Table 4. External paternal factors and pregnancy outcomes.

Citation	Study design	Subject	Exposure		Long-term reproductive outcome	OR (95% CI), p-value, overall trend	Key finding
Magnus et al (2019) [55]	Cohort	1,381 cases and 618,322 controls	Smoking		Diabetes	HR 0.97 (0.82–1.2)	No association between paternal or second-hand smoking during pregnancy with childhood-onset type I diabetes.
Mejia-Lancheros et al (2018) [56]	Cohort	1,021 newborns	Smoking		Overweight/obesity	aOR 1.76 (1.14–2.71)	After adjustment, positive correlation between paternal smoking and offspring's overweight/obesity at 5- and 9-years follow-up.
						p<0.01
Accordini et al (2018) [54]	Cohort	1,964 males	Smoking		Asthma	RR 1.43 (1.01–2.01)	Fathers' smoking starting in early adolescence may independently increase asthma risk without allergies in offspring.
Alati et al (2013) [10]	Cohort	7,062 males	Alcohol		Cognitive development	KS2 score 0.27 (0.07–0.46)	No strong evidence of intrauterine mechanisms linking paternal alcohol use with offspring cognitive development expressed in mean change of KS2 scoresa.
Karalexi et al (2017) [57]	Meta-analysis	39 studies	Alcohol		Leukemia (any type)	OR 1.05 (0.91–1.22)	No association between paternal preconceptional alcohol consumption and risk of any type of leukemia cancer at 0–14 age.
						p=0.931
					Acute lymphoblastic leukemia	OR 1.10 (0.93–1.30)
						p=0.361
					Acute myeloid leukemia	OR 1.23 (0.83–1.82)
						p=0.489
Lindblad et al (2011) [59]	Cohort	7,960 cases and 1,154,564 controls	Addictive drugs disorder		ADHD		Parental addiction to illicit drugs is associated with the highest OR for ADHD medication to treat the offspring.
					Boys	OR 3.7 (3.4–4.2)
					Girls	OR 4.6 (3.5–5.9)
Fang et al (2018) [58]	Cohort	3,210 infants	Opioids		Premature death	aHR 4.79 (1.16–19.79)	The risk of premature death (0–6 years) increases 2.5–5.2 times in relation to the severity of paternal opioid use.
						p<0.05
Sallmén et al (2016) [62]	Cohort	11,863 cases and 23,720 controls	Lead blood level (μmol/L)		Schizophrenia, spectrum disorder		Paternal occupational exposure to lead does not increase risk for schizophrenia in the offspring no matter the metal blood level.
				<0.5		aHR 0.97 (0.52–1.83)
				0.5–0.9		aHR 1.25 (0.85–1.82)
				1.0–1.4		aHR 0.90 (0.54–1.49)
				≥1.5 μmol/L		aHR 1.38 (0.65–2.92)
Nieuwenhuijsen et al (2013) [60]	Meta-analysis	3 studies	Solvents		Anencephaly	OR pooled 2.18 (1.52–3.11)	Evidence for association between paternal solvents exposure and child NTDs or anencephaly. No causative role of pesticides for hypospadias.
					NTDs	OR pooled 1.86 (1.40–2.46)
					Spina bifida	OR pooled 1.59 (0.99–2.56)
			Pesticides		Hypospadias	RR 1.19 (1.00–1.41)
Jørgensen et al (2014) [63]	Cohort	600,000 births	Pesticides		Cryptorchidism	aHR 1.04 (0.96–1.12)	No increased risk of cryptorchidism after pesticide exposure.
Messerlian et al (2018) [105]	Cohort	346 singletons	Benzophenone-3		Birthweight gain	137 g (60–214 g)	For each log-unit increase of paternal preconception benzophenone-3 concentration in the urine, an average 137 g gain in birthweight is observed.
Chen et al (2018) [61]	Cohort	192,492 births	X-ray, CT, PET-CT, or other radionuclide imaging radiation		LBW	p<0.05	PTB and LBW are both associated with pregestational paternal radiations exposure for medical imaging purposes.
					PTB	p<0.01

OR: odds ratio, CI: confidence interval, HR: hazard ratio, aOR: adjusted odds ratio, RR: risk ratio, KS2: Key stage 2, ADHD: attention-deficit/hyperactivity disorder, aHR: adjusted hazard ratio, NTD: neural tube diseases, CT: computed tomography, PET: positron emission tomography, LBW: low birthweight, PTB: preterm birth.

^aKey stage 2 scores are considered to be a ‘real world’ measure of academic performance.