Infertility, Infertility Treatment and Fetal Growth Restriction

Abstract

OBJECTIVE

To examine the association between infertility, with or without treatment, and fetal growth, as well as perinatal and infant mortality.

METHODS

From the Danish National Birth Cohort (1997–2003), we identified 51,041 singletons born of fertile couples (time to pregnancy ≤12 months), 5787 born of infertile couples conceiving naturally (time to pregnancy >12 months), and 4317 born after treatment. We defined SGA as the lowest 5% of birth weight by sex and gestational age.

RESULTS

Crude estimates suggested an increased risk of perinatal mortality and SGA among infertile couples (treated and untreated), but the odds ratios (ORs) of perinatal mortality among infertile couples were attenuated after adjustment for maternal age and body mass index [1.32, 95% confidence interval (CI) 0.95–1.84 among untreated and 1.26, 95% CI 0.86–1.85 among treated couples]. The elevated risk of SGA among infertile couples persisted after adjustment for maternal age, parity and smoking (OR 1.24, 95% CI 1.10–1.40 among untreated, and OR 1.40, 95% CI 1.23–1.60 among treated). The risk of SGA increased with time to pregnancy, and a longer time to pregnancy was associated with a small reduction in birth weight across the whole distribution.

CONCLUSION

The increased risk of SGA observed among infertile couples with or without infertility treatment suggests that infertility may be a risk factor for intrauterine growth restriction. Treatment per se may have little effect on fetal growth. A small to moderate increased risk of perinatal mortality in infertile couples cannot be ruled out due to the small number of cases.

Compared with naturally conceived children, singletons born after assisted reproductive technology (ART) have an elevated risk of perinatal mortality, preterm birth, low birth weight, small-for-gestational-age (SGA), and congenital malformations.^1–3 These findings have been interpreted as reflecting side effects of infertility treatment but could, in part, reflect an increased risk among infertile couples. Infertility per se has been associated with a number of the same adverse pregnancy outcomes.^4–10

Although infertility appears to be associated with decreased birth weight,^4,9 the relation between infertility and fetal growth has not been examined in detail. Fetal growth restriction (FGR) reflects a failure to fulfill a baby’s biologic growth potential but, at present, we have no good measure for this phenomenon.¹¹ The criterion of SGA usually identifies babies below the 5^th or 10^th percentile of the distribution of birth weight at any given gestational age. A large proportion of FGR babies will be captured by this definition, although it does not reflect changes in growth rate during fetal life. SGA is associated with an increased risk of perinatal mortality and morbidity.^12,13 Using data from the Danish National Birth Cohort (DNBC),¹⁴ we examined the association between infertility, with or without treatment, and fetal growth, as well as perinatal and infant mortality.

METHODS

Study Population

The DNBC was established to study the importance of environmental and lifestyle factors during pregnancy and early childhood on the health and development of children.¹⁴ The first of four interviews was administered during the 1^st and 2^nd trimester of pregnancy (median 16^th week) between 1997 and 2003. Of the 92,892 pregnancies with available data, we excluded 2700 from women no longer pregnant at the time of interview, 22,336 unplanned or partly planned pregnancies, and 29 pregnancies with unknown infertility treatment, leading to 67,827 planned pregnancies with a known time to pregnancy. To avoid informative clusters, we only included the first pregnancy contributed by each participant, thus excluding 3973 pregnancies. We also excluded 66 pregnancies for which infertility treatment not associated with this pregnancy was reported, and 233 conceived after treatment other than intracytoplasmic sperm injection (ICSI), in vitro fertilization (IVF), intrauterine insemination (IUI), or hormonal treatment (HT). Pregnancy outcome was ascertained through linkage to the National Hospital Register and the Medical Birth Register by means of the unique civil registration number assigned to all residents. For this analysis, we excluded pregnancies terminated by spontaneous or induced abortions, ectopic pregnancies, hydatidiform moles (N=752), pregnancies with unknown outcome (N=44), and those resulting in the delivery of twins or triplets (N=1614). We divided the remaining 61,145 singletons into 3 groups: A) 51,041 born of fertile couples (time to pregnancy ≤12 months), B) 5787 born of infertile couples conceiving naturally (time to pregnancy >12 months), and C) 4317 born after infertility treatment. While couples in group A were considered fertile, couples in groups B and C were categorized as infertile.

Time to Pregnancy and Infertility Treatment

In the first interview, women were asked if their pregnancy was planned and, if so, for how long they had tried to become pregnant before succeeding. Response categories for time to pregnancy were: “right away”, 1–2, 3–5, 6–12, and >12 months. We interpreted “right away” as conceiving within the first cycle and labeled this category as a time to pregnancy of 0. Participants reporting a time to pregnancy of >6 months were further asked if they or their male partner had received any infertility treatment, including ICSI, IVF, IUI, and HT. Treatment procedure was classified using the above sequence to establish priority when women reported more than one procedure (21%).

Definition of Outcomes

Information on stillbirth, infant death (from birth to 1 year), birth weight, and gestational age were obtained from the Medical Birth Register.¹⁵ We defined as perinatal deaths all stillbirths and deaths occurring within the first 7 days after birth. According to the definition used in Denmark during the study period, stillbirth was a fetal death occurring from 28 completed weeks of gestation. A priori, we defined SGA as the lowest 5% of the birth weight distribution by gestational age and sex, using all live-born singletons from the Danish National Birth Cohort as the standard.

We had three sources to determine gestational age: last menstrual period reported by the participants in the consent form, expected date of delivery reported in a later interview during pregnancy (at about 30 weeks of gestation), and the gestational age recorded in the Medical Birth Register (the latter two estimates are usually based on ultrasound measures). To avoid systematic misclassification of gestational age by ultrasound measurements if early fetal growth is influenced by the exposure under study,¹⁶ we used the estimate based on last menstrual period if it agreed within 2 weeks with either the expected date of delivery or the gestational age recorded in the register. If the difference was more than 2 weeks, we used the one that fitted best with the observed birth weight.¹⁷ The proportion of gestational age determined by the last menstrual period was 95.4% among fertile couples, 94.8% among infertile couples conceiving spontaneously, and 96.8% among infertile couples receiving treatment.

Statistical Analysis

We estimated odds ratios (ORs) and 95% confidence intervals (CIs) of SGA, perinatal death, and infant death (8th –365th days) by means of logistic regression models in STATA 9.1 (StataCorp, College Station, Texas, USA). By including in the model categories of time to pregnancy as a continuous variable, we tested for a trend between time to pregnancy and outcomes. Potential confounders included maternal age at conception, height, pre-pregnancy body mass index, smoking, coffee consumption, alcohol intake, occupation, and history of hypertension and metabolic disorders. Maternal age was included in the final logistic models, together with potential confounders that produced a change in estimate of more than 10%. Since parity is an intermediate variable between infertility and pregnancy outcomes, but a potential confounder for the relation between infertility treatment and the outcomes, we estimated the effect of infertility and treatment with and without adjustment for parity. By including an interaction term for parity and infertility (and treatment), we also examined possible interactions by using the Wald test (ratio of the maximum likelihood estimate of the parameter to an estimate of its standard error, which follows a standard normal distribution)¹⁸ with a level of significance set at 0.05.

Constitutionally small babies may be wrongly classified as growth-restricted by our criterion. Conversely, some growth-restricted babies will fall outside our criterion. We further examined birth weight as a continuous variable, estimating the effect of infertility and treatment through multiple linear regression models, with and without parity, with birth weight as the dependent variable. We used as predictors gestational age, maternal age at conception, height, pre-pregnancy body mass index, smoking, coffee consumption, alcohol intake, occupation, sex of child, and a variable indicating the exposure status as independent variables. We modeled gestational age as a third degree polynomial and the other covariates as categorical variables (as reported in Table 1). The regression model with (and without) parity accounted for 41% (and 40%) of the birth weight variance. By restricting the analyses to only infertile couples, we estimated the effect of treatment. We estimated the association between time to pregnancy and birth weight among couples without treatment.

Table 1.

Selected Characteristics of the Study Populations

	Group A: Singletons born of fertile couples (time to pregnancy ≤12 m)		Group B: Singletons born of infertile couples conceiving naturally (time to pregnancy >12 m)		Group C: Singletons born after infertility treatment
	n	%	n	%	n	%
Maternal age (years)
<25	6285	12.3	496	8.6	165	3.8
25–29	23218	45.5	2170	37.5	1342	31.1
30–34	17044	33.4	2186	37.8	1838	42.6
35+	4494	8.8	935	16.2	972	22.5
Parity
1	24242	47.5	3103	53.6	3177	73.6
2+	26779	52.5	2679	46.3	1135	26.3
Missing	20	0.0	5	0.1	5	0.1
Smoking
No	39475	77.3	4018	69.4	3430	79.5
1–9	6620	13.0	936	16.2	538	12.5
10+	4921	9.6	829	14.3	347	8.0
Missing	25	0.0	4	0.1	2	0.0
Pre-pregnancy body mass index (kg/m2)
<18.5	2094	4.1	243	4.2	158	3.7
18.5–24.9	34618	67.8	3482	60.2	2685	62.2
25–29.9	9827	19.3	1235	21.3	913	21.1
30+	3728	7.3	706	12.2	486	11.3
Missing	774	1.5	121	2.1	75	1.7
Pregnancy outcomes
Stillbirths	144	0.3	23	0.4	22	0.5
Live births	50897	99.7	5764	99.6	4295	99.5
Infant deaths*	186	0.4	28	0.5	20	0.5
Sex of child*
Girl	24841	48.8	2821	48.9	2082	48.5
Boy	26056	51.2	2943	51.1	2213	51.5
Gestational age (days)*
Mean ± SD	281±13		280±14		279±15
Range	152–321		146–314		165–313
Birth weight (g)*†
Mean ± SD	3599±560		3537±593		3479±632
Range	390–6170		250–5650		475–5680

^*Among live births.

^†With missing information: 283 for Group A, 42 for Group B, and 24 for Group C.

The establishment of the Danish National Birth Cohort was approved by the regional scientific ethics committee (ref no. KF 01-471/94). The Danish Data Protection Agency granted authorization for the implementation of the project (ref. no. 2005-41-5488), and the Danish National Birth Cohort Steering Committee granted authorization for the use of data from the DNBC (ref. no. 2005-10).

RESULTS

Characteristics of the study population are shown in Table 1. Among infertile couples, regardless of treatment, mothers were more likely to be older, nulliparous, and with a higher body mass index.

Perinatal and Infant Death

The study population included 326 perinatal deaths. Compared to singletons born of fertile couples, those born of infertile couples, regardless of treatment, had a higher perinatal mortality (Table 2, reference Group A: crude ORs). After adjustment for maternal age and pre-pregnancy body mass index, all the estimates were attenuated and no longer statistically significant (Table 2, reference Group A: first column of adjusted ORs). Among infertile couples, singletons conceived after treatment had a perinatal mortality similar to that of naturally conceived babies, regardless of adjustment for maternal age and body mass index (Table 2, reference Group B: crude and first column of adjusted ORs).

Table 2.

Perinatal Death in Singletons According to Parental Infertility and Treatment

			Reference: Group A			Reference: Group B
	No. of singletons	No. of perinatal deaths (mortality, 1/1000)	Crude OR (95% CI)	Adjusted OR* (95% CI)	Adjusted OR† (95% CI)	Crude OR (95% CI)	Adjusted OR* (95% CI)	Adjusted OR† (95% CI)
Group A:
Fertile couples	51041	253 (5.0)	1.00 Ref	1.00 Ref	1.00 Ref
Group B:
Infertile couples conceiving naturally	5787	42 (7.3)	1.47 (1.06–2.04)	1.32 (0.95–1.84)	1.27 (0.91–1.77)	1.00 Ref	1.00 Ref	1.00 Ref
Group C:
Infertile couples receiving treatment	4317	31 (7.2)	1.45 (1.00–2.11)	1.26 (0.86–1.85)	1.11 (0.75–1.64)	0.99 (0.62–1.58)	0.91 (0.57–1.45)	0.82 (0.50–1.34)
ICSI	402	4 (10. 0)	2.02 (0.75–5.44)	1.78 (0.66–4.83)	1.48 (0.54–4.05)	1.37 (0.49–3.85)	1.23 (0.44–3.45)	1.06 (0.37–3.03)
IVF	1489	10 (6.7)	1.36 (0.72–2.56)	1.17 (0.61–2.22)	0.99 (0.51–1.90)	0.92 (0.46–1.85)	0.78 (0.39–1.58)	0.69 (0.33–1.42)
IUI	1338	10 (7.5)	1.51 (0.80–2.85)	1.33 (0.70–2.52)	1.17 (0.61–2.23)	1.03 (0.52–2.06)	0.94 (0.47–1.89)	0.86 (0.43–1.75)
HT	1088	7 (6.4)	1.30 (0.61–2.76)	1.17 (0.55–2.48)	1.07 (0.50–2.29)	0.89 (0.40–1.98)	0.92 (0.41–2.07)	0.88 (0.39–1.97)

Logistic regression; OR: odd ratios; CI: confidence interval; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; IUI: intrauterine insemination; HT: hormonal treatment.

^*Adjusted for maternal age, and pre-pregnancy body mass index.

^†Adjusted for maternal age, pre-pregnancy body mass index, and parity.

Among naturally conceived babies, we saw no significant trend between time to pregnancy and perinatal mortality (Table 3, perinatal deaths: crude and first column of adjusted ORs).

Table 3.

Perinatal, Infant Death, and Small-for-Gestational-Age in Singletons Born of Untreated Couples According to Time to Pregnancy

		Perinatal deaths				Infant deaths (8–365 days)				Small-for-gestational-age*
	No. of singletons	No. (mortality, 1/1000)	Crude OR (95% CI)	Adjusted OR† (95% CI)	Adjusted OR‡ (95% CI)	No. (mortality, 1/1000)	Crude OR (95% CI)	Adjusted OR† (95% CI)	Adjusted OR‡ (95% CI)	No. (%)	Crude OR (95% CI)	Adjusted OR§ (95% CI)	Adjusted OR|| (95% CI)
Time to pregnancy (months)
0–2	28,110	132 (4.7)	1.00 Ref	1.00 Ref	1.00 Ref	42 (1.5)	1.00 Ref	1.00 Ref	1.00 Ref	1169 (4.2)	1.00 Ref	1.00 Ref	1.00 Ref
3–5	13,138	74 (5.6)	1.20 (0.90–1.60)	1.18 (0.88–1.57)	1.15 (0.87–1.54)	18 (1.4)	0.92 (0.53–1.59)	0.91 (0.53–1.59)	0.94 (0.54–1.64)	572 (4.4)	1.05 (0.95–1.16)	1.04 (0.94–1.15)	1.00 (0.90–1.10)
6–12	9,793	47 (4.8)	1.02 (0.73–1.43)	0.98 (0.70–1.37)	0.95 (0.68–1.33)	17 (1.7)	1.16 (0.66–2.04)	1.16 (0.66–2.04)	1.22 (0.69–2.14)	459 (4.7)	1.13 (1.01–1.27)	1.10 (0.98–1.23)	1.03 (0.92–1.15)
>12	5,787	42 (7.3)	1.55 (1.09–2.20)	1.39 (0.97–1.97)	1.32 (0.93–1.88)	9 (1.6)	1.04 (0.51–2.15)	1.09 (0.53–2.26)	1.18 (0.57–2.44)	345 (6.0)	1.47 (1.30–1.66)	1.38 (1.22–1.56)	1.25 (1.10–1.42)
P for trend			0.054	0.19	0.30		0.73	0.67	0.51		<0.001	<0.001	0.005

Logistic regression; OR: odd ratios; CI: confidence interval.

^*Among live births.

^†Adjusted for maternal age, and pre-pregnancy body mass index.

^‡Adjusted for maternal age, pre-pregnancy body mass index, and parity.

^§Adjusted for maternal age, and smoking.

^||Adjusted for maternal age, smoking, and parity.

Overall, 97 infants died between the 8^th and the 365^th day after birth: 77 born of fertile couples, and 9 and 11 born of infertile couples conceiving without and with infertility treatment, respectively. Compared with infants of fertile couples, the ORs adjusted for maternal age and body mass index were 1.07 (95% CI 0.53–2.14) and 1.83 (95% CI 0.96–3.49) for those born of infertile couples conceiving without and with infertility treatment, respectively. The small number of cases did not permit analysis of infant death by treatment procedures. Among untreated couples, we saw no trend between time to pregnancy and death between the 8^th and 365^th day of life (Table 3, infant deaths: crude and first column of adjusted ORs).

Further adjustment for parity did not substantially change the above estimates (Tables 2 and 3). We saw no interactions in the risk of perinatal and infant death between parity and categories of infertility or time to pregnancy (P=0.48~0.88). Restricting the analyses to primiparas yielded estimates similar to those adjusted for parity in Tables 2 and 3. Our analyses included babies born alive at any gestation but, during the time of the study, delivery of a dead baby prior to the 28^th week was considered a miscarriage and thus not recorded in the Birth Register. However, the estimates did not change after excluding the 115 babies born alive before 28 weeks.

Small-for-Gestational-Age

Compared with singletons born of fertile couples, those born of infertile couples had an increased risk of SGA, regardless of treatment or adjustment (Table 4, reference Group A: crude and first column of adjusted ORs). Compared to singletons born of infertile couples conceiving naturally, those born after treatment had a slightly higher risk of SGA (Table 4, reference Group B: crude and first column of adjusted ORs).

Table 4.

Small-for-Gestational-Age Singletons According to Parental Infertility and Treatment

			Reference: Group A			Reference: Group B
	No. of singletons	No. of small-for-gestational-age (%)	Crude OR (95% CI)	Adjusted OR* (95% CI)	Adjusted OR† (95% CI)	Crude OR (95% CI)	Adjusted OR* (95% CI)	Adjusted OR† (95% CI)
Group A:
Fertile couples	50614	2200 (4.3)	1.00 Ref	1.00 Ref	1.00 Ref
Group B:
Infertile couples conceiving naturally	5722	345 (6.0)	1.41 (1.26–1.59)	1.33 (1.18–1.50)	1.24 (1.10–1.40)	1.00 Ref	1.00 Ref	1.00 Ref
Group C:
Infertile couples receiving treatment	4271	304 (7.1)	1.69 (1.49–1.91)	1.78 (1.56–2.02)	1.40 (1.23–1.60)	1.19 (1.02–1.40)	1.31 (1.11–1.54)	1.14 (0.96–1.35)
ICSI	396	30 (7.6)	1.80 (1.24–2.62)	1.94 (1.33–2.82)	1.40 (0.96–2.05)	1.28 (0.87–1.88)	1.43 (0.97–2.12)	1.14 (0.77–1.70)
IVF	1474	93 (6.3)	1.48 (1.20–1.84)	1.58 (1.27–1.96)	1.17 (0.94–1.46)	1.05 (0.83–1.33)	1.16 (0.91–1.48)	0.95 (0.74–1.22)
IUI	1322	103 (7.8)	1.86 (1.51–2.28)	1.96 (1.59–2.41)	1.57 (1.27–1.94)	1.32 (1.05–1.66)	1.45 (1.15–1.83)	1.27 (1.00–1.61)
HT	1079	78 (7.2)	1.71 (1.36–2.17)	1.75 (1.39–2.22)	1.52 (1.20–1.93)	1.21 (0.94–1.57)	1.31 (1.01–1.69)	1.22 (0.94–1.58)

Logistic regression; OR: odd ratios; CI: confidence interval; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; IUI: intrauterine insemination; HT: hormonal treatment.

^*Adjusted for maternal age, and smoking.

^†Adjusted for maternal age, smoking, and parity.

Analyses among naturally conceived babies showed a statistically significant trend between time to pregnancy and the risk of SGA (Table 3, small-for-gestational-age: crude and first column of adjusted ORs).

Adjustment for parity resulted in attenuated estimates but a similar conclusion, except that the overall difference between treated and untreated couples was no longer statistically significant (Tables 3 and 4). We detected no interaction in the risk of SGA between categories of infertility or time to pregnancy and parity (P=0.62~0.87), and restricting the analyses to primiparas resulted in estimates similar to those adjusted for parity in Tables 3 and 4.

Birth Weight Distribution

Before adjustment, we saw a small shift in the birth weight distribution of babies born to infertile couples, regardless of treatment (Figure 1). The linear regression model not including parity suggested differences in birth weight of −42.7 grams (95% CI: −54.9 to −30.4) and −96.1 grams (95% CI: −110.1 to −82.1) among babies born of infertile couples conceiving naturally and after treatment, respectively. Including parity in the model suggested a more modest reduction in birth weight [−21.2 grams (95% CI: −33.3 to −9.1) and −34.5 grams (95% CI: −48.6 to −20.4) for babies born of infertile couples conceiving naturally and after infertility treatment, respectively]. All the following estimates were adjusted for parity. Restricting to infertile couples resulted in a small borderline significant effect of treatment [−17.6 grams (95% CI: −36.1 to 0.9)]. Compared to babies born of infertile couples conceiving naturally, babies born after IUI [−37.8 grams (95% CI: −65.2 to −10.5)] and HT [−35.8 grams (95% CI: −65.4 to −6.3)] were smaller, but not babies born after ICSI [−3.6 grams (95% CI: −50.0 to 42.9)] or IVF [11.9 grams (95% CI: −14.6 to 38.5)].

Fig. 1.

Birth weight distributions (kernel density estimators) for singletons according to infertility and infertility treatment in parents

Figure 2 shows the unadjusted birth weight distributions as a function of time to pregnancy. After adjustment and compared to babies with time to pregnancy of 0–2 months, the differences in birth weight were 0.6 (95% CI: −8.5 to 9.7), −13.2 (95% CI: −23.3 to −3.1), and −24.3 grams (95% CI: −36.9 to −11.7) for babies with time to pregnancy of 3–5, 6–12, and >1 months, respectively.

Fig. 2.

Birth weight distributions (kernel density estimators) for singletons born of untreated couples according to time to pregnancy (TTP)

DISCUSSION

Singletons born of infertile couples were slightly more likely to be small-for-gestation than singletons born of fertile couples, and time to pregnancy correlated with the risk among spontaneously conceived babies. Estimates were similar between treated and untreated infertile couples, suggesting that part of the increased risk may be due to the underlying infertility or its determinants, rather than to treatment. The crude increased relative risk of perinatal mortality among babies born of infertile couples was in part explained by older maternal age, higher body mass index, and primiparity.

Infertile couples not receiving treatment may have a less severe form of infertility than infertile couples recurring to treatment. However, use of this group as the reference for assessing the side effects of treatment reduces the potential for confounding by indication.

In this population-based cohort, information on birth outcome was collected from national registers and was virtually complete. Although time to pregnancy and treatment were retrospectively collected during pregnancy, they were reported prior to the occurrence of the outcomes under study. Thus, differential recall and differential loss to follow-up are not likely sources of bias in this study. Even though participants in the DNBC were somewhat healthier than mothers in the general population(eg, fewer smokers), the effect of non-participation on our estimates is expected to be small, as showed in a validation study.¹⁹ The 21,771 singletons excluded from this analysis because of unplanned and partly planned pregnancies had a risk of perinatal and infant (8–365 days) death (5.6 and 1.6 per 1000 births, respectively) comparable to that of singletons born of fertile couples. The risk of SGA was slightly higher (5.1%), but not significantly different after adjustment for maternal age, parity, and smoking (OR 1.04, 95% CI 0.97–1.12).

The validity of time to pregnancy reported by women has been found to be high even after more than a decade.²⁰ Participants in this cohort had to recall the time to pregnancy of the current pregnancy, thus with a short time lag. Excluding pregnancies reported as conceived right away (labeled as a time to pregnancy of 0) did not change our results (data not shown). Long or irregular cycles may result in a time to pregnancy of longer than 12 months, which could cause bias if associated with the studied outcomes. However, excluding all women reporting long (>33 days) or irregular cycles (15%) resulted in slightly stronger estimates (with a change of less than 20%).

Women reporting a time to pregnancy of less than 6 months were not asked about treatment for infertility, but we expect only a small proportion of treated couples to have been wrongly classified as untreated. About 45% of women with a time to pregnancy longer than12 months reported treatment, whereas only 7% of women with a time to pregnancy of 6–12 months reported treatment. Treatment type was also self-reported, but most women would be aware of the treatment they received, especially since the time period of recall was relatively short. Among women reporting more than one procedure, we prioritized the treatment based on an a priori assessment of potential risk to the baby. Analyses restricted to women who reported only one procedure (79%) yielded estimates similar to those presented. Additionally, our previous findings for twinning and congenital malformations in relation to infertility treatment suggest that the reporting of treatment procedures was, overall, reasonably accurate.^10,21

The rates of stillbirth and infant mortality in our study population (0.3% and 0.4%) were comparable with the national figures between 1997 and 2001 (0.3%–0.4% and 0.4%–0.5%, respectively)(homepage of the Danish Society of Obstetrics and Gynecology. http://www.dsog.dk/). We used SGA defined as the lowest 5% of the distribution of birth weight by sex and gestational-age, instead of 10%, to increase specificity. Babies defined as SGA in this study had a rate of infant death (0–365 days of life) of 1.90%, compared to 0.28% in non-SGA babies. Among the several options to determine gestational age, we used the one that we considered as the best estimate. Using only gestational age recorded in the Medical Birth Register (likely based on ultrasound estimates) yielded similar results (data not shown).

In a case-control study, Draper and colleagues found that history of infertility and untreated infertility were associated with an increased risk of perinatal mortality,⁶ but recall bias could not be ruled out. Some authors have reported an increased risk of perinatal mortality among children born after ART compared to naturally conceived children.^1,2,22 Our findings suggest that the increased risk may be due to the characteristics of infertile women, consistent with two large studies showing no significant difference between singletons born after IVF or ovarian stimulation and population controls, after adjustment for covariates including maternal age and parity.^23,24 Due to the limited number of cases in our study, we cannot, however, rule out a small to moderate increased risk of perinatal mortality.

Several studies reported an association between a long time to pregnancy and low birth weight or preterm birth.^4,7–9 One, however, reported no association with these outcomes and SGA.²⁵ Participants in the study were enrolled between 1959 and 1966, a time period characterized by limited availability of effective contraception. The small proportion of pregnancies with a known time to pregnancy (15%) may reflect a selected low-risk group. Our finding of a higher risk of SGA in singletons born after infertility treatment is in line with previous studies reporting a 40–60% excess risk of SGA in ART children.^1,2,22,26 The increased risk, however, may be at least partly due to the underlying infertility or, more likely, to its determinants, although some evidence suggests otherwise.²⁷ IUI was associated with a slightly increased risk of SGA, which may be explained by the indication for treatment (type or severity of infertility). IVF, including ICSI, usually involves selection of embryos, which may reduce the excess risk of SGA induced by treatment. When analyzing the entire birth weight distribution, however, we saw a small effect, possibly due to residual confounding. If our results reflect a true association, it is possible that only specific types (or causes) of infertility are associated with elevated risk. Studies with detailed clinical diagnoses are necessary for understanding the mechanisms by which infertility may correlate with fetal growth disruption.

Using a segment of the Danish National Birth Cohort including births between 1998 and 2001, we previously reported an increased risk of neonatal death with increasing time to pregnancy among primiparas.⁵ However, we could not replicate this finding with the data for the whole period, although the estimates were in the same direction. Compared to primiparas with a time to pregnancy of 0–2 months, we found adjusted ORs of 1.21 (95% CI 0.63–2.35) and 1.46 (95% CI 0.76–2.79) for untreated and treated infertile couples, respectively. The discrepancy with the previous analysis may have resulted from a higher rate of neonatal deaths among women with a TTP of 0–2 months (used as the reference category) in 2002–2003 compared to the previous years. The number of neonatal deaths was too small to further examine this difference. On the other hand, we still saw an elevated risk of preterm birth among infertile women.⁴ Compared to primiparas with a time to pregnancy of 0–2 months, we saw adjusted ORs of 1.26 (95% CI 1.05–1.52) and 1.49 (95% CI 1.23–1.81) for untreated and treated infertile couples, respectively.

Infertility is a result of environmental/lifestyle exposures and/or of genetic predisposition, and several of these factors, in women as well as men, may also affect fetal growth. Male factors may be more present in some groups, such as couples treated with ICSI. Maternal factors may, however, play a more direct role during pregnancy. In our data, primiparity, advanced maternal age, and smoking were associated with a higher risk of SGA. The association between time to pregnancy and SGA was reduced after adjustment for these factors. Advanced maternal age, inherently linked to ovarian aging and decreased fertility,²⁸ may explain part of the increased risk of perinatal mortality among infertile couples. Maternal chronic conditions such as pre-existing hypertension or metabolic diseases did not affect our estimates, consistent with previous findings.²⁵

A long time to pregnancy may be associated with reduced fetal growth. The reported increased risk of SGA in singletons born after infertility treatment could be, in part, due to the underlying infertility or to its determinants. Treatment procedures per se may have little effect on fetal growth in singletons.