this potential misclassification, we compared the median gestational age at interview for users and nonusers of a hot tub or Jacuzzi: 68 days for users and 72 days for nonusers. Therefore, the recall period was relatively short and comparable between users and nonusers.
Third, the participation rate in our study was relatively low. If women who used a hot tub or Jacuzzi and were destined to miscarry (exposed high risk) or women who did not use a hot tub or Jacuzzi and were not going to miscarry (unexposed low risk) were more likely to participate, the observed association may be explained by this bias. Because we did not have information on gestational age at study entry for nonparticipants, we could not meaningfully compare the risk of miscarriage between participants and nonparticipants. Low participation may also limit generalizability.
The majority of our participants did not use a regular bathtub (table 1). Use of a regular bathtub was not associated with the risk of miscarriage (aHR = 1.2, 95 percent CI: 0.8, 1.7), nor did it affect the association between hot tub or Jacuzzi use and the risk of miscarriage. We could not find any literature on the difference associated with raising core body temperature between hot tubs or Jacuzzis and regular bathtubs. Separating the effect of hot tub or Jacuzzi use from that of a regular bathtub showed similar results: the adjusted hazard ratios were 2.2 (95 percent CI: 1.0, 4.8) for use of both a hot tub or Jacuzzi and a regular bathtub, 1.9 (95 percent CI: 1.2, 3.2) for use of a hot tub or Jacuzzi only, and 1.2 (95 percent CI: 0.8, 1.8) for use of a regular bathtub only. We did not have information on use of a sauna or steam bath, both of which could be additional external heat sources, although their ability to raise body temperature may be limited because of perspiration. The lack of information on use of a sauna or steam bath may have led to misclassifying some women who were exposed to a sauna or steam bath only as belonging to the unexposed group. Because this potential misclassification applied to all participants regardless of their miscarriage status, thus being nondifferential, the effect of this misclassification was likely to attenuate the observed association. Furthermore, although the actual frequency of use in this particular study population is unknown, the reported prevalence of sauna use among pregnant women in other US populations is quite low (<1.6 percent) (5). Therefore, missing information on sauna use was unlikely to explain our findings. Finally, there was a relatively larger number of users of a hot tub or Jacuzzi who did not remember the water temperature settings, and we did not ascertain information on the length of use of a hot tub or Jacuzzi, both of which limited our ability to examine the temperature effect more extensively.
Survival analysis usually assumes that censoring and truncation are independent of the outcomes to be studied. This assumption may not always be true when studying pregnancy outcomes, especially for follow-up at early gestational ages. Compared with the entire cohort of pregnant women, those who enter into a study at early gestational ages (<78 weeks) could be either at a higher risk of miscarriage because of their history and symptoms related to miscarriage or at a lower risk because of their health consciousness, usually an indicator for being healthy. To test whether this potential nonindependence of left truncation would bias our estimates, we reanalyzed the data by excluding women who had a miscarriage less than 2 days after their positive pregnancy test in case their contact with the medical providers was due to their impending miscarriage, thus having a higher risk of miscarriage than those remaining at large (truncated). We also excluded the first 2 days of follow-up after study entry for all other women. The results were essentially the same (aHR = 1.9, 95 percent CI: 1.1, 3.0).
In this population-based prospective cohort study, we observed an increased risk of miscarriage with hot tub or Jacuzzi use after conception. There also seemed to be a dose-response relation because the risk increased with increasing water temperature and frequency of use. The association was also stronger when the exposure occurred during early pregnancy, when embryos and fetuses are more vulnerable to environmental risk factors. Animal studies have shown that early embryos are more sensitive to heat damage and require a less elevated body temperature (1.5°C) to result in death compared with more mature embryos (22.5°C) (1, 18, 19).
Of course, there might be alternative explanations for a stronger association related to use of a hot tub or Jacuzzi during early pregnancy. For example, symptoms of impending miscarriage, such as vaginal bleeding, might have prevented some women from initiating use of a hot tub or Jacuzzi beyond early pregnancy.
While it is often difficult to establish hyperthermia as the underlying cause for an observed association of miscarriage with fever from illnesses such as febrile infections because of the difficulty of separating the effect of fever itself from the causes of fever, the association of prenatal hot tub or Jacuzzi use with miscarriage may provide more direct evidence of hyperthermia as the potential underlying cause. Although one can always speculate that something else (e.g., infectious agents in the water) may be the underlying cause, our findings that the risk of miscarriage increased with increasing water temperature setting is more consistent with a direct effect of high temperature. Nevertheless, we did not directly measure a womans temperature, and a significant number of women who reported use of a hot tub or Jacuzzi did not remember its temperature setting (table 2).
We did not observe an association between self-reported fever above 100°F (37.8°C) and miscarriage. It could be that a temperature of 100°F was not high enough to reach the threshold that would increase the risk of miscarriage. Unfortunately, we did not have information on specific temperatures above 100°F. However, a recent study also did not find such an association (20). Although a lack of association between fever and miscarriage may be considered inconsistent with the hypothesis of hyperthermia, a hyperthermic effect on a fetus from fever and external sources of heat could be very different and is currently unknown. We also did not observe an association between use of a hot tub or Jacuzzi during the current pregnancy and a history of subfertility (table 1). However, in our study, a history of subfertility was defined as self-reported lifetime episodes of having unprotected intercourse for 12 months or more without becoming pregnant. Since we did not ascertain use of a hot tub or Jacuzzi during the period of reduced fertility, the lack of an association may not be informative to the association between hot tub or Jacuzzi use and the risk of subfertility.
If the underlying mechanism for the association between hot tub or Jacuzzi use and the risk of miscarriage is increased core body temperature, it is conceivable that embryos and early fetuses are more vulnerable to the effect of hyperthermia than their mothers are. Therefore, a detrimental effect on embryos or fetuses could occur before maternal intolerance to hyperthermia becomes apparent. On the basis of animal studies, the hypothesized mechanisms for the deleterious effect of hyperthermia include direct heat damage to cells, placenta, and the vascular system (1, 21) and damage due to heat-induced heat shock response. Heat shock response is the cellular response to stress caused by hyperthermia. Through a process still not well understood, strong heat shock response could eventually lead to cell death (1).
To our knowledge, this study observed for the first time an association between exposure to external heat sources and an increased risk of miscarriage. Our finding needs to be further verified in future studies. In our study population, about 10 percent of the pregnant women had used a hot tub or Jacuzzi by the time of our interview, and the proportion is likely higher because our interview was conducted early in pregnancy.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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