Maternal age and birth defects after the use of assisted reproductive technology in Japan, 2004–2010

Figures & data

Table 1 Demographic and perinatal outcome data of ART pregnancies with birth defect

	Maternal age class	25–29 (n = 171)		30–34 (n = 658)		35–39 (n = 796)		40+ (n = 292)		Pa
		n	%	n	%	n	%	n	%
Method of treatment	IVF	34	19.9	166	25.2	176	22.1	71	24.3	0.508
	ICSI	47	27.5	136	20.7	179	22.5	63	21.6
	IVF and ICSI	7	4.1	25	3.8	32	4.0	6	2.1
	Frozen embryo transfer	83	48.5	330	50.2	408	51.3	152	52.1
	Unknown/missing values	0	0.0	1	0.2	1	0.1	0	0.0
Blastocyst transfer	Yes	94	55.0	365	55.5	420	52.8	156	53.4	0.731
	No	76	44.4	289	43.9	373	46.9	135	46.2
	Unknown/missing values	1	0.6	4	0.6	3	0.4	1	0.3
Gestational weeks	Range		11–42		10–42		13–42		13–42
	Mean ± SD		36.5 ± 5.6		36.1 ± 6.0		36.4 ± 5.1		35.8 ± 5.6
	Median		38		38		38		37
	Unknown/missing values	15	8.8	57	8.7	90	11.3	62	21.2
Sex (fetuses/neonates)	Male	93	54.1	329	49.3	397	49.4	109	37.1	0.046
	Female	58	33.7	260	38.9	307	38.2	119	40.5
	Unknown/missing values	21	12.2	79	11.8	100	12.4	66	22.4
Perinatal outcome (fetuses/neonates)	Abortion (<22 weeks)	8	4.7	42	6.3	36	4.5	15	5.1	0.394
	Stillbirths (≥22 weeks)	2	1.2	13	1.9	15	1.9	7	2.4
	Live births	153	89.0	566	84.7	684	85.1	217	73.8
	Unknown/missing values	9	5.2	47	7.0	69	8.6	55	18.7
Abortion	Spontaneous	0	0	2	4.8	1	2.8	1	6.7
	Artificial	7	87.5	28	66.7	25	69.4	11	73.3
	Unknown/missing values	1	12.5	12	28.6	10	27.8	3	20.0
Early neonatal death (neonatal death up to day 6 after birth)	Yes	5	3.3	18	3.2	30	4.4	12	5.5	0.264
	No	113	73.9	413	73.0	497	72.7	134	61.8
	Unknown/missing values	35	22.9	135	23.9	157	23.0	71	32.7

Notes:

a Comparison among all four groups by the χ² test. Unknown/missing values were excluded from the statistical tests.

Abbreviations: ART, assisted reproductive technology; n, number; IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection; SD, standard deviation.

Table 2 Distribution of classification of cases using the EUROCAT computer algorithm according to maternal age class

Final classification	25–29		30–34		35–39		40+		P
	n	%	n	%	n	%	n	%
Chromosomal cases	13	7.6	55	8.2	179	22.3	137	46.6
Syndromes	2	1.2	25	3.7	23	2.9	10	3.4
Isolated single anomalies	135	78.5	541	81.0	554	68.9	135	45.9	0.092
Multiple birth defects	22	12.8	47	7.0	48	6.0	12	4.1

Note: The χ² test was performed between multiple birth defects and isolated birth defects according to maternal age class (the 2 × 4 contingency table).

Abbreviations: EUROCAT, European Surveillance of Congenital Anomalies; n, number.

Figure 1 Crude prevalence of birth defects according to maternal age, 2004–2010. (A) Prevalence per 10,000 pregnancies. (B) Prevalence per 10,000 live births.

Table 3 Crude birth defect prevalence, RR, and 95% CI in ART according to maternal age class (prevalence per 10,000 pregnancies)

	25–29 n	Prevalence	RR	95% CI	30–34 n	Prevalence	RR	35–39 n	Prevalence	RR	95% CI	40+ n	Prevalence	RR	95% CI
Q00-Q07
Congenital malformations of the nervous system	27	14.9	1.47	0.95–2.27	80	10.2	1 (reference)	68	7.3	0.71	0.52–0.98	12	4.3	0.42	0.23–0.78
Q10-Q18
Congenital malformations of eye, ear, face and neck	17	9.4	1.61	0.92–2.80	46	5.9	1 (reference)	51	5.4	0.93	0.62–1.38	10	3.6	0.62	0.31–1.22
Q17 Other congenital malformations of ear	11	6.1	1.41	0.71–2.77	34	43	1 (reference)	36	3.8	0.89	0.56–1.42	7	2.5	0.58	0.26–1.32
Q20-Q28
Congenital malformations of the circulatory system	69	38.1	1.14	0.87–1.48	264	33.6	1 (reference)	306	32.6	0.97	0.82–1.15	90	32.4	0.97	0.76–1.23
Q20 Congenital malformations of cardiac chambers and connections	4	2.2	Insufficient		18	2.3	1 (reference)	15	1.6	0.70	0.35–1.39	8	2.9	1.26	0.55–2.89
Q21 Congenital malformations of cardiac septa	32	17.7	0.96	0.65–1.41	145	18.5	1 (reference)	183	19.5	1.06	0.85–1.32	45	16.2	0.88	0.63–1.23
Q210 Ventricular septal defect	23	12.7	1.00	0.64–1.57	100	12.7	1 (reference)	119	12.7	1.00	0.76–1.30	29	10.5	0.82	0.54–1.24
Q211 Atrial septal defect	6	3.3	0.84	0.35–2.01	31	3.9	1 (reference)	43	4.6	1.16	0.73–1.84	10	3.6	0.91	0.45–1.86
Q23 Congenital malformations of aortic and mitral valves	5	2.8	3.10	0.99–9.77	7	0.9	1 (reference)	6	0.6	0.72	0.24–2.14	7	2.5	2.83	0.99–8.07
Q24 Other congenital malformations of heart	1	0.6	Insufficient		17	2.2	1 (reference)	25	2.7	1.23	0.67–2.28	6	2.2	1.00	0.39–2.53
Q25 Congenital malformations of great arteries	19	10.5	1.68	0.99–2.86	49	6.2	1 (reference)	47	5.0	0.80	0.54–1.20	17	6.1	0.98	0.57–1.71
Q250 Patent ductus arteriosus	10	5.5	1.50	0.73–3.07	29	3.7	1 (reference)	30	3.2	0.87	0.52–1.44	12	4.3	1.17	0.60–2.30
Q30-Q34
Congenital malformations of the respiratory system	4	2.2	Insufficient		12	1.5	1 (reference)	16	1.7	1.12	0.53–2.36	1	0.4	Insufficient
Q35-Q37
Cleft lip and cleft palate	14	7.7	1.11	0.62–1.99	55	7.0	1 (reference)	57	6.1	0.87	0.60–1.26	15	5.4	0.77	0.44–1.37
Q37 Cleft palate with cleft lip	3	1.7	Insufficient		31	3.9	1 (reference)	26	2.8	0.70	0.42–1.18	9	3.2	0.82	0.39–1.73
Q38-Q45
Other congenital malformations of the digestive system	23	12.7	1.64	1.01–2.64	61	7.8	1 (reference)	62	6.6	0.85	0.60–1.21	21	7.6	0.97	0.59–1.60
Q41 Congenital absence, atresia and stenosis of small intestine	4	2.2	Insufficient		7	0.9	1 (reference)	7	0.7	0.84	0.29–2.39	7	2.5	2.83	0.99–8.07
Q50-Q56
Congenital malformations of genital organs	11	6.1	1.49	0.75–2.96	32	4.1	1 (reference)	30	3.2	0.79	0.48–1.29	3	1.1	Insufficient
Q60-Q64
Congenital malformations of the urinary system	7	3.9	0.95	0.42–2.15	32	4.1	1 (reference)	39	4.2	1.02	0.64–1.63	12	4.3	1.06	0.55–2.06
Q62 Congenital obstructive defects of renal pelvis and congenital malformations of ureter	2	1.1	Insufficient		14	1.8	1 (reference)	17	1.8	1.02	0.50–2.06	7	2.5	1.42	0.57–3.51
Q620 Congenital hydronephrosis	0	0.0	Insufficient		11	1.4	1 (reference)	15	1.6	1.14	0.53–2.49	6	2.2	1.54	0.57–4.18
Q65-Q79
Congenital malformations and deformations of the musculoskeletal system	34	18.8	1.13	0.77–1.64	131	16.7	1 (reference)	142	15.1	0.91	0.72–1.15	34	12.3	0.73	0.50–1.07
Q69 Polydactyly	9	5.0	1.15	0.55–2.40	34	4.3	1 (reference)	34	3.6	0.84	0.52–1.35	7	2.5	0.58	0.26–1.32
Q70 Syndactyly	2	1.1	Insufficient		16	2.0	1 (reference)	15	1.6	0.79	0.39–1.59	5	1.8	0.88	0.32–2.42
Q79 Congenital malformations of the musculoskeletal system, not elsewhere classified	3	1.7	Insufficient		28	3.6	1 (reference)	30	3.2	0.90	0.54–1.50	7	2.5	0.71	0.31–1.62
Q790 Congenital diaphragmatic hernia	1	0.6	Insufficient		12	1.5	1 (reference)	10	1.1	0.70	0.30–1.62	5	1.8	1.18	0.42–3.35
Q80-Q89
Other congenital malformations	4	2.2	Insufficient		38	4.8	1 (reference)	33	3.5	0.73	0.46–1.16	13	4.7	0.97	0.52–1.82
Q87 Other specified congenital malformation syndromes affecting multiple systems	2	1.1	Insufficient		8	1.0	1 (reference)	7	0.7	0.73	0.27–2.02	6	2.2	2.12	0.74–6.12
Q90-Q99
Chromosomal abnormalities, not elsewhere classifieda	13	7.2	1.01	0.55–1.84	56	7.1	1 (reference)	181	19.3	2.71	2.01–3.65	137	49.4	6.93	5.08–9.45
Q90 Down syndrome	5	2.8	0.72	0.28–1.87	30	3.8	1 (reference)	110	11.7	3.07	2.05–4.60	83	29.9	7.83	5.16–11.89
Q91 Edwards syndrome and Patau syndrome	7	3.9	2.34	0.93–5.86	13	1.7	1 (reference)	46	4.9	2.96	1.60–5.49	40	14.4	8.71	4.66–16.29
Q913 Edwards syndrome, unspecified	5	2.8	2.17	0.74–6.35	10	1.3	1 (reference)	37	3.9	3.10	1.54–6.23	34	12.3	9.63	4.76–19.48
Q917 Patau syndrome, unspecified	2	1.1	Insufficient		3	0.4	1 (reference)	9	1.0	Insufficient		6	2.2	Insufficient
Q99 Other chromosome abnormalities, not elsewhere classified	0	0.0	Insufficient		8	1.0	1 (reference)	14	1.5	1.47	0.62–3.50	6	2.2	2.12	0.74–6.12
Any birth defects (number of mothers)	171	94.5	1.13	0.96–1.33	658	83.7	1 (reference)	796	84.9	1.01	0.91–1.12	292	105.2	1.26	1.10–1.44
Nonchromosomal birth defects (number of mothers)	158	87.3	1.13	0.95–1.34	609	77.5	1 (reference)	643	68.6	0.88	0.79–0.99	172	62.0	0.80	0.68–0.95

Notes: The estimated numbers of pregnancies according to maternal age class were as follows: 18,095 for 25–29 years; 78,576 for 30–35 years; 93,787 for 35–39 years; and 27,751 for 40+ years. The numbers in boldface represent a statistically significant association.

a The values were different from those of chromosomal cases given in Table 2, since some fetuses/neonates had two different chromosomal abnormalities.

Abbreviations: RR, relative risk; CI, confidence interval; ART, assisted reproductive technology; n, number.

Table 4 Crude birth defect prevalence, RR, and 95% CI in ART according to maternal age class (prevalence per 10,000 live births)

	25–29 n	Prevalence	RR	95% CI	30–34 n	Prevalence	RR	35–39 n	Prevalence	RR	95% CI	40+ n	Prevalence	RR	95% CI
Q00-Q07
Congenital malformations of the nervous system	16	11.2	1.66	0.93–2.97	40	6.7	1 (reference)	37	5.7	0.85	0.54–1.33	7	4.8	0.72	0.32–1.60
Q10-Q18
Congenital malformations of eye, ear, face and neck	16	11.2	1.58	0.89–2.82	42	7.1	1 (reference)	50	7.7	1.10	0.73–1.65	10	6.9	0.98	0.49–1.95
Q17 Other congenital malformations of ear	10	7.0	1.34	0.66–2.73	31	5.2	1 (reference)	35	5.4	1.04	0.64–1.69	7	4.8	0.93	0.41–2.10
Q20-Q28
Congenital malformations of the circulatory system	69	48.2	1.12	0.86–1.46	257	43.2	1 (reference)	301	46.5	1.08	0.91–1.27	88	60.6	1.40	1.10–1.79
Q20 Congenital malformations of cardiac chambers and connections	4	2.8	Insufficient		18	3.0	1 (reference)	15	2.3	0.77	0.39–1.52	8	5.5	1.82	0.79–4.19
Q21 Congenital malformations of cardiac septa	32	22.3	0.93	0.63–1.36	143	24.0	1 (reference)	183	28.3	1.18	0.95–1.47	44	30.3	1.26	0.90–1.77
Q210 Ventricular septal defect	23	16.1	0.97	0.61–1.52	99	16.6	1 (reference)	119	18.4	1.11	0.85–1.44	28	19.3	1.16	0.76–1.76
Q211 Atrial septal defect	6	4.2	0.80	0.34–1.93	31	5.2	1 (reference)	43	6.6	1.28	0.81–2.03	10	6.9	1.32	0.65–2.70
Q23 Congenital malformations of aortic and mitral valves	5	3.5	3.46	1.06–11.35	6	1.0	1 (reference)	5	0.8	0.77	0.23–2.51	7	4.8	4.78	1.61–14.23
Q24 Other congenital malformations of heart	1	0.7	Insufficient		15	2.5	1 (reference)	22	3.4	1.35	0.70–2.60	5	3.4	1.37	0.50–3.76
Q25 Congenital malformations of great arteries	19	13.3	1.61	0.95–2.74	49	8.2	1 (reference)	47	7.3	0.88	0.59–1.32	17	11.7	1.42	0.82–2.47
Q250 Patent ductus arteriosus	10	7.0	1.43	0.70–2.94	29	4.9	1 (reference)	30	4.6	0.95	0.57–1.59	12	8.3	1.70	0.87–3.32
Q30-Q34
Congenital malformations of the respiratory system	4	2.8	Insufficient		9	1.5	1 (reference)	16	2.5	1.64	0.72–3.70	1	0.7	Insufficient
Q35-Q37
Cleft lip and cleft palate	14	9.8	1.10	0.61–1.98	53	8.9	1 (reference)	57	8.8	0.99	0.68–1.44	13	9.0	1.01	0.55–1.84
Q37 Cleft palate with cleft lip	3	2.1	Insufficient		29	4.9	1 (reference)	26	4.0	0.83	0.49–1.40	7	4.8	0.99	0.43–2.26
Q38-Q45
Other congenital malformations of the digestive system	23	16.1	1.59	0.99–2.58	60	10.1	1 (reference)	61	9.4	0.94	0.66–1.34	21	14.5	1.43	0.87–2.36
Q41 Congenital absence, atresia and stenosis of small intestine	4	2.8	Insufficient		7	1.2	1 (reference)	7	1.1	0.92	0.32–2.62	7	4.8	4.10	1.44–11.69
Q50-Q56
Congenital malformations of genital organs	11	7.7	1.43	0.72–2.83	32	5.4	1 (reference)	30	4.6	0.86	0.52–1.42	3	21	Insufficient
Q60-Q64
Congenital malformations of the urinary system	5	3.5	0.83	0.32–2.17	25	4.2	1 (reference)	36	5.6	1.33	0.80–2.21	11	7.6	1.80	0.89–3.67
Q62 Congenital obstructive defects of renal pelvis and congenital malformations of ureter	2	1.4	Insufficient		14	2.4	1 (reference)	17	2.6	1.12	0.55–2.27	7	4.8	2.05	0.83–5.08
Q620 Congenital hydronephrosis	0	0.0	Insufficient		11	1.8	1 (reference)	15	2.3	1.26	0.58–2.73	6	4.1	2.24	0.83–6.05
Q65-Q79
Congenital malformations and deformations of the musculoskeletal system	31	21.6	1.17	0.79–1.74	110	18.5	1 (reference)	120	18.6	1.00	0.78–1.30	28	19.3	1.04	0.69–1.58
Q69 Polydactyly	9	6.3	1.13	0.54–2.37	33	5.5	1 (reference)	33	5.1	0.92	0.57–1.49	7	4.8	0.87	0.39–1.97
Q70 Syndactyly	2	1.4	Insufficient		16	2.7	1 (reference)	15	2.3	0.86	0.43–1.75	5	3.4	1.28	0.47–3.50
Q80-Q89
Other congenital malformations	4	2.8	Insufficient		31	5.2	1 (reference)	31	4.8	0.92	0.56–1.51	11	7.6	1.45	0.73–2.89
Q87 Other specified congenital malformation syndromes affecting multiple systems	2	1.4	Insufficient		8	1.3	1 (reference)	7	1.1	0.81	0.29–2.22	5	3.4	2.56	0.84–7.83
Q90-Q99
Chromosomal abnormalities, not elsewhere classified	9	6.3	1.17	0.56–2.45	32	5.4	1 (reference)	114	17.6	3.28	2.22–4.85	74	51.0	9.48	6.27–14.35
Q90 Down syndrome	4	2.8	Insufficient		23	3.9	1 (reference)	83	12.8	3.32	2.09–5.27	50	34.4	8.91	5.44–14.60
Q91 Edwards syndrome and Patau syndrome	4	2.8	Insufficient		8	1.3	1 (reference)	16	2.5	1.84	0.79–4.30	17	11.7	8.71	3.76–20.18
Q913 Edwards syndrome, unspecified	2	1.4	Insufficient		6	1.0	1 (reference)	14	2.2	2.15	0.83–5.59	13	9.0	8.88	3.38–23.37
Any birth defects	153	106.8	1.12	0.94–1.34	566	95.1	1 (reference)	684	105.8	1.11	0.99–1.24	217	149.4	1.57	1.35–1.84
Nonchromosomal birth defects	144	100.5	1.11	0.92–1.33	540	90.7	1 (reference)	595	92.0	1.01	0.90–1.14	158	108.8	1.20	1.01–1.43

Notes: The estimated numbers of live births according to the maternal age class were as follows: 14,322 for 25–29 years; 59,532 for 30–35 years; 64,676 for 35–39 years; and 14,521 for 40+ years. The numbers in boldface represent a statistically significant association.

Abbreviations: RR, relative risk; CI, confidence interval; ART, assisted reproductive technology; n, number.