Table 3:

Survey of Studies Concerned with Ambient Temperature Exposure and Congenital Malformations

First Author, Year Study design: size, location, years	Exposures and method of assessment	Outcomes	Results	Key findings	Newcastle-Ottawa Quality Assessment Scale Score
Agay-Shay, 2013 PMID: 23739216 Registry-based retrospective cohort study, 135, 527 live and stillbirths in the Tel-Aviv region of Israel in 2000–2006	Average ambient temperature and extreme heat events (>90th percentile); data from automatic monitoring stations in Tel-Aviv region (half-hourly measurements), Israeli Ministry of Environmental Protection and the Israel Electric Corporation	Congenital heart defects	-After stratifying by season of conception, continuous exposure to average ambient temperature and maximum peak temperature (1°C increase) during the cold season increased the risk for multiple clinical heart defects [odds ratio (OR) 1.05, 95% confidence interval (CI): 1.00, 1.10 and OR 1.03, 95% CI: 1.01, 1.05, respectively]. A 1-day increase in extreme heat events increased the risk for multiple clinical heart defects (OR 1.13, 95% CI: 1.06, 1.21) and also for isolated atrial septal defects (OR 1.10, 95% CI: 1.02, 1.19).	Maternal exposure to extreme heat days during the cold season (weeks 3–8 postconception) increased the risk for multiple CHDs and isolated ASD cases	5/9
Aminzadeh, 2010 PMID: 20956721 Case control study, 47,075 births in Iraq from 2006–2008	Ambient temperature exposure (average monthly from meteorological station)	Suspected or confirmed congenital hypothyroidism (CH)	- The lowest proportion of births for those suspicious for CH and those with confirmed CH in summer were 19.9% and 13.4%; their highest frequencies in winter were 31.3% and 35.2%, respectively. -32.4% of cases born in warm period and 67.6% of cases were born in cold period -The traditional warmest (July/August) and coldest (January/February) months were the exact time of nadir (2.8%) and peak (15.5%) for CH. -The fifth month (July/August) was the warmest month at 28.3 – 50C (AMT=38.98C) and correlated with the lowest incidence of CH. -The tenth month (January/February) was the coldest month at 20.2 – 23.9C (AMT=11.15C) and correlated with the highest incidence of CH -Relationship between the occurrence of CH and average temperature at the time of birth (Spearman’s rho correlation method. r= 0.87; P< 0.001) -For each 1 degrees C increase in temperature at the time of birth, infants were 4% less likely to be a case of CH (OR 0.96, 95% CI 0.94 – 0.98; P,0.001).	The prevalence of CH was negatively correlated with temperature – the risk of delivering an infant with CH was significantly higher during the cold season and lower during the warm season regardless of sex. Geographical region is of interest due to extremely hot summers (mean temperature > 50 degrees C) and cold winters (mean temperature < 0 degrees C)	5/9
Auger, 2017 PMID: 27494594 Retrospective cohort study, 704,209 fetuses between 2–8 weeks post conception from April-September in Quebec, Canada, 1988– 2012	Exposure to maximum temperature ≥ 30°C; data from 18 meteorological stations representative of each health region in Quebec from Environment Canada	Congenital heart defects (both critical and noncritical)	-Fetuses exposed to 15 days of temperature ≥ 30°C between 2 and 8 weeks post conception had 1.06 times the risk of critical defects (0.67, 1.67) and 1.12 times the risk of noncritical defects (0.98, 1.29) relative to 0 days exposure. Associations strengthened progressively as more days of exposure to temperatures ≥ 30C.	First trimester extreme heat exposure may be associated with noncritical heart defects, particularly atrial septal defects.	6/9
Auger, 2017 PMID: 27881468 Retrospective cohort study, 3–4 weeks postconception for 887,710 fetuses in utero in Quebec between 1988–2012	Maximum daily/weekly temperature (historical weather data from meteorological station)	Neural tube defects: spina bifida & anencephaly/encephalocele	Compared to 20°C, a maximum daily temperature of 30°C was associated with 1.56 times the risk of any neural tube defect on day 5 (95% CI 1.04 to 2.35) and 1.49 times the risk of day 6 (95% CI 1.00 to 2.21) of the fourth week postconception which fell between April and September. The prevalence of spina bifida was slightly higher for maximum weekly temperatures of ≥30°C during the fourth week post-conception compared with 20–24.9°C [29.5 per 100 000 (95% CI 21.3 to 37.8) vs 25.0 per 100 000 (95% CI 18.2 to 31.7].	The risk of neural tube defects was weakly associated with elevated ambient temperatures between April and September – the prevalence of spina bifida was slightly higher for maximum weekly temperatures of ≥30°C during the fourth week postconception.	6/9
Gu, 2007 PMID: 17956160 Retrospective Study, 1,586 participants identified as having CH by neonatal screening in Japan from 1994–2003	Monthly average temperatures at 11 main observatories in Japan were obtained from the electronic database of the Japan Meteorological Agency	Congenital hyperthyroidism (at birth— neonatal screening)	-A statistically significant negative correlation was observed between monthly incidence and monthly average temperature among males (Spearman r = −0.84, n = 703, p < 0.001), females (Spearman r = −0.82, n = 876, p < 0.001), and total cases (Spearman r =− 0.89, n = 1586, p < 0.001).	Higher incidence of CH was associated with lower temperature in both males and females. The highest incidence of cases occurred when the average temperature was 5.4C (January). Warm temperature at birth were unrelated to CH, conception period was not addressed.	4/9
Judge, 2004 PMID: 15367322 Case control study, Cases and controls (845 cases, 1983 controls) were drawn from the population of all liveborn infants born in New York state (all 14 counties) from 1988–1991	Participants reported number of hours/week spent in ‘extreme cold (<0 degrees F)’, in ‘extreme heat (>100 degrees F)’, and number of times/week they used a ‘hot bath, hot tub or sauna’ during the ‘before’ and ‘early’ stages of pregnancy; data collected 3–8 years after infant’s birth	CCM (congenital cardiovascular malformations)	-No significant increased risk of CCM was found in mothers who reported exposure to extreme heat (> 100F) early in pregnancy (OR = 1.13,95% CI 0.59, 2.19) or exposure to extreme cold (< 0F) (OR = 1.19, 95% CI 0.66, 2.15). Reported use of a hot tub, hot bath, or sauna during early pregnancy had no increased risk of CCM in offspring (OR = 0.88, 95% CI 0.65, 1.18).	In early pregnancy, no significantly increased risk of CCM was found in mothers who reported exposure to extreme heat, exposure to extreme cold, or use of hot tub/hot bath/sauna.	9/9
Kilinc, 2016 PMID: 27567375 Retrospective case-control study, children whose gestational periods (8–14 weeks) occurred in the Ankara and Istanbul regions and who had hypospadias repair or other urological treatments between 2000 and 2015	The monthly maximum and average temperatures measured in Ankara and Istanbul were obtained from the records of the Turkish General Directorate of Meteorology	Hypospadias repair or other urological treatments (circumcision, urinary tract infection, pyeloplasty, nephrolithotomy, etc.)	-For patients with hypospadias, gestational weeks 8–14 occurred in in July (207 patients, 12.1%) and August (191 patients, 11.1%); the average and maximum monthly temperatures during this period were significantly higher (p = 0.01) -Compared to other seasons, the average and maximum monthly ambient temperatures during the summer increased the risk for hypospadias (OR, 1.32; 95% CI, 1.08–1.52; and OR, 1.22; 95% CI, 0.99–1.54, respectively).	High ambient temperature exposure during the period of hypospadias development (weeks 8–14 of gestation) may contribute to its increased incidence. The magnitude of mean monthly temperature in summer was significantly related to increased hypospadias risk.	4/9
Lin, 2018 PMID: 29886237 Case control study, 5,848 CHD cases and 5,742 controls in Arkansas, Texas, North Carolina, Georgia, New York, Utah, California, and Iowa from 1997–2007	Extreme heat events (EHEs) were defined by using the 95th (EHE95) or 90th (EHE90) percentile of daily maximum temperature and its frequency and duration at 3–8 weeks GA	Congenital heart defect	-Findings of 2.17–3.24 fold increased risk for VSD was found after cumulative exposure to EHE (3–11 days) during summer -A long duration of unseasonably warm weather in spring was associated with CHDs in multiple regions with ORs ranging from 1.23 to 9.62 (10 days of cumulative EHE90 for VSD).	Cumulative exposure to EHE in pregnant women may be associated with an increased risk for CHDs in spring.	9/9
Soim, 2017 PMID: 28766872 Case control study, Cases - 326 NTDs (210 spina bifida, 81 anencephaly, 35 encephalocele) and Controls – 1781 in the USA (10 states) from 1997 to 2007	Data obtained on daily maximum temperature (Tmax) in degrees F, dew point (F), wind speed (knots), and atmospheric pressure (millibars) for each site from the National Center for Atmospheric Research. Daily universal apparent maximum temperature (UATmax) was exposure	Neural tube defects: anencephaly, craniorachischisis, spina bifida, encephalocele	-No significant association between EHEs and NTDs was observed. Authors did not observe any statistically significant associations between NTDs and EHE95 or EHE90. Consistently elevated estimates observed for EHE95 in New York (Northeast), North Carolina and Georgia (Southeast), and Iowa (Upper Midwest) for two consecutive days of exposure to extreme heat events (temperature > 95th percentile UATmax) though findings were not significant.	No significant findings found	9/9
Soim, 2018 PMID: 30338937 Case control study, 907 OFC cases (294 CP cases and 613 CL +/−P cases) and 2,206 controls in the USA (8 states) from 1997 to 2007	Daily maximum temperature in degrees F, dew point, wind speed, and atmospheric pressure data was obtained from the National Centers for Environmental Information for each weather monitoring station. Maternal residential addresses from 3 months before conception through the end of pregnancy were geocoded centrally and linked with the closest weather monitoring station.	Cleft palate, cleft lip +/− palate	-Assessment of heat events (temperature > 90th percentile) and extreme heat events (temperature > 95th percentile) in first 8 weeks of gestation after conception -Significantly increased aORs [1.89 CI (1.11, 3.23)] were found in NC and GA (Southeast) among mothers who experienced 3-day long EHE95 but not 2- or 4-day long EHE95 -Compared to no exposure to EHE90, significantly increased aORs [1.70 CI (1.02, 2.81)] were observed among mothers who experienced 4-day long EHE90, but not 3 or 5-day long EHE90	Prolonged duration of EHEs may increase the risk of OFCs in some geographic locations. No statistically significant general association was observed between maternal exposure to EHEs and OFCs.	9/9
Stingone, 2019 PMID: 32091506 Case control study, 4,0333 controls and 2,632 cases with dates of delivery between 1999–2007 in the USA (6 states)	Meteorological data (daily temperature, dew point, wind speed, atmospheric pressure) for each participating NBDPS study center from the National Center for Atmospheric Research was garnered. Geocoded maternal residencies were linked with the closest weather station and assigned meteorological data from that station.	Congenital heart defects - conotruncal heart defects, left/right ventricular outflow tract obstruction defects (LVOTO and RVOTO, respectively), and septal defects, as well as further subgrouping for total perimembranous ventricular septal defects and atrial septal defects	-Compared with low PM2.5 exposure and no EHE exposure, the odds of a ventricular septal defect in offspring associated with high PM2.5 exposure was elevated only among women who experienced an EHE (OR 2.14 95% CI 1.19, 3.38 vs. OR 0.97 95% CI 0.49, 1.95; RERI 0.82 95% CI −0.39, 2.17) [The elevated odds observed for VSDpm (OR: 2.14; 95% CI: 1.19, 3.83) occurred for mothers with at least 1 day of early pregnancy in the summer season who experienced both high PM2.5 exposure and an EHE95 during early pregnancy] -Among those exposed to an EHE, women exposed to high levels of PM2.5 had 1.59 (95% CI 0.94, 2.71) times the odds of having a child with a VSDpm than women with low PM2.5 exposure -Among women unexposed to an EHE, the association between PM2.5 and VSDpm was estimated at 0.97 (95% CI 0.49, 1.95)	EHEs may contribute to the association between prenatal exposure to PM2.5 and CHD occurrence - the odds of VSD development among those with high PM2.5 exposure was elevated only among women who experienced an EHE	9/9
VanZutphen, 2014 PMID: 24407473 Case control study, 13,044 selected birth defect cases and 59,884 controls from New York State resident live births in 19922006	Authors divided New York state into 14 weather regions - each weather region was assigned a daily average value of temperature (minimum, mean, and maximum in 1C), barometric pressure, dew point, and wind speed by using all available airport data for that region. Universal apparent temperature was calculated using temperature, vapor pressure, and wind speed.	Birth defect cases were classified into the 45 birth defects categories; of these the following were excluded: chromosomal anomalies (Trisomies 13, 18, and 21), fetal alcohol syndrome, and case groups with fewer than 50 cases (anencephalus, encephalocele, anophthalmia/mi crophthalmia, aniridia, tricuspid atresia/stenosis, Ebstein's anomaly, biliary atresia, bladder exstrophy, and amniotic bands)	-For every 1 degrees C decrease in the average daily mean universal apparent temperature during the critical period (3–8 weeks post-conception), there was a significantly associated increase in the odds of coarctation of the aorta (OR 1.06, 95% CI 1.02–1.11) and reduced odds of hypoplastic left heart syndrome (OR 0.92, 95% CI 0.86–0.98) -Increased odds of coarctation of the aorta was associated with cold spell (OR 1.61, 95% CI 1.11–2.34) and number of extreme cold days (OR 1.04, 95% CI 1.01–1.08)	Positive and consistent associations were found between cold exposure indices during the critical period (3–8 weeks post-conception) and development of coarctation of the aorta.	7/9
Van Zutphen, 2012 PMID: 23031822 23031822 Population-based case-control study, 6,422 cases from the New York State Congenital Malformations Registry and 59,328 controls (10% random sample of live births) that shared at least 1 week of the critical period of embryogenesis in summer from 1992–2006 in New York, US	Universal apparent temperature, heat wave prevalence, number of heat waves, and number of days above the 90th percentile; data obtained from the National Center for Atmospheric Research, 14 regions of relatively homogeneous weather and ozone exposures	Congenital structural malformations (CNS, eye, cardiovascular, craniofacial, genitourinary, and musculoskeletal) rate	- A 5° F increase in mean daily minimum apparent temperature was significantly associated with higher rates of congenital cataracts (adjusted odds ratio (aOR) = 1.51: 1.14, 1.99) and lower rates of anophthalmia/microphthalmia (aOR = 0.71: 0.54,0.94). -Congenital cataracts were associated with heat waves (aOR = 1.97: 1.17–3.32), number of heat waves (aOR = 1.45” 1.04–2.02), and number of days above the 90th percentile (aOR = 1.09: 1.02,1.17).	Positive and consistent associations were found between multiple heat indices during the critical period of embryogenesis (weeks 3–8 post-conception) and congenital cataracts.	7/9
Zhang, 2019 PMID: 30696385 Case control study, 5742 Controls, 5848 Cases in the USA (10 states) from 1997–2007	Daily maximum temperatures were assessed using hourly temperature estimates within grid cell (accounted for 36×36-km regions). Exposure period average heat exposure during 3–8 weeks post conception for pregnant women with at least 1 day of this post conception period overlapping with spring or summer. For each pregnancy, the count of excessively hot days (EHD) was the number of days with Tmax exceeding either the 90th (EHD90) or 95th (EHD95) percentile for the same season of the baseline period. Frequency and duration of extreme heat events were evaluated as well. The frequency of extreme heat events (EHE) were described as the number of occurrences of at least 3 consecutive EHD90 days (EHE90) or 2 consecutive EHD95 days (EHE95). Duration of EHE was described as the number of days for the longest EHE within the 42-day period.	Congenital heart defects	-Midwest found to have the highest potential increase in summer maternal exposure to excessively hot days (3.42; 95% CI, 2.99–3.88 per pregnancy), heat event frequency (0.52; 95% CI, 0.44–0.60) and heat even duration (1.73; 95% CI, 1.49–1.97) -In the South, potential increases in frequency of exposure to spring EHE95 may be related to a 12.3% (95%CI, 5.9%–18.9%) increase in the number of total CHDs, a 19.7% (95% CI, 7.4%– 33.5%) increase in conotruncal heart defects, and an 18.9% (95% CI, 6.7%–32.6%) increase in VSD. -Large increases in specific CHD subtypes during spring were found, including a 34.0% (95% CI, 4.9%–70.8%) increase in conotruncal CHD in the South and a 35.3% (95% CI, 6.2%–72.1%) increase in VSDs-Duration of similar exposures in Northeast may result in a 38.6% (95% CI, 9.9%–75.1%) increase in ASDs, a 17.9% (95%CI, 7.2%–30.1%) increase in septal heart defects, and a 23.4% (95% CI, 9.9%–39.0%) increase in VSDs. -In the Northeast, septal defects may increase by 33.9% (95% CI,14.9%–56.8%) due to maternal exposure to increased number of excessively hot days; similar changes were projected with EHE90.	Maternal heat exposure is projected to increase across the US (projection period: 2025–2035) especially in the Midwest. The South and Northeast regions were found to have the largest number of projected CHD increases related to frequency of exposure to elevated temperatures especially during the spring	8/9