. 2021 Sep 29;129(9):097012. doi: 10.1289/EHP9122

Table 2.

Associations between total trihalomethanes (TTHM) in municipal drinking water during the first trimester of pregnancy and major congenital malformations, expressed as odds ratios (ORs) and 95% confidence intervals (CIs) and using nonchlorinated densely populated areas as reference.

Groups of congenital malformations	Categories		Total births ( $n$ )	Nonchlorinated (OR)	$< 5 μ g$ TTHM/L [OR (95% CI)]	$5 - 15 μ g$ TTHM/L [OR (95% CI)]	$> 15 μ g$ TTHM/L [OR (95% CI)]	$p_{trend}$
Nervous system	All	Cases ( $n$ )	623,468	37	129	67	58	0.5
		Noncases ( $n$ )		65,117	289,786	179,115	89,159
		Crude		1.00 (Ref)	0.78 (0.54, 1.13)	0.66 (0.44, 0.98)	1.14 (0.76, 1.73)
		Multivariable-adjusted		1.00 (Ref)	0.87 (0.56, 1.34)	0.71 (0.44, 1.14)	1.27 (0.78, 2.05)
	Hypochlorite	Cases ( $n$ )	198,225	37	22	30	20	0.3
		Noncases ( $n$ )		65,117	30,861	54,114	48,024
		Crude		1.00 (Ref)	1.26 (0.74, 2.13)	0.98 (0.60, 1.58)	0.73 (0.43, 1.26)
		Multivariable-adjusted		1.00 (Ref)	1.35 (0.75, 2.45)	1.07 (0.62, 1.84)	0.73 (0.39, 1.37)
	Chloramine	Cases ( $n$ )	312,651	37	78	9	36	0.006
		Noncases ( $n$ )		65,117	188,350	18,925	40,099
		Crude		1.00 (Ref)	0.73 (0.49, 1.08)	0.84 (0.40, 1.73)	1.58 (0.99, 2.50)
		Multivariable-adjusted		1.00 (Ref)	0.85 (0.53, 1.36)	0.89 (0.35, 2.21)	1.82 (1.07, 3.12)
Heart defects	All	Cases ( $n$ )	623,468	586	2,218	1,185	723	0.002
		Noncases ( $n$ )		64,568	287,697	177,997	88,494
		Crude		1.00 (Ref)	0.85 (0.77, 0.93)	0.73 (0.66, 0.81)	0.90 (0.81, 1.00)
		Multivariable-adjusted		1.00 (Ref)	0.82 (0.74, 0.91)	0.70 (0.63, 0.79)	0.87 (0.77, 0.99)
	Hypochlorite	Cases ( $n$ )	198,225	586	262	453	372	0.03
		Noncases ( $n$ )		64,568	30,621	53,691	47,672
		Crude		1.00 (Ref)	0.94 (0.81, 1.09)	0.93 (0.82, 1.05)	0.86 (0.75, 0.98)
		Multivariable-adjusted		1.00 (Ref)	0.91 (0.78, 1.07)	0.92 (0.81, 1.05)	0.85 (0.74, 0.98)
	Chloramine	Cases ( $n$ )	312,651	586	1,355	139	345	0.8
		Noncases ( $n$ )		64,568	187,073	18,795	39,790
		Crude		1.00 (Ref)	0.80 (0.72, 0.88)	0.81 (0.68, 0.98)	0.96 (0.84, 1.09)
		Multivariable-adjusted		1.00 (Ref)	0.75 (0.67, 0.85)	0.74 (0.60, 0.91)	0.92 (0.79, 1.06)
Orofacial clefts	All	Cases ( $n$ )	623,468	107	385	246	117	0.3
		Noncases ( $n$ )		65,047	289,530	178,936	89,100
		Crude		1.00 (Ref)	0.81 (0.65, 1.00)	0.84 (0.66, 1.05)	0.80 (0.61, 1.04)
		Multivariable-adjusted		1.00 (Ref)	0.84 (0.66, 1.06)	0.86 (0.67, 1.11)	0.85 (0.64, 1.13)
	Hypochlorite	Cases ( $n$ )	198,225	107	44	87	64	0.4
		Noncases ( $n$ )		65,047	30,839	54,057	47,980
		Crude		1.00 (Ref)	0.87 (0.61, 1.23)	0.98 (0.74, 1.30)	0.81 (0.59, 1.11)
		Multivariable-adjusted		1.00 (Ref)	0.88 (0.61, 1.28)	0.94 (0.69, 1.27)	0.87 (0.63, 1.20)
	Chloramine	Cases ( $n$ )	312,651	107	247	27	51	0.4
		Noncases ( $n$ )		65,047	188,181	18,907	40,084
		Crude		1.00 (Ref)	0.80 (0.63, 1.00)	0.87 (0.57, 1.33)	0.77 (0.55, 1.08)
		Multivariable-adjusted		1.00 (Ref)	0.83 (0.64, 1.08)	0.95 (0.61, 1.49)	0.80 (0.55, 1.15)
Digestive system	All	Cases ( $n$ )	623,468	87	312	198	132	0.3
		Noncases ( $n$ )		65,067	289,603	178,984	89,085
		Crude		1.00 (Ref)	0.81 (0.63, 1.03)	0.83 (0.64, 1.07)	1.11 (0.84, 1.46)
		Multivariable-adjusted		1.00 (Ref)	0.90 (0.68, 1.18)	0.89 (0.66, 1.19)	1.20 (0.88, 1.64)
	Hypochlorite	Cases ( $n$ )	198,225	87	37	70	77	0.2
		Noncases ( $n$ )		65,067	30,846	54,074	47,967
		Crude		1.00 (Ref)	0.90 (0.61, 1.32)	0.97 (0.70, 1.33)	1.20 (0.88, 1.64)
		Multivariable-adjusted		1.00 (Ref)	0.94 (0.62, 1.44)	0.96 (0.67, 1.37)	1.25 (0.88, 1.77)
	Chloramine	Cases ( $n$ )	312,651	87	202	14	54	0.5
		Noncases ( $n$ )		65,067	188,226	18,920	40,081
		Crude		1.00 (Ref)	0.80 (0.62, 1.04)	0.55 (0.31, 0.98)	1.01 (0.72, 1.42)
		Multivariable-adjusted		1.00 (Ref)	0.92 (0.68, 1.23)	0.62 (0.33, 1.17)	1.14 (0.78, 1.68)
Urinary	All	Cases ( $n$ )	623,468	101	932	259	195	0.2
		Noncases ( $n$ )		65,053	288,983	178,923	89,022
		Crude		1.00 (Ref)	2.08 (1.69, 2.55)	0.93 (0.74, 1.17)	1.41 (1.11, 1.80)
		Multivariable-adjusted		1.00 (Ref)	2.15 (1.70, 2.73)	0.95 (0.73, 1.23)	1.44 (1.10, 1.89)
	Hypochlorite	Cases ( $n$ )	198,225	101	63	72	62	0.2
		Noncases ( $n$ )		65,053	30,820	54,072	47,982
		Crude		1.00 (Ref)	1.31 (0.96, 1.80)	0.86 (0.63, 1.16)	0.83 (0.61, 1.14)
		Multivariable-adjusted		1.00 (Ref)	1.39 (0.99, 1.94)	0.88 (0.64, 1.22)	0.90 (0.65, 1.26)
	Chloramine	Cases ( $n$ )	312,651	101	668	66	128	0.001
		Noncases ( $n$ )		65,053	187,760	18,868	40,007
		Crude		1.00 (Ref)	2.29 (1.86, 2.83)	2.25 (1.65, 3.07)	2.06 (1.58, 2.68)
		Multivariable-adjusted		1.00 (Ref)	2.37 (1.85, 3.04)	2.33 (1.64, 3.29)	2.06 (1.53, 2.78)
Genital	All	Cases ( $n$ )	623,468	161	843	491	325	0.01
		Noncases ( $n$ )		46,993	289,072	178,691	88,892
		Crude		1.00 (Ref)	1.18 (0.99, 1.40)	1.11 (0.93, 1.33)	1.48 (1.22, 1.79)
		Multivariable-adjusted		1.00 (Ref)	1.18 (0.97, 1.42)	1.14 (0.93, 1.39)	1.47 (1.18, 1.81)
	Hypochlorite	Cases ( $n$ )	198,225	161	97	167	145	0.09
		Noncases ( $n$ )		46,993	30,786	53,977	47,899
		Crude		1.00 (Ref)	1.27 (0.99, 1.64)	1.25 (1.00, 1.55)	1.22 (0.97, 1.53)
		Multivariable-adjusted		1.00 (Ref)	1.36 (1.04, 1.77)	1.30 (1.03, 1.64)	1.24 (0.97, 1.58)
	Chloramine	Cases ( $n$ )	312,651	161	544	63	178	$< 0.001$
		Noncases ( $n$ )		64,993	187,884	18,871	39,957
		Crude		1.00 (Ref)	1.17 (0.98, 1.40)	1.35 (1.01, 1.81)	1.80 (1.45, 2.23)
		Multivariable-adjusted		1.00 (Ref)	1.15 (0.93, 1.41)	1.45 (1.05, 1.98)	1.77 (1.38, 2.26)
Limbs	All	Cases ( $n$ )	623,468	274	1,299	742	430	0.3
		Noncases ( $n$ )		64,880	288,616	178,440	88,787
		Crude		1.00 (Ref)	1.07 (0.93, 1.22)	0.98 (0.86, 1.13)	1.15 (0.98, 1.34)
		Multivariable-adjusted		1.00 (Ref)	1.04 (0.89, 1.20)	0.95 (0.82, 1.11)	1.14 (0.96, 1.34)
	Hypochlorite	Cases ( $n$ )	198,225	274	146	230	194	0.5
		Noncases ( $n$ )		64,880	30,737	53,914	47,850
		Crude		1.00 (Ref)	1.12 (0.92, 1.38)	1.01 (0.85, 1.21)	0.96 (0.80, 1.16)
		Multivariable-adjusted		1.00 (Ref)	1.12 (0.90, 1.38)	0.98 (0.82, 1.19)	0.96 (0.79, 1.17)
	Chloramine	Cases ( $n$ )	312,651	274	864	91	232	0.02
		Noncases ( $n$ )		64,880	187,564	18,843	39,903
		Crude		1.00 (Ref)	1.09 (0.95, 1.25)	1.14 (0.90, 1.45)	1.38 (1.15, 1.64)
		Multivariable-adjusted		1.00 (Ref)	1.06 (0.91, 1.25)	1.02 (0.78, 1.33)	1.34 (1.10, 1.64)
Chromosomal	All	Cases ( $n$ )	623,468	88	381	229	119	0.6
		Noncases ( $n$ )		65,066	289,534	178,953	89,098
		Crude		1.00 (Ref)	0.97 (0.77, 1.23)	0.95 (0.74, 1.21)	0.99 (0.75, 1.30)
		Multivariable-adjusted		1.00 (Ref)	0.87 (0.67, 1.14)	0.87 (0.66, 1.15)	0.92 (0.68, 1.25)
	Hypochlorite	Cases ( $n$ )	198,225	88	39	61	68	0.8
		Noncases ( $n$ )		65,066	30,844	54,083	47,976
		Crude		1.00 (Ref)	0.93 (0.64, 1.37)	0.83 (0.60, 1.16)	1.05 (0.76, 1.44)
		Multivariable-adjusted		1.00 (Ref)	0.87 (0.57, 1.31)	0.81 (0.56, 1.15)	0.99 (0.70, 1.40)
	Chloramine	Cases ( $n$ )	312,651	88	245	24	49	0.6
		Noncases ( $n$ )		65,066	188,183	18,910	40,086
		Crude		1.00 (Ref)	0.96 (0.75, 1.23)	0.94 (0.60, 1.48)	0.90 (0.64, 1.28)
		Multivariable-adjusted		1.00 (Ref)	0.83 (0.62, 1.10)	0.66 (0.38, 1.13)	0.89 (0.61, 1.30)

Note: The study included a total of 623,468 children born during 2005–2015 to mothers living in large urban areas ( $> 10,000$ inhabitants) in Sweden. Models multivariable-adjusted for the following factors: maternal age, BMI, diabetes, any use of teratogenic drugs, parity, smoking at registration to the antenatal care, highest attained education, and household income using inverse probability weighting. BMI, body mass index; Ref, reference; TTHM, average of the four most common trihalomethanes (total trihalomethanes).