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Subfertility was associated with increased risks of preterm delivery, low birthweight at term and cesarean delivery
ARTICLE IN PRESS REPRODUC TIVE ENDOCRINOLOGY & INFERTILIT Y
Subfertility was associated with increased risks of preterm delivery, low birthweight at term and cesarean delivery Basso O, Baird DD. Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort. Hum Reprod 2003; 18:2478 ^2484.
who became pregnant right away (TTP o1 month), and in subfertile women who received fertility treatment compared to those who did not.
OBJECTIVE To determine if singleton infants born to couples experiencing subfertility (taking more than one year to conceive) are at increased risk of preterm birth, cesarean delivery, and low birthweight.
MAIN RESULTS Pregnancy was planned and achieved within 1 year in 60% of primiparas and 67% of multiparas. Among primiparas, 15.3% of women required 41 year to conceive; among multiparas, the ¢gure was 8.2%. The remainder (25% in each parity group) either partly planned or did not plan the pregnancy, thus TTP was not relevant. Subfertile women were more likely than non-subfertile women to be 430 years old, be obese, or have irregular cycles. The results of the analyses are shown inTable 1.
DESIGN Prospective cohort study. SETTING Population-based study in Denmark. SUBJECTS A total of 55,906 singleton live births, 25,475 (46%) in primiparas and 30,431 (54%) in multiparas. METHODS The mothers were interviewed by telephone in early pregnancy (median 16 weeks gestation) to obtain information on whether the pregnancy was planned and time to achieve pregnancy. Birth outcomes were determined from the hospital birth record.
CONCLUSION Subfertility, de¢ned as taking more than 1 year to conceive, was associated with signi¢cantly increased risks of preterm and very preterm delivery in primiparous women, and preterm delivery, low birthweight at term, and cesarean delivery in multiparous women. Among subfertile women, those who received fertility treatment had signi¢cantly increased risks of these outcomes, but only in multiparous women.
MAIN OUTCOME MEASURES Odds ratio (OR, 95% CI, strati¢ed by parity and adjusted for other risk factors) for preterm birth (o37 weeks), very preterm birth (o34 weeks), cesarean delivery, and low birthweight (o2500 g) at term, in subfertile women (time-to-pregnancy, TTP, 41 year) compared to those
Table 1
Birth outcomes by time-to-pregnancy and use of fertility treatment Outcome
Time-to-pregnancy p1 year
Primiparas (n) Birth at o37 weeks (%) Birth at o34 weeks (%) Term low birthweight (%) Planned cesarean (%) Emergency cesarean (%) Multiparas (n) Birth at o37 weeks (%) Birth at o34 weeks (%) Term low birthweight (%) Planned cesarean (%) Emergency cesarean (%)
192
15,302 5.4 1.3 1.1 4.2 12.3 20,280 2.9 0.7 0.6 5.9 5.6
41 year No fertility treatment
Fertility treatment
1968 7.4 2.2 1.6 5.2 15.0 1858 4.8 1.0 0.9 7.6 6.7
1931 7.6 2.4 2.1 6.5 16.3 653 7.0 1.8 2.3 10.1 12.1
Evidence-based Obstetrics and Gynecology (2004) 6,192^193 doi:10.1016/j.ebobgyn.2004.09.008
Odds ratio (95% CI) TTP41 year vs o1 month
Odds ratio (95% CI) Fertility treatment, yes vs no
1.4 (1.1^1.7) 1.5 (1.1^2.2) 1.4 (0.9^2.2) 1.1 (0.9^1.4) 1.2 (1.0^1.3)
1.1 (0.8^1.4) 1.1 (0.7^1.7) 1.3 (0.8^2.1) 1.1 (0.9^1.5) 1.0 (0.8^1.2)
1.8 (1.4^2.3) 1.5 (0.9^2.4) 1.9 (1.1^3.3) 1.3 (1.1^1.6) 1.2 (1.0^1.5)
1.7 (1.2^2.5) 2.5 (1.1^5.5) 2.5 (1.1^5.4) 1.3 (0.9^1.8) 1.9 (1.4^2.5)
ARTICLE IN PRESS Commentary This study presented very useful, population-based information on the possible adverse consequences of subfertility (as indicated by a 412 month delay in conception) on birth outcomes. Adverse obstetrical outcomes, including perinatal death, are thought to be increased amongst subfertile women who conceive.1 The nature of this adverse relationship is not entirely clear, particularly when exploring whether it is infertility itself, the cause of the infertility, or the intervention of specif|c treatment, such as in vitro fertilization, that predisposes to the adverse outcomes.The f|ndings of this prospective observational cohort study strengthen the suggestion that infertile women (regardless of whether they have treatment) are more likely to have cesarean delivery, and babies that are born before term or underweight. The methodological approach of using a prospective cohort of singleton pregnancies was appropriate, given that multiple gestations are more prone to preterm birth.This study, unlike previous ones, prospectively compared the likelihood of adverse pregnancy outcomes between subfertile women and women who took a short time to conceive, and also attempted to control for biologically plausible confounding factors. Data on previous preterm delivery in multiparous women were not presented. A history of preterm delivery has an adverse effect on subsequent pregnancies; therefore, such information might have helped to elucidate why fertility treatment was observed to have a more profound effect on the likelihood of an adverse outcome in the multiparous group. The recruitment of a high proportion of eligible subjects is central to the validity of cohort studies. The study’s attainment of 60% of eligible subjects theoretically meets this requirement. Nonetheless, there is a possibility that the subjects not included might have altered the f|ndings and it is not entirely clear how representative were the subjects studied, in comparison to the overall population. For example, the observation that fertility treatment was associated with an increased risk of preterm delivery only in multiparous women is diff|cult to explain, but may imply that such women were more willing to participate in the survey due to previous adverse events, which might not have been accounted for. If subfertility is, indeed, an independentrisk factor for adverse obstetrical outcomes, then further important questions arise.
The present study was limited in trying to attribute a reason for the f|ndings and explored associations using odds ratios. It is known that different causes of infertility are associated with different probabilities of conception. It is also known that there are different reasons for preterm delivery, especially as infertile women are more likely to undergo induction of labour.2 Data on these factors might have been helpful in elucidating the nature of the relationship between subfertility and preterm labour. Nonetheless, a study of women with infertility that was ‘‘unexplained’’ also found similar adverse obstetrical outcomes.2 This f|nding supports the assertion that infertility itself, and not a specif|c cause, is a risk factor for adverse outcomes. On the other hand, another study showed that adverse outcomes were more likely to occur following infertility treatment, particularly if it was complex.3 Subfertility is common and, while an association with adverse obstetrical outcome has been strongly implied by this and other studies, a causal link has yet to be conf|rmed. Furthermore, even amongst infertile women, the absolute risk of having a birth before 34 weeks remains small (o2.5% in the present study). Nonetheless, this study has raised important questions that require further investigation and, until more research shows how infertility or delay in achieving pregnancy alone alters the outcome of pregnancy, the issue will remain controversial. Valentine A. Akande, MBBS, PhD, Joanna F. Crofts, BMedsci, BMBS Southmead Hospital, Bristol, UK
Literature cited 1. Draper ES, Kurinczuk JJ, Abrams KR, Clarke M. Assessment of separate contributions to perinatal mortality of infertility history and treatment: a case-control analysis. Lancet 1999; 353: 1746^1749. 2. Pandian Z, Bhattacharya S, Templeton A. Review of unexplained infertility and obstetric outcome: a 10 year review. Hum Reprod 2001; 16: 2593^2597. 3. Wang JX, Norman RJ, Kristiansson P. The effect of various infertility treatments on the risk of preterm birth. Hum Reprod 2002; 17: 945^949.
Evidence-based Obstetrics and Gynecology (2004) 6,192^193
193
Subfertility was associated with increased risks of preterm delivery, low birthweight at term and cesarean delivery Basso O, Baird DD. Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort. Hum Reprod 2003; 18:2478 ^2484.
who became pregnant right away (TTP o1 month), and in subfertile women who received fertility treatment compared to those who did not.
OBJECTIVE To determine if singleton infants born to couples experiencing subfertility (taking more than one year to conceive) are at increased risk of preterm birth, cesarean delivery, and low birthweight.
MAIN RESULTS Pregnancy was planned and achieved within 1 year in 60% of primiparas and 67% of multiparas. Among primiparas, 15.3% of women required 41 year to conceive; among multiparas, the ¢gure was 8.2%. The remainder (25% in each parity group) either partly planned or did not plan the pregnancy, thus TTP was not relevant. Subfertile women were more likely than non-subfertile women to be 430 years old, be obese, or have irregular cycles. The results of the analyses are shown inTable 1.
DESIGN Prospective cohort study. SETTING Population-based study in Denmark. SUBJECTS A total of 55,906 singleton live births, 25,475 (46%) in primiparas and 30,431 (54%) in multiparas. METHODS The mothers were interviewed by telephone in early pregnancy (median 16 weeks gestation) to obtain information on whether the pregnancy was planned and time to achieve pregnancy. Birth outcomes were determined from the hospital birth record.
CONCLUSION Subfertility, de¢ned as taking more than 1 year to conceive, was associated with signi¢cantly increased risks of preterm and very preterm delivery in primiparous women, and preterm delivery, low birthweight at term, and cesarean delivery in multiparous women. Among subfertile women, those who received fertility treatment had signi¢cantly increased risks of these outcomes, but only in multiparous women.
MAIN OUTCOME MEASURES Odds ratio (OR, 95% CI, strati¢ed by parity and adjusted for other risk factors) for preterm birth (o37 weeks), very preterm birth (o34 weeks), cesarean delivery, and low birthweight (o2500 g) at term, in subfertile women (time-to-pregnancy, TTP, 41 year) compared to those
Table 1
Birth outcomes by time-to-pregnancy and use of fertility treatment Outcome
Time-to-pregnancy p1 year
Primiparas (n) Birth at o37 weeks (%) Birth at o34 weeks (%) Term low birthweight (%) Planned cesarean (%) Emergency cesarean (%) Multiparas (n) Birth at o37 weeks (%) Birth at o34 weeks (%) Term low birthweight (%) Planned cesarean (%) Emergency cesarean (%)
192
15,302 5.4 1.3 1.1 4.2 12.3 20,280 2.9 0.7 0.6 5.9 5.6
41 year No fertility treatment
Fertility treatment
1968 7.4 2.2 1.6 5.2 15.0 1858 4.8 1.0 0.9 7.6 6.7
1931 7.6 2.4 2.1 6.5 16.3 653 7.0 1.8 2.3 10.1 12.1
Evidence-based Obstetrics and Gynecology (2004) 6,192^193 doi:10.1016/j.ebobgyn.2004.09.008
Odds ratio (95% CI) TTP41 year vs o1 month
Odds ratio (95% CI) Fertility treatment, yes vs no
1.4 (1.1^1.7) 1.5 (1.1^2.2) 1.4 (0.9^2.2) 1.1 (0.9^1.4) 1.2 (1.0^1.3)
1.1 (0.8^1.4) 1.1 (0.7^1.7) 1.3 (0.8^2.1) 1.1 (0.9^1.5) 1.0 (0.8^1.2)
1.8 (1.4^2.3) 1.5 (0.9^2.4) 1.9 (1.1^3.3) 1.3 (1.1^1.6) 1.2 (1.0^1.5)
1.7 (1.2^2.5) 2.5 (1.1^5.5) 2.5 (1.1^5.4) 1.3 (0.9^1.8) 1.9 (1.4^2.5)
ARTICLE IN PRESS Commentary This study presented very useful, population-based information on the possible adverse consequences of subfertility (as indicated by a 412 month delay in conception) on birth outcomes. Adverse obstetrical outcomes, including perinatal death, are thought to be increased amongst subfertile women who conceive.1 The nature of this adverse relationship is not entirely clear, particularly when exploring whether it is infertility itself, the cause of the infertility, or the intervention of specif|c treatment, such as in vitro fertilization, that predisposes to the adverse outcomes.The f|ndings of this prospective observational cohort study strengthen the suggestion that infertile women (regardless of whether they have treatment) are more likely to have cesarean delivery, and babies that are born before term or underweight. The methodological approach of using a prospective cohort of singleton pregnancies was appropriate, given that multiple gestations are more prone to preterm birth.This study, unlike previous ones, prospectively compared the likelihood of adverse pregnancy outcomes between subfertile women and women who took a short time to conceive, and also attempted to control for biologically plausible confounding factors. Data on previous preterm delivery in multiparous women were not presented. A history of preterm delivery has an adverse effect on subsequent pregnancies; therefore, such information might have helped to elucidate why fertility treatment was observed to have a more profound effect on the likelihood of an adverse outcome in the multiparous group. The recruitment of a high proportion of eligible subjects is central to the validity of cohort studies. The study’s attainment of 60% of eligible subjects theoretically meets this requirement. Nonetheless, there is a possibility that the subjects not included might have altered the f|ndings and it is not entirely clear how representative were the subjects studied, in comparison to the overall population. For example, the observation that fertility treatment was associated with an increased risk of preterm delivery only in multiparous women is diff|cult to explain, but may imply that such women were more willing to participate in the survey due to previous adverse events, which might not have been accounted for. If subfertility is, indeed, an independentrisk factor for adverse obstetrical outcomes, then further important questions arise.
The present study was limited in trying to attribute a reason for the f|ndings and explored associations using odds ratios. It is known that different causes of infertility are associated with different probabilities of conception. It is also known that there are different reasons for preterm delivery, especially as infertile women are more likely to undergo induction of labour.2 Data on these factors might have been helpful in elucidating the nature of the relationship between subfertility and preterm labour. Nonetheless, a study of women with infertility that was ‘‘unexplained’’ also found similar adverse obstetrical outcomes.2 This f|nding supports the assertion that infertility itself, and not a specif|c cause, is a risk factor for adverse outcomes. On the other hand, another study showed that adverse outcomes were more likely to occur following infertility treatment, particularly if it was complex.3 Subfertility is common and, while an association with adverse obstetrical outcome has been strongly implied by this and other studies, a causal link has yet to be conf|rmed. Furthermore, even amongst infertile women, the absolute risk of having a birth before 34 weeks remains small (o2.5% in the present study). Nonetheless, this study has raised important questions that require further investigation and, until more research shows how infertility or delay in achieving pregnancy alone alters the outcome of pregnancy, the issue will remain controversial. Valentine A. Akande, MBBS, PhD, Joanna F. Crofts, BMedsci, BMBS Southmead Hospital, Bristol, UK
Literature cited 1. Draper ES, Kurinczuk JJ, Abrams KR, Clarke M. Assessment of separate contributions to perinatal mortality of infertility history and treatment: a case-control analysis. Lancet 1999; 353: 1746^1749. 2. Pandian Z, Bhattacharya S, Templeton A. Review of unexplained infertility and obstetric outcome: a 10 year review. Hum Reprod 2001; 16: 2593^2597. 3. Wang JX, Norman RJ, Kristiansson P. The effect of various infertility treatments on the risk of preterm birth. Hum Reprod 2002; 17: 945^949.
Evidence-based Obstetrics and Gynecology (2004) 6,192^193
193