Hum. Reprod. Advance Access originally published online on June 10, 2008
Human Reproduction 2008 23(9):2145-2150; doi:10.1093/humrep/den134
Perinatal outcome of twin pregnancies in women of advanced age
1 Department of Obstetrics and Gynaecology, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium 2 Department of Applied Mathematics and Informatics, Ghent University, Ghent, Belgium 3 Study Centre for Perinatal Epidemiology, Brussels, Belgium 4 Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium 5 Department of Public Health, Ghent University, Ghent, Belgium
6 Correspondence address. Tel: +32-9-240-48-53; Fax: +32-9-240-38-31; E-mail: ilse.delbaere{at}ugent.be
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Abstract |
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BACKGROUND: The aim of this study was to assess the outcome of twin pregnancies in women of advanced age (
35 years) compared with women aged 25–29 years old. METHODS: This population-based retrospective study compared perinatal outcome of twin pregnancies in primiparae aged 35 or older (N = 240) to that of twin pregnancies in primiparae aged 25–29 years (N = 940). Observed outcomes are adjusted for intermediate (mode of conception and hypertension during pregnancy) and confounding variables (level of education). The possible effect of zygosity and chorionicity was tested in a subset of this database, recorded in the East Flanders Prospective Twin Survey (EFPTS).
RESULTS: In twin pregnancies, maternal age of 35 or over is associated with a lower incidence of preterm birth [adjusted odds ratio (AOR) 0.59, 95% confidence interval (CI) 0.44–0.79] and low birthweight (AOR 0.75, 95% CI 0.58–0.98) compared with younger women. Differences in zygosity and chorionicity between both cohorts do not seem to affect the result.
CONCLUSIONS: In comparison with primiparae aged 25–29 years, perinatal outcome of twin pregnancies is more favourable in primiparae aged 35 or over.
Key words: multiple pregnancy/advanced maternal age/pregnancy outcome/ART/zygosity
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Introduction |
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In singleton pregnancies, advanced maternal age (
35 years) is associated with increased obstetric and perinatal risks, as is documented in numerous studies (Hansen, 1986
; van Katwijk et al., 1998; Gilbert et al., 1999; Seoud et al., 2002; Cleary-Goldman et al., 2005; Joseph et al., 2005; Delbaere et al., 2007). Women of advanced age are reported to have higher odds for chronic diseases during pregnancy (Gilbert et al., 1999) and for obstetric interventions, including higher rates of Caesarean section (Hansen, 1986; van Katwijk et al., 1998; Gilbert et al., 1999; Seoud et al., 2002; Cleary-Goldman et al., 2005; Joseph et al., 2005; Delbaere et al., 2007). In addition, adverse pregnancy outcomes including preterm birth (Jacobsson et al., 2004; Joseph et al., 2005), low birthweight (Gilbert et al., 1999), small for gestational age (SGA) infants (Gilbert et al., 1999) and perinatal mortality (Joseph et al., 2005) are significantly more common in children of older mothers. Nonetheless, the number of women who delay childbearing is still rising in developed countries (Joseph et al., 2005).
The trend to postpone motherhood, in combination with an additional twinning odds (Derom et al., 1995; Lambalk et al., 1998; Endres and Wilkins, 2005) and a higher use of assisted reproductive technologies in older women (Cleary-Goldman et al., 2005), is likely to contribute to the current multiple pregnancy epidemic in most Western countries (Oleszczuk et al., 1999; Blondel and Kaminski, 2002). Between 1991 and 2004, the twin birth rate in Flemish primiparae aged 35 and over nearly doubled from 2.9% to 5.9% (Cammu et al., 2004). In contrast, throughout the years, primiparae aged 25–29 years old, account consistently for 21–24% of twin pregnancies in SPE Flanders (2004).
In contrast to singletons, current evidence concerning the association between advanced maternal age and perinatal outcome in multiple pregnancies [although based on few literature reports (Blickstein et al., 2001b; Zhang et al., 2002; Oleszczuk et al., 2005; Branum et al., 2005)] seems to suggest that the outcome of multiple pregnancies is similar in women of advanced age, compared with younger equivalents (Blickstein et al., 2001b; Zhang et al., 2002; Branum et al., 2005). The contribution of assisted reproductive technologies in the relationship between maternal age and pregnancy outcome among twin gestations has not been well-tested so far.
The purpose of this study is to examine the outcome of twin pregnancies in primiparous women of advanced age compared with pregnancy outcome in twins of primiparae aged 25–29 years old, thereby accounting for the potential effects of mode of conception, hypertension and level of education on pregnancy outcome. Because a considerable number of women aged 35 or older become pregnant after assisted reproduction, the proportion of dizygotic twins may be higher in this group. Twins of the dichorionic type are known to have better outcomes; as such, we corrected for zygosity and chorionicity separately in a subpopulation.
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Materials and Methods |
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Study population and definitions
We included all primiparous women aged 35 years or more (N = 240) and all primiparous women between 25 and 29 years old (N = 940), who delivered twins between 1 January 2001 and 31 December 2004 in the Flemish part of Belgium. Only twins with a birthweight of minimum 500 g were included and since parity may influence the relationship between maternal age and perinatal outcomes, we restricted our study-population to first-time mothers only (Branum et al., 2005
). The control group is confined to the age group 25–29 years old, because this is the category with the largest number of births (the mean age at first delivery in Flanders is 27.7 years). The age of 35 or older is considered as advanced maternal age. The institutional review board of the University Hospital Ghent approved the protocol of this study.
Mode of conception is recorded as ‘spontaneous’, after ‘artificial induction of ovulation (AIO)’ or through ‘assisted reproductive techniques (ART)’. In the multivariate analysis, we account for the differential effects of AIO and ART on the outcomes assessed. For the variables ‘hypertensive disorders during pregnancy’ and ‘diabetes during pregnancy’, the data do not allow the distinction between chronic or pregnancy induced hypertension and chronic or pregnancy induced diabetes. When a diastolic blood pressure of 90 mmHg was found at two different assessments during pregnancy, the woman was diagnosed as being hypertensive. Diabetes is registered only for the years 2002–2004. Maternal educational level is handled as an indicator for socio-economic status (SES). Though there are numerous parameters to assess SES, education has consistently been found the most valid indicator for SES (Kramer et al., 2000). The majority of international studies consistently define maternal education as the most valuable indicator for SES (Liberatos et al., 1988). Education level is classified into two categories: women who went to school until the age of 18 years as the lower educated category, women who received higher education are considered as the higher educated category. Delivery before 37 or 32 completed weeks of gestation is defined as preterm birth and very preterm birth, respectively. Birthweights below 2500 or 1500 g are defined as low birthweight and very low birthweight, respectively. For the variable ‘birthweight’, no distinction is made between preterm and SGA children. SGA is defined as a birthweight-for-gestational-age below the 10th percentile according to customized BWGA curves for this population, thereby accounting for birth order and sex of the child. The congenital malformations included in this study were diagnosed in the first week post-partum.
Data collection
Data were obtained from the existing computer files of a regional population-based perinatal database, the Flemish Study Centre for Perinatal Epidemiology (SPE) (Vleugels and Bekaert, 1992). For each newborn of at least 500 g, an official and coded perinatal form is completed (most often by the midwife) and sent to the SPE, where all data are controlled by an error detection programme and feedback is provided (Cammu et al., 2002). A qualitative assessment of SPE-data shows that there is <5% discrepancy between electronic data and data out of medical files. Data concerning education of the mother are obtained through linkage of the medical birth certificates of the SPE with official birth declarations.
In the East Flanders province, special attention is given to all twin births since 1964 (Loos et al., 1998). When a twin is born at any maternity of this province, a separate form with data concerning pregnancy and birth is filled out by the midwife. This form, together with the placenta(s), is then collected by a collaborator of the East Flanders Prospective Twin Survey (EFPTS). After examination of the placenta and assessment of chorionicity, all data are entered in the database. In the case of a dichorionic placenta in same sexed twins, it is not clear whether it concerns a monozygotic or dizygotic twin. In these cases, DNA fingerprinting is performed on a sample of the placenta in order to determine the zygosity. As such, the EFPTS database contains data of >7500 twins, including their zygosity and chorionicity.
Statistical analysis
Univariate analysis (
2-test) was used to examine the association between maternal age and pregnancy outcome, and crude odds ratios (OR) and 95% confidence intervals (CI) were obtained in this manner. Analyses were subsequently corrected for possible intermediate (hypertension and mode of conception) and confounding (level of education) factors. Logistic regression was used to calculate adjusted odds ratios (AOR) and 95% CI. For the analyses on child-related variables, mixed models (random intercept model with compound symmetry correlation structure) were used to account for intra-twin correlation. Interactions between maternal age and confounding/intermediate variables were explored. Because of the possible importance of zygosity or chorionicity, the impact of both factors was assessed separately on a subpopulation (EFPTS). The number of older primiparae in this subpopulation was very small (N = 49), so for this analysis we included all women aged 25–29 or >35 and adjusted for parity. Since pregnancy outcomes are dynamic over the years (Kogan et al., 2000), we restricted this analysis to the same time-span (2001–2004) as the analyses on SPE data. All results were adjusted for year of birth.
Unfortunately, it was not possible to adjust for hypertension, diabetes or level of education in the EFTPS data. Although there was a strong correlation between assisted reproduction and zygosity/chorionicity, we adjusted for mode of conception along with zygosity/chorionicity, because women of advanced age also have an increased chance of dizygotic twins in natural cycles (Beemsterboer, 2006). Analyses were performed with the statistical package SPSS 15.0 (SPSS Inc., Chicago, IL, USA) for the univariate analysis and logistic regression and SAS 9.1 (SAS Inc., Cary, NC, USA) for the mixed-model.
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Results |
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In 2004, there were 61 647 births in Flanders, of which 1.6% were twin deliveries. The year 2004 was special for twin epidemiology, in that there was an important decrease in twin births compared with the year before (1.9% twins). This decrease was due to the introduction of the IVF-imbursement law of the Belgian government 1 July 2003. As a consequence of this law, six IVF/ICSI cycles are refunded per couple when single embryo transfer is applied in the first two cycles of young patients with good embryos available. Between 1 January 2001 and 31 December 2004, 940 twin pregnancies in primiparae aged 25–29 years were registered, resulting in 1842 registered deliveries of twins, of which each child has a birthweight minimum of 500 g. Primiparae aged 35 or more, account for 240 twin pregnancies and 470 twin deliveries in this period. The mean age in the older women included was 37.7 years and the oldest mother in this cohort was 50 years (natural conception). Women aged 35 or older made up 6.6% of the deliveries in 2004, whereas women aged 25–29 accounted for 44.1%.
The discrepancies between the number of twin pregnancies and deliveries are attributable to missing values for one of both twins. Also due to missing values, the denominators may be different for some variables.
Maternal characteristics are presented in Table I. Twins in women of advanced age are significantly more likely to have been conceived by means of assisted reproductive technologies (P < 0.001), whereas AIO without a subsequent ART procedure is significantly more common in younger mothers (P < 0.05). Twin pregnancies in younger mothers are more frequently complicated by hypertensive disorders (P < 0.05), whereas no difference is found for gestational diabetes (P = 0.926).
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Table II summarizes the findings related to pregnancy and labour in relation to maternal age in twin pregnancies. After adjustment for mode of conception, hypertensive disorders during pregnancy, level of education and year of birth, preterm birth (gestational age <37 weeks) is significantly less common in twin pregnancies of older mothers (AOR 0.59; 95% CI 0.44–0.79). A difference in rates of very preterm birth (AOR 0.89; 95% CI 0.56–1.40) is not observed. There is a marginal significant difference between mean gestational ages in older (247.4 ± 21.4 days) versus younger mothers (244.4 ± 20.9 days) (P = 0.051).
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Findings relative to delivery and neonatal outcome are shown in Table III. Again, we adjusted for mode of conception, hypertension during pregnancy, level of education and year of birth. Low birthweight is significantly less frequent in children of older mothers (AOR 0.75; 95% CI 0.58–0.98). The mean birthweight of twins in younger mothers is not significantly different compared with the mean birthweight in their older counterparts (2211.8 ± 567.7 g versus 2273.2 ± 593.9 g, P = 0.05).
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Because of the introduction of the IVF-imbursement law, twins born in 2004 from of younger mothers may be disadvantaged because these mothers failed to conceive by means of SET. As such, subanalyses on twins born in 2001–2002 were performed for the main pregnancy outcomes. We found no differences in these results compared with the results in the total group.
Although pregnancy complications such as diabetes and non-vertex presentation are similar in older and younger mothers while hypertensive disorders are more common in younger mothers, women of advanced age run a higher risk of delivering by Caesarean section (AOR 1.71; 95% CI 1.28–2.27). Significant interactions between maternal age and confounding/intermediate variables are not found.
The availability of the EFTPS database enabled us to assess the impact of zygosity and chorionicity on a subpopulation. In this analysis, we compared 312 women aged 25–29 years old with 134 women aged 35 years or older. In Table IV, characteristics concerning mode of conception and zygosity/chorionicity are depicted. Again, there is a higher (although not significant) incidence of ovulation induction in the younger age group (19.1% versus 12.6%, P = 0.094) and a higher incidence of IVF/ICSI in the older women (35.6% versus 22.3%, P < 0.01). Twins in older women are significant more likely to be of the dizygotic type, compared with twins in younger women (77.8% versus 64.6%, P < 0.01). Consequently, the proportion of dichorionic twins is also higher in the older age group, but no significant difference was found for this variable.
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In concordance with the above mentioned results, we found a longer mean duration of twin pregnancy in women of advanced age when compared with younger women (P < 0.01) (Table V) in the EFPTS data. With correction, we found an effect of assisted reproduction for this variable, but no effect from zygosity or chorionicity. Although the incidence of preterm birth was considerably higher in the younger age cohort (63.1% versus 55.2%), the difference was marginally significant (OR 0.69, 95% CI 0.67–1.03). For this variable, we only found a significant effect from mode of conception as well.
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Table VI illustrates that in the EFTPS data, there is no statistically significant difference in mean birthweight between younger and older mother (P = 0.303) after adjustment. The incidence of low birthweight was comparable in both groups as well (59.5% versus 54.4%; OR 0.80, 95% CI 0.60–1.07). For these variables, we found an effect from assisted reproduction but not from chorionicity or zygosity. As for perinatal death, no differences between both groups were found, nor was there any effect of the considered intermediate factors.
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Discussion |
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Our results show that, after adjustment for mode of conception, hypertensive disorders in pregnancy, zygosity/chorionicity and level of education, twins of older primiparae are not exposed to higher risks of preterm birth and low birthweight in comparison with twins of younger mothers. On the contrary, preterm birth and low birthweight rates are significantly higher in twin pregnancies of women aged 25–29 years old than in women aged 35 years or older.
Previous studies analysing the association between maternal age and perinatal complications in twin pregnancies find no age-related differences for preterm birth, low birthweight or perinatal death. Blickstein used the Israeli Birth Registry to examine the differences of twin birthweight characteristics in relation to maternal age. He concludes that maternal age in primiparae is not associated with birthweight differences in their twins (Blickstein et al., 2001a). The study of Zhang et al. (2002) finds similar rates of very preterm birth, very low birthweight and perinatal death in twin pregnancies of older mothers (35 years) with high SES, compared with their younger counterparts (25–29 years). When the mother is older, pregnant with twins and with lower SES, the risk for unfavourable pregnancy outcome is higher compared with younger women. A later study of Branum et al. draws similar conclusions: no differences are found in very preterm birth rates of twin pregnancies in primiparae aged 35 years or older versus primiparae aged 25–29 years old. When women had >12 years of education, very preterm birth rates are decreased in older primiparae (Branum et al., 2005). Zhang concludes that the better financial situation of older women, resulting in less physical stress and a better health insurance, can be a possible explanation for the favourable outcome in twin pregnancies (Zhang et al., 2002). In the present study, we did not find differences in very preterm birth rates between the different age groups either. However, after adjustment for level of education which is believed to be the most appropriate indicator for socio-economic differences (Kramer et al., 2000), preterm birth is more frequent in younger twin-mothers.
Major drawbacks of this study were the inability to adjust for smoking behaviour, oocyte donation and natural or induced embryo reduction, in general, given that we were not able to adjust for all confounding/intermediate variables in the same data set. As such, it was not possible to assess the effect of zygosity/chorionicity together with underlying diseases and SES.
To the best of our knowledge, this is the first study to deal with outcome differences in twin pregnancies between younger and older twin mothers in a European setting and the first to correct for mode of conception and zygosity/chorionicity. The adjustment for reproductive technologies is crucial in this matter, since these techniques are more common in the older population and prior studies found preterm birth and low birthweight to be more common in IVF-twins, compared with spontaneously conceived twins (Dhont et al., 1999; Verstraelen et al., 2005).
Children resulting from assisted reproduction in women of advanced age are often perceived as premium babies, and these pregnancies are assumed to be monitored more thoroughly (Blickstein and Keith, 2003). The intense surveillance of artificial conceived pregnancies in older women is believed to be a possible rationale behind the better or similar outcome in multiple pregnancies of older mothers, compared with multiple pregnancies in younger women (Blickstein et al., 2001a; Zhang et al., 2002; Salihu et al., 2004). After adjustment for mode of conception, we nevertheless find outcomes to be better in primiparae of advanced age. Moreover, we believe that all twin pregnancies, irrespective of maternal age and mode of conception, are considered as high-risk and are therefore most likely managed analogously.
Next to the higher application of assisted reproductive technologies in older mothers (Zhang et al., 2002), also biological mechanisms are responsible for an increased proportion of dichorionic twins in women of advanced age (Bomsel-Helmreich et al., 1995; Lambalk et al., 1998; Beemsterboer et al., 2006). Since outcomes in dichorionic twin pregnancies are considerably better when compared with monochorionic multiple gestations (Cunningham et al., 2003), differences in twin characteristics related to chorionicity between older versus younger mothers have been hypothesized to lay on the basis of the better outcome in twins of older mothers. However, we corrected for mode of conception in our analyses of the SPE database, which should take these differences into account. Our analyses on a subset twins, of which the zygosity/chorionicity type are known, did not reveal any impact of zygosity or chorionicity. Moreover, since this study is performed on a twin population, assisted reproduction and thus dizygotic dichorionic twins are very common in the cohort of younger women as well.
Twins have more favourable outcomes when their mother is of advanced age; the mechanism behind this finding is not known yet and is likely due to multiple factors. This paper clarifies that this paradoxical outcome is not due to differences in SES or use of assisted reproductive technologies between older versus younger women pregnant with twins. Since fertility declines with female age, particularly from the mid-30s on, women of advanced age who are capable of conceiving twins may have a biological advantage. As FSH levels start to increase around a decade before the onset of the menopause, women aged 35 or more may have multiple follicle growth. When these women have good quality oocytes, the chance to become pregnant with dizygotic twins is increased (Beemsterboer et al., 2006). As such, it is likely that the findings of this study are contributable to a cohort effect of older women who are so fit that they are capable of becoming pregnant at an age where normally fertility is declined. Hypertension is generally more common in both twin pregnancies and after assisted reproduction (Cammu et al., 2004; Shevell et al., 2005). The incidence of hypertension we found in the older women matched with the incidence in the general population pregnant with twins, whereas the incidence in the younger age group was significantly higher. This may indicate that the younger women in our study imply an impaired cohort compared with the average population.
The results of this paper do not implicate a plea for the suspension of motherhood. As has been mentioned, older women pregnant with twins belong to the happy few who are still capable of conceiving, naturally or by means of assisted reproduction. Furthermore, even the more favourable pregnancy outcomes in older women assessed in this study compare unfavourably with pregnancy outcomes in singletons. The best outcomes of pregnancy are to be expected in singleton pregnancies in younger mothers. Subsequently, it must be stressed that only primiparous women are included in this study. It would be of interest to study this subject on multiparous women too.
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Funding |
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Since its origin, the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium). S.G. is funded by a Ph.D. grant of the Institute for the Promotion of Inovation through Science and Technology in Flanders (IWT-Vlaanderen).
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References |
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Beemsterboer SN, Homburg R, Gorter NA, Schats R, Hompes PGA, Lambalk CB. The paradox of declining fertility but increasing twinning rates with advancing maternal age. Hum Reprod (2006) 21:1531–1532.
Blickstein I, Goldman RD, Mazkereth R. Incidence and birth weight characteristics of twins born to mothers aged 40 years or more compared with 35–39 years old mothers: a populations study. J Perinat Med (2001) a 29:128–132.[CrossRef][Web of Science][Medline]
Blickstein I, Goldman RD, Mazkereth R. Maternal age and birth weight characteristics of twins born to nulliparous mothers: a population study. Twin Res (2001) b 4:1–3.[CrossRef][Medline]
Blickstein I, Keith DM. Aging, twinning, and perinatal outcomes. Fertil Steril (2003) 79:661.[Web of Science][Medline]
Blondel B, Kaminski M. Trends in the occurrence, determinants, and consequences of multiple births. Semin Perinatol (2002) 26:239–249.[CrossRef][Web of Science][Medline]
Bomsel-Helmreich O, Al Mufti W. The mechanism of monozygosity and double ovulation. In: Multiple Pregnancy: Epidemiology, Gestation and Perinatal Outcome—Keith LG, Papiernik E, Keith DM, eds. (1995) New York, London: The Parthenon Publishing Group. 25–40.
Branum AM, Schoendorf KC. The influence of maternal age on very preterm birth of twins: differential effects by parity. Paediatr Perinat Epidemiol (2005) 19:399–404.[CrossRef][Web of Science][Medline]
Cammu H, Martens G, Ruyssinck G, Amy J-J. Outcome after elective labor induction in nulliparous women: a matched cohort study. Am J Obstet Gynecol (2002) 186:240–244.[CrossRef][Web of Science][Medline]
Cammu H, Martens G, De Coen K, Van Mol C, Defoort P. Perinatal activities in Flanders, 2004. Yearly Report (2004) SPE.
Cleary-Goldman J, Malone FD, Vidaver J, Ball RH, Nyberg DA, Comstock CH, Saade GR, Eddleman KA, Klugman S, Dugoff L, et al. Impact of advanced maternal age on obstetric outcome. Obstet Gynecol (2005) 105:983–990.[Web of Science][Medline]
Cunningham FG, MacDonald PC, Gant NF, et al. Multifetal pregnancy. In: Williams Obstetrics—Cunningham FG, MacDonald PC, Gant NF, et al, eds. (2003) Norwalk, CT:: Appleton & Lange. 765.
Delbaere I, Verstraelen H, Goetgeluk S, Martens G, De Backer G, Temmerman M. Pregnancy outcome in primiparae of advanced maternal age. Eur J Obstet Gynecol Reprod Biol (2007) 135:41–46.[CrossRef][Web of Science][Medline]
Derom R, Orlebeke J, Eriksson A, Thiery M. The epidemiology of multiple births in Europe. In: Multiple Pregnancy: Epidemiology, Gestation and Perinatal Outcome—Keith LG, Papiernik E, Keith DM, et al, eds. (1995) London, New York: The Partenon Publishing Group. 145–161.
Dhont M, De Sutter P, Ruyssinck G, Martens G, Bekaert A. Perinatal outcome of pregnancies after assisted reproduction: a case - control study. Am J Obstet Gynecol (1999) 181:688–695.[CrossRef][Web of Science][Medline]
Endres MD, Wilkins I. Epidemiology and biology of multiple gestations. Clin Perinatol (2005) 32:301–314.[CrossRef][Web of Science][Medline]
Gilbert WM, Nesbitt TS, Danielsen B. Childbearing beyond age 40: pregnancy outcome in 24032 cases. Obstet Gynecol (1999) 93:9–14.[CrossRef][Web of Science][Medline]
Hansen JP. Older maternal age and pregnancy outcome: a review of literature. Obstet Gynecol Surv (1986) 41:726–742.[CrossRef][Medline]
Jacobsson BM, Ladfors LM, Milsom IM. Advanced maternal age and adverse perinatal outcome. Obstet Gynecol (2004) 104:727–733.[Web of Science][Medline]
Joseph KSM, Allen ACM, Dodds LP, Turner LAP, Scott HM, Liston RM. The perinatal effects of delayed childbearing. Obstet Gynecol (2005) 105:1410–1418.[Web of Science][Medline]
Kogan MD, Alexander GR, Kotelchuck M, et al. Trends in twin birth outcomes and intensive prenatal care utilization in the United States, 1981–1997. JAMA (2000) 284:335–341.
Kramer MS, Seguin L, Lydon J, Goulet L. Socio-economic disparities in pregnancy outcome: why do the poor fare so poorly? Paediatr Perinat Epidemiol (2000) 14:194–210.[CrossRef][Web of Science][Medline]
Lambalk CB, Boomsma DI, de Boer L, de Koning CH, Schoute E, Popp-Snijders C, Schoemaker J. Increased levels and pulsatility of follicle-stimulating hormone in mothers of hereditary dizygotic twins. J Clin Endocrinol Metab (1998) 83:481–486.
Liberatos P, Link BG, Kelsey JL. The measurement of social class in epidemiology. Epidemiol Rev (1988) 10:87–121.
Loos R, Derom C, Vlietinck R, Derom R. The East Flanders Prospective Twin Survey (Belgium): a population based register. Twin Res (1998) 1:167–175.[CrossRef][Medline]
Oleszczuk JJ, Keith DM, Keith L. Projections of population-based twinning rates through the year 2001. J Reprod Med (1999) 44:913–921.[Web of Science][Medline]
Oleszczuk JJ, Keith LG, Oleszczuk AK. The paradox of old maternal age in multiple pregnancies. Obstet Gynecol Clin North Am (2005) 32:69–80.[CrossRef][Web of Science][Medline]
Salihu HM, Aliyu MH, Kirby RS, Alexander GR. Effects of advanced maternal age on early mortality among quadruplets and quintuplets. Am J Obstet Gynecol (2004) 190:383–388.[CrossRef][Web of Science][Medline]
Seoud MAF, Nassar AH, Usta IM, Melhem Z, Kazma A, Khalil AM. Impact of advanced maternal age on pregnancy outcome. Am J Perinatol (2002) 19:1–7.[CrossRef][Web of Science][Medline]
Shevell T, Malone FD, Vidaver J, Porter TF, Luthy DA, Comstock CH, Hankins GD, Eddleman K, Dolan S, Dugoff L, et al. Assisted reproductive technology and pregnancy outcome. Obstet Gynecol (2005) 106:1039–1045.[Web of Science][Medline]
Study Centre for Perinatal Epidemiology (SPE) Flanders. Annual Report (2004).
van Katwijk C, Peeters LLH. Clinical aspects of pregnancy after the age of 35 years: a review of the literature. Hum Reprod Update (1998) 4:185–194.
Verstraelen H, Goetgeluk S, Derom C, Vansteelandt S, Derom R, Goetghebeur E, Temmerman M. Preterm birth in twins after subfertility treatment: population based cohort study. BMJ (2005) 331:1173.
Vleugels A, Bekaert A. The Flemish Centre for the study of perinatal epidemiology and its registry. Qual Assur Health Care (1992) 4:115–124.[Medline]
Zhang J, Meikle S, Grainger DA, Trumble A. Multifetal pregnancy in older women and perinatal outcome. Fertil Steril (2002) 78:562–568.[CrossRef][Web of Science][Medline]
Submitted on December 19, 2007; resubmitted on March 13, 2008; accepted on March 25, 2008.
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