Health of children born after ovulation induction

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1 OVULATION INDUCTION Health of children born after ovulation induction Reija Klemetti, Ph.D., a Tiina Sevon, M.Soc.Sc., a Mika Gissler, Dr.Phil., b and Elina Hemminki, Dr.PH. a a Health Services Research, STAKES, National Research and Development Centre for Welfare and Health, Helsinki; and b Information Unit, STAKES, National Research and Development Centre for Welfare and Health, Helsinki, Finland Objective: To study the health of children born after ovulation induction (OI). Design: Nationwide register-based study. Setting: The OI children were followed up to the age of 4 years and compared with other children. Patient(s): The OI children (N ¼ 4,467). Two control groups: all other children (excluding children born after IVF, N ¼ 190,398) and a random sample of those children (n ¼ 26,877). Intervention(s): Ovulation induction treatment in ordinary practice. Main Outcome Measure(s): Mortality rates and adjusted odds ratios for perinatal outcomes, hospitalizations, health-related benefits, and long-term medication use. Result(s): A total of 12% of OI and 2% of control children were multiples. Even after stratifying for multiplicity and adjusting for the available confounding factors (region, smoking, maternal age, socioeconomic position, and parity for perinatal health and mother s socioeconomic position for other indicators), most indicators showed worse health among OI children compared with control children. The OI children had poorer perinatal health and more episodes of long hospitalization than the control children. Singleton OI children had more long-term illnesses in childhood, as measured by child disability allowance, long-term medication use, and hospital care episodes. Conclusion(s): Either OI treatment or the reasons for the treatment increase the risk of health problems in early childhood. (Fertil Steril Ò 2010;93: Ó2010 by American Society for Reproductive Medicine.) Key Words: Ovulation induction, perinatal health, childhood health, morbidity, register-based study Ovulation induction (OI) has been a common infertility treatment for many decades, even after the introduction of IVF in the late 1970s. Ovulation induction and ovarian (hyper)stimulation are two methods of hormonal treatment used in ovarian stimulation (1), and both can be combined with intrauterine insemination (IUI). In Finland, an estimated 2.5% of infants in the late 1990s were born after OI (2). More recent data do not exist, because the proportion of OI children is not registered. This figure is the same as for Denmark in 2002 of 2.3% (3). Regardless of the wide and long-term use of OI, very little is known of the health of children born after it. Studies on perinatal health show that OI children are more often premature and/or of low birth weight, and/or were more often Received May 7, 2008; revised December 9, 2008; accepted December 11, 2008; published online January 25, R.K. has nothing to disclose. T.S. has nothing to disclose. M.G. has nothing to disclose. E.H. has nothing to disclose. Supported by the Academy of Finland (number 73159), the Social Insurance Institution, the Ministry of Education (The School of Doctoral Programs in Public Health), and the National Research and Development Centre for Welfare and Health. Some results of this study have been presented at The Nordic Meeting on Register-based Health Research, Helsinki, Finland, September 22 23, Reprint requests: Reija Klemetti, P.O. Box 220, Helsinki, Finland (FAX: ; reija.klemetti@stakes.fi). treated in the neonatal intensive care unit than naturally conceived children (4 9); in all studies some kind of hormonal stimulation was used with or without IUI. Results on congenital anomalies are inconclusive. Three relatively small-sized studies reported no statistically significant difference in the occurrence of congenital anomalies between OI and control children (6, 10, 11). However, two larger studies showed an increased risk for congenital anomalies (12, 13), but the risk was partly explainable by plurality (12) or underlying infertility or its determinants (13). Sufficiently large long-term follow-up studies beyond the perinatal period are lacking. This article reports the health effects for OI children up to 4 years of age, separately for singletons and multiples, based on a combination of data from several population-based registers. MATERIALS AND METHODS This study is based on children whose mothers were treated with OI (including here ovulation induction and low stimulation with or without insemination) in 1996 to 1998 in Finland (12, 14 16). The OI women were identified with a predesigned algorithm from the drug reimbursement files of the Social Insurance Institution (SII) (14). The children born after OI (N ¼ 4,467) and their perinatal health were obtained from the Finnish Medical Birth Register (MBR) (12, 15, /10/$36.00 Fertility and Sterility â Vol. 93, No. 4, March 1, doi: /j.fertnstert Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 16) using women s personal identification (ID) numbers and the children s dates of birth as the linkage keys. The quality of the MBR is high for the variables used in this study (17). The identified children were linked to four other nationwide registers by children s ID numbers: the Cause-of-Death Register, the Hospital Discharge Register (HDR), the Care Register for Social Welfare, and reimbursement files of health-related social benefits from the SII. As controls, two groups of children were selected from the MBR: all children other than OI and IVF children who have been conceived during the same time period (N ¼ 190,398) and a random sample among the live borns in the first control group (size of the group ¼ 26,877). The second control group was made to reduce the workload caused by large registry linkages, and its size was threefold the number of IVF and OI children in the cohort. Stillbirths were excluded. Information on use of health care services during the pregnancy and child birth and on infant outcomes, first including all children and then including first births only, were gathered from the MBR. As infant health outcomes we used very low/ low birth weight (under 1,500/2,500 g), very preterm/preterm birth (under 32/37 weeks), low 1-minute Apgar scores (0 6), treatment in an intensive care/neonatal surveillance unit, need for respiratory treatment, hospitalization of the child 7 or more days after birth, and perinatal mortality. Information on all hospitalizations (hospital episodes with information on admission and discharge date and diagnosis according to 10th revision of the International Classification of Diseases, ICD-10 codes) before the age of 4 years were received from the 1996 to 2003 HDR. From the Care Register for Social Welfare we received information on numbers of OI children having at least one period of care in social institutions up to the end of 2004, most often because of severe intellectual disabilities. We compared the rates of institutionalized OI children to national rates of children born in 1997 to 1998, excluding the number of children born after IVF and OI. Information on both child disability allowance and long-term medication use (excluding cow s milk intolerance) in 1996 to 2001 before the age of 2 years was gathered from the SII. From the Cause-of-Death Register we received the number and causes of deaths of all children before the age of 2 years in 1996 to Finally, we combined information from the different data sources for eight diseases or conditions (Table 4). We calculated the number of children who had used services up to age of 2 years recorded in the three registers; the registers defined diseases and conditions by the ICD-10 classification. The differences between the OI and control groups were tested with a chi-square test, t test for relative proportions, and with logistic regression analyses, adjusting for available background characteristics (region, smoking, maternal age, marital status, socioeconomic position at birth, and parity for perinatal outcomes and socioeconomic position for hospitalizations, reimbursement of long-term medication, child disability allowance, and for the combined analysis). The adjustment for other factors was not possible because of the small number of cases. The socioeconomic position of the women was defined by using their own occupation at delivery. All analyses were also made separately for singletons and multiples. The study plan was approved by the STAKES research ethics committee. For register linkages, the National Data Protection Authority was consulted and permissions from the register keepers were obtained. RESULTS Of the 4,467 OI children 490 (11%) were twins and 51 (1.1%) were from triplet pregnancies. Among the 190,398 control children 4,143 (2.2%) were twins and only 39 were triplets (<0.01%). OI mothers were somewhat older, more often married, and from a higher socioeconomic position than the other mothers (Table 1). They were less frequently smokers and more often primipara. Compared with other mothers, OI mothers were more often hospitalized during pregnancy, gave birth by Caesarean section, and had long hospital stays after the delivery (Table 2). Adjustment for mothers background characteristics did not change the results. Results for singletons were similar than for all OI children. For OI multiple pregnancies, a statistically significant higher risk was found only for hospitalization during pregnancy. The indicators of perinatal health showed worse health for OI children (Table 2). The perinatal health of OI singletons was worse than that of control singletons. Among OI multiples, risks were increased less and only the differences for low birth weight, special care, and respiratory treatment were statistically significant. When the analysis was restricted to twins, the statistical significance disappeared: the adjusted odds ratios (95% confidence interval [CI]) were 0.96 ( ) for low birth weight rate, 1.09 ( ) for special care, and 1.23 ( ) for respiratory treatment. No statistically significant difference in the rate of stillbirth was found among OI children compared with control children (4.3/1,000 vs. 3.9/1,000). The main causes of stillbirths were related to conditions originating in the perinatal period (chapter P in the ICD-10 classification). The three most common causes of death were P95 (fetal death of unspecified cause), P20 (intrauterine hypoxia) and P50 (fetal blood loss). For live births, the total mortality rate up to age of 2 years was 1.8-fold higher among OI children compared with control children (7.2/1,000 vs. 4.1/1,000, P¼.001, test for relative proportions), but this was explained by plurality. Among singletons, the main causes were congenital anomalies and conditions originating in the perinatal period. Among multiples the main causes were conditions originating in the perinatal period Klemetti et al. Health of OI children Vol. 93, No. 4, March 1, 2010

3 Fertility and Sterility â 1159 TABLE 1 Mother s background characteristics by plurallty and group (ovulation induction and control mothers). a OI (n [ 4,188) All Singleton births Multiple births Controls (n [ 188,298) P value OI (n [ 3,926) Controls (n [ 186,216) P value OI (n [ 262) Controls (n [ 2,084) P value Maternal age at delivery, y (%) b Mean (SD) c < < < or more < < Marital status (%) b Married or cohabiting Single Unknown < < Socioeconomic position (%) b Upper white-collar Lower white-collar Blue-collar Others Unknown < < Smoked during pregnancy (%) d < < <.001 First birth (%) d < < <.001 Note: OI ¼ ovulation induction. a Control group consisting of all other mothers (excluding mohers of IVF children) whose children were fertilized in the same time period as OI children. b For chi-square tests between OI and controls. c For t-test in comparisons between OI and controls. d For t-test for relative proportions in comparisons between OI and controls.

4 1160 Klemetti et al. Health of OI children Vol. 93, No. 4, March 1, 2010 TABLE 2 Proportions (%) and odds ratios a (95% confidence intervals) of treatments and infant outcomes, by plurality and group. Total Singletons Multiples No. or proportion No. or proportion No. or proportion OI Controls OR (95% CI) OI Controls OR (95% CI) OI Controls OR (95% CI) N Deliveries, n 4, ,298 3, , ,084 Infants, n 4, ,398 3, , ,182 Mother, % Hospital treatment ( ) ( ) ( ) during pregnancy Hospitalization after ( ) ( ) ( ) delivery R7 days Caesarean section ( ) ( ) ( ) Infant, % Very preterm (<32 gw) ( ) ( ) ( ) Preterm (<37 gw) ( ) ( ) ( ) Birth weight <1,500 g ( ) ( ) ( ) Birth weight <2,500 g ( ) ( ) ( ) Apgar score ( ) ( ) ( ) Special care b ( ) ( ) ( ) Respiratory treatment ( ) ( ) ( ) Hospitalization R7 d ( ) ( ) ( ) Perinatal mortality ( ) ( ) ( ) Note: OR ¼ odds ratio; CI ¼ confidence interval; OI ¼ ovulation induction. a Adjusted for mother s region, smoking, age, marital status, previous births, socioeconomic position. b Treatment in intensive care unit or in newborn survelliance unit. Reference group (OR ¼ 1) ¼ controls.

5 TABLE 3 Raw proportions (%) of children and adjusted odds ratios a (95% confidence intervals) of having any period of child disability allowance or any long-term medication use until the age of 2 years, by plurality and group. All Singletons Multiples No. or proportion No. or proportion No. or proportion OI Controls OR (95% CI) OI Controls OR (95% CI) OI Controls OR (95% CI) No. of children 4,448 26,877 3,912 28, Any child disability ( ) ( ) ( ) allowance Any long-term ( ) ( ) ( ) medication use b Note: OI ¼ ovulation induction; OR ¼ odds ratio; CI ¼ confidence interval. a Adjusted for mother s socioeconomic position. Reference group (OR ¼ 1) ¼ controls. b Reimbursement for cow s milk or soy milk intolerance were excluded. According to the Care Register for Social Welfare Institutions, 2.9 out of 1,000 OI children had had at least one period of institutional care at social welfare institutions. For other children born in 1997 and 1998, the rate was similar, at 2.7 per 1,000 children. Up to the age of 2 years, a larger proportion of OI children and separately OI singletons received child disability allowance than controls (Table 3). This was also true when inspected by plurality, but only the results for singletons remained statistically significant. The most common reasons (by ICD-10 classification) for receiving child disability allowance were the same for OI and control singletons: diseases of the skin and subcutaneous tissue, the respiratory system, eyes and ears. For multiples the most common reasons included, in addition, certain conditions originating in the perinatal period. OI children (in total and singletons separately) had an increased risk for long-term medication use during the first 2 years of life. Among OI and control children the most common reasons for using medication were the same: asthma and epilepsy. When combining information from different data sources up to the age of 2 years, all OI children had an increased risk for cerebral palsy, allergy, asthma, and diarrhea (Table 4). With the exception of asthma, this was found also for multiples, but all differences were statistically nonsignificant. Up to 4 years of age a somewhat larger proportion of OI children were hospitalized, OI children had more often long hospital episodes (7 days or more), and their length of episodes per child was longer than control children (Table 5). For all ages OI children had more hospital episodes than control children, but the difference was most prominent during infancy. The most common diagnoses recorded as the reason for hospitalization for singletons were diseases of the respiratory system, conditions originating from the perinatal period, infectious, and parasitic diseases, and diseases of the eyes and ears. For multiples, the most common hospitalization diagnoses were conditions originating from the perinatal period. Compared with control children, the risk for being hospitalized was increased among OI singletons for 12 of 16 categories of diseases (according to ICD-10 grouping), even after adjusting for the mother s socioeconomic position. For example, OI had twofold risk for diseases of the circulatory system, neoplasms, and for diseases of the nervous system. Similar increased risks were found also for multiples, but the differences were statistically nonsignificant with the exception of an excess risk of having problems originating from the perinatal period (1.78, ). In almost every category the proportion of hospitalized children was higher among multiples than among singletons (data not shown). In the subanalysis for first births, the results were mainly similar to the results for all children: among singleton births, the risk for very preterm birth was not more statistically significant and among multiples none of the risks of perinatal Fertility and Sterility â 1161

6 1162 Klemetti et al. Health of OI children Vol. 93, No. 4, March 1, 2010 TABLE 4 Raw proportions (per 1,000) of children and adjusted odds ratios a of having an allergic or chronic disorder or a common condition (ICD-10 codes) until the age of 2 years, by plurality and group (by any available data source). All Singletons Multiples No. or proportion No. or proportion No. or proportion OI Controls OR (95% CI) OI Controls OR (95% CI) OI Controls OR (95% CI) Number of children 4,448 26,877 3,912 26, Cerebral palsy (G80) b ( ) ( ) ( ) Epilepsy (G40 G41) b ( ) ( ) ( ) Behavioral disorders ( ) ( ) ( ) (F80 F98) b,d Diabetes (E10) c ( ) ( ) NA Asthma (J45 J46) c ( ) ( ) ( ) Allergy (L20 L23, L27, L50) c ( ) ( ) ( ) Pneumonia (J12 J18) c ( ) ( ) ( ) Diarrhea (A08 A09) c ( ) ( ) ( ) Note: OI ¼ ovulation induction; CI ¼ confidence interval; OR ¼ odds ratio; HDR ¼ hospital discharge register. a Adjusted for mother s socioeconomic position. b Data sources: the HDR and child-disability allowance. c Data sources: the HDR, long-term medication and child-disability allowance. d Disorders of psychological development and behavioral and emotional disorders.

7 TABLE 5 Use of hospital services until the age of 4 years among OI and control children, by plurality and group. Total Singleton Multiple OI (n [ 4,448) Controls (n [ 189,656) OI (n [ 3,912) Controls (n [ 185,530) OI (n [ 536) Controls (n [ 4,126) Use of hospital services Total number of hospital episodes Hospitalized children, % OR (95% CI) a , ,782 3, , , ( ) ( ) ( ) Time in hospital per child, d b Proportion of long hospital episodes (0 7days), % c Note: OI ¼ ovulation induction; OR ¼ odds ratio; CI ¼ confidence interval. a Adjusted for mother s socioeconomic position. Reference group (OR ¼ 1) ¼ controls. b For t-test: P<.001 in all comparisons. c For t-test of relative proportions: P<.001 for OI in total and OI singletons and P<.05 for OI multiples compared to controls outcomes were statistically significant (Table 6). However, perinatal mortality of OI children reached a borderline significance. Furthermore, some of the increased risks for childhood morbidity (Table 6), long-term medication use, and child disability allowance (data not shown) could be found also among OI singleton births. Compared with our previous results of IVF children (16) OI children had better perinatal health than IVF children (Appendix). However, some health indicators in the early childhood showed worse health among OI than among IVF children. DISCUSSION Most indicators showed worse health effects among OI children compared with control children, even with stratifying for multiplicity. They had poorer perinatal health and more periods of long hospitalization than control children. Singleton OI children had more long-term illnesses in childhood. The occurrence of less-serious diseases cannot be estimated from the registers, because the use of outpatient care is not registered unless it includes an operation. Possible sources of bias in our study could be identification and misclassification of children, the quality of the registers used in the study, different thresholds in hospital admission between the groups, use of nonregistered health care services, or parents ability to apply for available health-related benefits (16). In brief, the number of missing or misclassified children is not likely to be large (14 16). Once a reimbursement application for a used service has been made, it is correctly recorded by SII. For prescribed drugs, reimbursement is made in pharmacies at the time of purchase, and information transferred electronically to SII. There is no information of whether OI drugs were actually used, but for subfertile women having a child soon after buying the drug, the use is very likely. Proportion of OI women in the control groups (drugs bought abroad or reimbursement not wished for) is very small among the large number of women. Most data on perinatal health received from the MBR (17, 18) and data on deaths are reliable. Other outcome measures depend on service use (using the purchased and reimbursed drugs, seeking care or an application for benefits); technically the registers are considered to be of good quality (19). It is possible that parents of OI children searched care more or less frequently than other parents. Care-seeking is likely to depend on the socioeconomic position of the parents. Our results were adjusted for socioeconomic position, but there may have been some residual confounding. Because OI children did not have an increased rate of hospitalizations in all 16 categories of diseases, it is unlikely that varying concern of parents or lower threshold for hospitalization could solely explain the higher frequency of visits; the higher frequency very likely reflects higher morbidity among singleton OI children. Fertility and Sterility â 1163

8 1164 Klemetti et al. Health of OI children Vol. 93, No. 4, March 1, 2010 TABLE 6 Proportions (%) and odds ratios a (95% confidence intervals) of perinatal outcomes, and rates (1/1,000) and odds ratios c (95% CI) of childhood outcomes among OI children of primiparous women, by plurality and group. Total Singletons Multiples Proportion or rate Proportion or rate Proportion or rate OI Controls OI Controls OI Controls (n [ 2,431) (n [ 74,062) OR (95% CI) (n [ 2,122) (n [ 72,600) OR (95% CI) (n [ 309) (n [ 1,462) OR (95% CI) Perinatal outcomes, % a Very preterm (<32 gw) ( ) ( ) ( ) Preterm (<37 gw) ( ) ( ) ( ) Birth weight <1500 g ( ) ( ) ( ) Birth weight <2500 g ( ) ( ) ( ) Apgar score ( ) ( ) ( ) Special care b ( ) ( ) ( ) Respiratory treatment ( ) ( ) ( ) Hospitalization R7 days ( ) ( ) ( ) Perinatal mortality ( ) ( ) ( ) Childhood outcomes, 1/1,000 c Cerebral palsy (G80) d ( ) ( ) ( ) Epilepsy (G40 G41) d ( ) ( ) ( ) Behavioral disorders ( ) ( ) ( ) (F80 F98) d Diabetes (E10) e ( ) ( ) NA Asthma (J45 J46) e ( ) ( ) ( ) Allergy (L20 L23, L27, ( ) ( ) ( ) L50) e Pneumonia (J12 J18) e ( ) ( ) NA Diarrhea (A08 A09) e ( ) ( ) ( ) Note: OR ¼ odds ratio; OI ¼ ovulation inductions; CI ¼ confidence interval. Reference group (OR ¼ 1) ¼ controls. a Adjusted for mother s region, smoking, age, marital status, socioeconomic position. b Treatment in intensive care unit or in newborn surveillance unit. c Adjusted for mother s socioeconomic position. d Data sources: the HDR and child-disability allowance. e Data sources: the HDR, long-term medication and child-disability allowance.

9 In Finland, no private hospitals for children exist, but in 2005 about 28% of children up to 4 years of age had visited private physicians (SII, unpublished data, 2005). If OI children were treated more or less frequently in private care instead of hospital care, then a bias would result. Our results were adjusted for socioeconomic position, and it is unlikely that use of OI would otherwise relate to the use of private services. We have also no reason to believe that OI parents would be more or less able or interested to apply for available benefits for long-term medication or child disability allowance (16). Our study confirms earlier findings of the poorer perinatal health of OI singletons (5, 6, 8) and increased risk for preterm (9) or very preterm birth and low birth-weight of OI multiples (8), although not all our results were statistical significant because of the low number of multiples in our study. The long-term health of OI children was worse than that of other children. According to our previous results OI children in total had a slightly increased risk for congenital anomalies, but after stratifying the analysis to multiplicity and gender the risks were not more statistically significant (12). We could find no other previous study examining the long-term health of OI children. The poorer long-term health of OI children can be partly explained by the poorer perinatal health. Although perinatal health of OI singletons was worse than that of control singletons, it was not as poor as the perinatal health of IVF singletons (16), which is in accordance with other previous findings (6, 9). However, this was not systematically so after the perinatal period. Some indicators of childhood morbidity, such as the use of long-term medication and payment of child disability allowance, as well as some typical childhood illnesses (asthma, allergy, and diarrhea) even showed worse health among OI singletons compared with IVF singletons. No differences were found in the use of institutional care. Potential reasons for the poorer health of OI children include infertility itself, infertility treatments (ovulation induction and/or IUI), varying background characteristics, including mother s health, mother s varying behavior during pregnancy, multiplicity, zygosity, and vanishing twins ; singletons originating from twin pregnancies had a higher risk for preterm birth and low birth weight compared with singletons originated from singleton gestations (20). Low pregnancy-associated plasma protein levels as an indicator of poorer placental function in the first trimester can also have a role in poorer outcome of children born after infertility treatments (21, 22). Infertile women even without infertility treatments have had a higher risk for adverse birth outcomes (23). We did not have any information on the reason or length of infertility. Experience from a Swedish study (24) suggests that if we had been able to adjust for the number of years of maternal infertility, the overall risk for hospitalization might have been smaller. It is difficult to separate the effect of infertility from the effect of infertility treatments on the infant outcomes in nonexperimental study designs. The risk for poor infant outcomes among infertile or subfertile couples has increased from nontreatment groups to low-technology treatment groups, being highest in high-technology treatment groups (6, 7, 9, 23), which suggests that infertility is unlikely to be the sole cause for problems. The reason for the poorer outcome in the high-technology treatment groups can also be because of their poorer reproductive prognosis and longer duration of infertility compared with the patients in the lowtechnology treatment groups. In terms of OI, possible origins for problems could be the insemination technique, the medication used in ovulation induction, or hyperstimulation. We could not analyze separately OI with and without IUI, because IUI is not registered with a specific code in the files of the SII. The evidence on the association between the use of CC and infant outcomes (25) is still lacking. The evidence on the use of gonadotrophins combined with IUI suggests that one effect might be lower birth weights of infants (26, 27). We had detailed information on the drugs purchased for use in OI, but the exact date and duration of their use was not known. Because many women bought both CC and gonadotrophins, it was not possible to identify which drug may carry specifically harmful effects. The question of hormonal stimulation of ovaries and the outcomes of OI children remains open. We adjusted the results for background variables available from registers, but residual differences may have remained. Perinatal outcomes for OI children were adjusted for smoking, but otherwise we had no information on mothers health behavior during pregnancy. The health of OI multiples was much worse than that of singletons, as found earlier (8), and risks for many health indicators were increased, although not statistically significantly because of the low number of multiples. Zygosity plays a significant role when the health of OI multiples are compared with the health of other multiples. In general, monozygotic twins have had poorer perinatal outcomes than dizygotic twins. After adjusting for zygosity, OI twins have had a slightly increased risk for preterm birth (9). We did not have data on zygosity, but 51% of OI and 30% of control twins were opposite-gender twins, which suggested that more OI children were dizygotic. Neither did we have information on vanishing twins. Decreasing the multiplicity among OI children is more complicated than reducing the multiplicity in IVF, which can be made by favoring single-embryo transfers. OI has been considered even combined with IUI as a lighter and less invasive than IVF, but particularly the number of oocytes cannot be fully controlled in OI. The epidemic of multiple births may continue despite single embryo transfer because of the wide use of ovulation induction drugs (9). Strategies for decreasing multiplicity in OI could be weight reduction in obese women before treatment, adequate monitoring, strict cancellation criteria, aspirations of excess follicle, favoring natural cycle IUI, use of clomiphene citrate Fertility and Sterility â 1165

10 instead of gonadotrophins, and when gonadotrophins are used to favor low-dose protocols (1). Infertile couples should be informed about the risk of multiplicity after OI and risks related to multiple pregnancies and births. The way to improve the health of singletons is more problematic because we do not know the reasons for poorer health outcomes. Reducing multiplicity may reduce the instances of vanishing twins and thereby also slightly improve the health of singletons. Further initial and follow-up studies are needed to explain the poorer health of OI singletons and to examine the health of OI children from 4 years and upward. REFERENCES 1. Fauser BC, Devroey P, Macklon NS. Multiple birth resulting from ovarian stimulation for subfertility treatment [see comment]. Lancet 2005;365: Gissler M. Hedelm allisyys suomessa ennen, nyt ja tulevaisuudessa [Fertility in Finland in the past, present and future]. Yhteiskuntapolitiikka 2003;6: Nyboe Andersen A, Erb K. 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11 APPENDIX Comparison of OI and IVF children. Total No. or proportion OR (95% CI) IVF OI Controls IVF OI Number of Infants 4,559 4, ,398 Perinatal outcomes, a % Very preterm (<32 gw) ( ) 2.40 ( ) Preterm (<37 gw) ( ) 2.03 ( ) Birth weight <1,500 g ( ) 2.79 ( ) Birth weight <2,500 g ( ) 2.55 ( ) Apgar score ( ) 1.36 ( ) Special care b ( ) 1.81 ( ) Respiratory treatment ( ) 2.29 ( ) Hospitalization R7 days ( ) 1.88 ( ) Perinatal mortality ( ) 1.33 ( ) Childhood outcomes (ICD-10), c,d 1/1,000 Cerebral palsy (G80) e ( ) 2.36 ( ) Epilepsy (G40 G41) e ( ) 1.26 ( ) Behavioral disorders (F80 F98) e ( ) 1.45 ( ) Diabetes (10) f ( ) 0.84 ( ) Asthma (J45 J46) f ( ) 1.28 ( ) Allergy (L20 L23, L27, L50) f ( ) 1.23 ( ) Pneumonla (J12 J18) f ( ) 1.11 ( ) Diarrhea (A08 A09) f ( ) 1.30 ( ) Hospitalization, f,g % ( ) 1.40 ( ) Any long-term medication use, d,h % ( ) 1.37 ( ) Any child disability allowance, d,h % ( ) 1.37 ( ) Note: Proportions (%) or rates (1/1,000) and odds ratios (95% confidence Intervals [CI]) of perinatal outcomes, childhood outcomes, hospitalization, and long-term medication use and any child disability allowance by plurality. HDR ¼ hospital discharge register; OR ¼ odds ratio; CI ¼ confidence interval; OI ¼ ovulation induction. Reference group (OR ¼ 1) ¼ controls. a Adjusted for mother s region, smoking, age, marital status, previous births, socioeconomic position. b Treatment in intensive care unit or in newborn surveillance unit. c Having an allergic or chronic disorder or a common condition (ICD-10 codes) until the age of 2 years by any available data source. d Adjusted for mother s socioeconomic position. e Data sources: the HDR and child-disability allowance. f Data sources: the HDR, long-term medication and child-disability allowance. g Use of hospital services until the age of 4 years. h Having any period of child disability allowance or any long-term medication use until the age of 2 years. Fertility and Sterility â 1167

12 APPENDIX Continued. Singletons Multiples No. or proportion OR (95% CI) No. or proportion OR (95% CI) IVF OI Controls IVF OI IVF OI Controls IVF OI 2,930 3, ,216 1, , ( ) 1.52 ( ) ( ) 1.24 ( ) ( ) 1.32 ( ) ( ) 0.95 ( ) ( ) 1.78 ( ) ( ) 1.27 ( ) ( ) 1.43 ( ) ( ) 1.23 ( ) ( ) 1.11 ( ) ( ) 1.20 ( ) ( ) 1.35 ( ) ( ) 1.27 ( ) ( ) 1.46 ( ) ( ) 1.40 ( ) ( ) 1.34 ( ) ( ) 1.05 ( ) ( ) 0.87 ( ) ( ) 1.05 ( ) ( ) 2.09 ( ) ( ) 1.23 ( ) ( ) 1.34 ( ) ( ) 0.48 ( ) ( ) 1.52 ( ) ( ) 0.98 ( ) ( ) 1.01 ( ) ( ) NA ( ) 1.28 ( ) ( ) 0.93 ( ) ( ) 1.25 ( ) ( ) 1.20 ( ) ( ) 1.06 ( ) ( ) 1.92 ( ) ( ) 1.20 ( ) ( ) 1.31 ( ) ( ) 1.30 ( ) ( ) 1.32 ( ) ( ) 1.34 ( ) ( ) 1.08 ( ) ( ) 1.35 ( ) ( ) 1.14 ( ) 1168 Klemetti et al. Health of OI children Vol. 93, No. 4, March 1, 2010