The impact of assisted reproductive technology on pregnancies with very advanced maternal age

Objective

Since assisted reproductive technology has become an available choice of conceiving, maternal age of 45 years or more has increased significantly. For this group of women, medical literature uses the term “very advanced maternal age”. It was demonstrated in a number of studies that very advanced maternal age was highly associated with an increased risk of pregnancy complications and adverse perinatal outcomes. Asisted reproductive technology is also a risk factor for potential pregnancy complications. In this study, we aimed to report pregnancy complications and outcomes in women with very advanced maternal age who conceived with assisted reproductive technology compared with spontaneous conceptions.

 

Methods

In this retrospective cohort study we examined the outcome of pregnant women aged 45 years or more who presented to our outpatient clinic consecutively between 2015 and 2023. Demographic and obstetrical data were recorded in all patients within the study window. The study group were divided into two groups: women those who conceived spontaneously and those who conceived with ART. The ART group included patients who underwent in-vitro fertilisation(IVF) or intra-uterine insemination(IUI) treatment.
 

Results

More  than half of pregnancies in very advcanced maternal age resulted in pregnancy loss. We found no significant results in terms of, BMI, HTDP, DM and FGR. We did found that VAMA with ART pregnancies had higher CD rate(OR 4.0, 95% CI= 1.7-9.2), NICU admission(OR 4.3, 95% CI= 1.3-13.6), PB(OR 11.9, 95% CI= 3.2-43.2), and live birth rate(OR 2.3, 95% CI= 0.9-5.3) compared with VAMA with spontaneous pregnancies, but lower rates of birth weight(OR 0.9, 95% CI= 0.997-0.999), gestational age at birth(OR 0.5, 95% CI= 0.5-0.9), and pregnancy loss(OR 0.3, 95% CI= 0.1-0.8).
 

Conclusion

The use of assisted repsoductive technology in women with very advanced maternal age is a risk factor for advanced perinatal outcome. However, despite increased advanced perinatal outcome, higher live birth rates were detected. This may be a result of more attentive perinatal care.

 

Keywords

advanced maternal age, assisted reproductive technology, preeclampsia, pregnancy complications, preterm birth

Introduction

Medical literature uses the term “advanced maternal age(AMA)” for pregnancies in women aged over 35 years and “very advanced maternal age (VAMA)” for pregnancies in women aged over 45 [1-3].
Numerous studies demonstrated that VAMA were highly associated with an increased risk of pregnancy complications and adverse perinatal outcomes(APO)[4-5]. Diabetes mellitus (DM), hypertensive disorders of pregnancy (HTDP), higher cesarean delivery rates (CD), preterm birth (PB), low birthweight, and fetal growth restriction (FGR) are more common among these women [4-7,19,20]. ART is also a risk factor for potential pregnancy complications and has become very common among patients over 45 years [8-10]. Although we know that VAMA is associated with APO, we really do not know whether these results are associated with increasing use of ART or with advanced maternal age itself. Most studies on this subject compare AMA or/and VAMA groups with normal age groups(<35years) but does not examine the effect of ART on APO on this group [7,10,11]. There are few studies addressing outcomes in women with VAMA relative to ART despite its increased use. [12,13,18].
In this study, we aimed to report APO in women with VAMA and to compare women of VAMA conceived with ART and those who conceived spontaneously to better unterstand the effect of ART on APO in this age group.
 
 

Methods

This was a retrospective cohort study examining pregnant women aged 45 years or more who presented to our outpatient clinic consecutively between 2015 and 2023. Twins or higher order of pregnancies and patients with missing information were excluded from the study group. Ethical approval was obtained from Kartal Dr Lutfi Kırdar City Hospital ethics committee(no: 010.99/2/19). Descriptive data of the pregnant women such as age, gravidity, parity, gestational age during hospital admission, gestational age at birth, gestational weight at birth, height, pregnancy outcome, conceiving method, and perinatal outcome were recorded from our hospital’s electronic database. The families were contacted by phone to obtain information if the birth did not take place in our hospital.
Pregnancy loss was defined as a failure to achieve a healthy pregnancy before 24 weeks of gestation[14]. FGR were considered with an estimated fetal weight below the 10th centile[15]. HTDP was defined as a pregnant woman with chronic hypertension, gestational hypertension, or preeclampsia[16]. Preterm birth was defined as a birth occurring before 37 weeks of pregnancy[17]. All women who had pre-gestational diabetes or were diagnosed with diabetes during pregnancy were included in the DM group.
The study group were divided into two groups: women those who conceived spontaneously and those who conceived with ART. The ART group included patients who underwent in-vitro fertilisation(IVF) or intra-uterine insemination(IUI) treatment. It could not be recorded whether the patients concieved with oocyte donation or not because this method is not legal in our country so patients avoid saying even if they concieved with oocyte donation in other countries.
 
In the analysis results, the descriptive statistics of continuous variables are shown as mean ± standard deviation, and the descriptive statistics of categorical variables as numbers (n) and percentages (%). Analyses were conducted using the SPSS (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp) version 22 software package. The normality of distribution of continuous variables was assessed using the Kolmogorov-Smirnov test. The Mann-Whitney U test was used to analyze quantitative independent data, and the Chi-square test and Fisher’s exact test were used to analyze qualitative independent data. P-values ​​of <0.05 were considered statistically significant.
 

Results

During the study period, 166 pregnant women with VAMA were admitted to our hospital. Fifteen patients were excluded due to missing information or not meeting the inclusion criteria. A total of 151 women were finally included in the analysis, with a mean of 46±1.35SD years(range 45-51) Of these, 78 (51.6%) pregnancies resulted in pregnancy loss and 73 (48.4%) resulted in live birth. When we examined pregnancy losses, 48 (61.5%) resulted in spontaneous abortion, 27 (34.7%) in fetal demise, two (2.5%) in molar pregnancy, and one (1.3%) in ectopic pregnancy(Figure 1).
 When evaluating the results of live births, 50 (68.4%) of the live births were born by CD. 18 CD (36%) were performed due to a previous cesarean section; 12 (24%) were performed by maternal request, 6 (12%) were performed due to a preeclampsia with severe features, and 6 (12%) due to fetal distress. Primary CD ( first CD of a women) was performed in 32 (43.8%) patients.
Of the 151 pregnant women, 28 had an ART and 123 had a spontaneous pregnancy. When comparing the results (Table 1), we found no significant results in terms of , BMI, HTDP, DM and FGR. We did found that VAMA with ART pregnancies had higher CD rate(OR 4.0, 95% CI= 1.7-9.2), NICU admission(OR 4.3, 95% CI= 1.3-13.6), PB(OR 11.9, 95% CI= 3.2-43.2), and live birth rate(OR 2.3, 95% CI= 0.9-5.3) compared with VAMA with spontaneous pregnancies, but lower rates of birth weight(OR 0.9, 95% CI= 0.997-0.999), gestational age at birth(OR 0.5, 95% CI= 0.5-0.9), and pregnancy loss(OR 0.3, 95% CI= 0.1-0.8).
 
 

Discussion

In our study, we evaluated VAMA pregnancies and compared outcomes in women with VAMA who conceived with ART and those of spontaneous conceptions. We found that CD rates, NICU admissions, preterm labor, maternal age, and live birth rates were significantly higher in the ART group. There was no significance in terms of HTDP, diabetes, and FGR. However, birthweight, gestational age at birth, and pregnancy loss were significantly lower in the ART group.
In our population, more than half of all VAMA pregnancies resulted in pregnancy loss. In 2019, Magnus et al.[21] reported that the risk of miscarriage was 10% in women aged between 25-29 years and rose significantly after the age of 30 reaching 57% in VAMA. However, these rates include only clinically recognized pregnancies and the total rate among all ages may be as high as 31% [22].
The primary CD rate was 43.8% in VAMA group, which is quite high considering that the primary CD rate in our hospital in the last 3 years was 10-20%. In 2023, Sugai et al.[23] showed higher CD rate for pregnant patiens in older age(≥45 years) (OR, 2.87 95% CI, 2.50–3.30)than those aged <45 years. It has been suggested that the reason of higher CD rate among older patients is that arteriosclerosis of the uterine arteries which causes a decrease in contractility of myometrium and  negatively effect the progression of labor[24]. ART pregnancies are also found to be a risk factor for CD.  In our study, we found that CD rates were 4-fold increased in the VAMA group conceiving with ART than those who conceived spontaneously. In a meta-analysis in 2021, Lodge-Tulloch et al.[25] demonstrated that ART pregnancies were associated with a 1.91-fold increase of elective CD and 1.38-fold increase of emergency CDs .This increase in the elective CD rate may be explained by patients with long-term infertility and a possible difficulty of conceiving again due to advanced age requesting a CD out of fear of harm to the baby. The increase of emergency CD may also be a result of pregnancy complications due to ART. Another explanation might be that physicians have a lower threshold to recommending CD in this population.
            In recent studies, it has been suggested that women who become pregnant older are more often primiparous and they have higher socioeconomic status, which may ameliorate the effect of VAMA on perinatal outcomes [26-27]. Despite the more advanced age, the use of ART to conceive, and higher rates of preterm labor, more attentive maternal and perinatal care may increase rates of liveborn babies. In our study, the ART group had higher liveborn rate which may be a result of older and mostly nulliparous women in this group.
 
We found significantly higher rates of PB among pregnancies conceived with ART. In a multicenter cohort study in China, they also found higher risks of DM, HTDP, CD and PB for those aged ≥45 years[28]. In previous studies, ART was also found associated with higher rates of preterm labor. However, the reason for the higher rates of preterm birth was not iatrogenic due to pregnancy complications. It was thought that this may be the result of an unknown intrinsic factor [29-32]. This also may explain why, in our study, we found higher preterm birth rates in the ART group without higher rates of HTDP, diabetes, or FGR.
Many studies reported a higher incidence of HTDP, diabetes, and FGR in pregnancies with AMA [33-38]. Increased risks were also found in pregnancies with ART compared with spontaneously conceived pregnancies [39-41]. In a population based cohort study in Netherland, author  found markedly increased risks for gestational diabetes (four times higher), hypertensive disorders (11 times higher), SGA neonates (three times higher), and prematurity (three times higher) compared with the reference group. This risk was doubled even in women aged 40-44 and 45-49 years [42].
In our study, we found no significant difference in terms of HTDP, DM, and FGR between pregnant women age over 45 years who conceived with ART and who did not. The reason for this may be that we did not include multiple pregnancies in the study group. In practice guideline of Genetics Committee of Society of Obstetricians and Gynaecologists of Canada stated that the majority of APO after ART arise as a result of multiple pregnancies[43].  Another possible reason, as mentioned previously, women who become pregnant aged over 45 years have better socioeconomic status, self-care, and they usually have better prenatal care.
Our study has some strengths and limitations. The retrospective nature of the study and the relatively small sample number are the main limitations. Due to the small number of cases, it is not possible to analyze ART subgroups such as intrauterine insemination or in vitro fertilization. Oocyte donation is not legal in our country, and some of patients do not state that they have received donated oocytes in other countries despite becoming pregnant in this way. Women who become pregnant through oocyte donation are increasing in daily practice and should be examined as a separate subgroup. Another limitation is we do not know genetic studies if performed and long-term outcomes of the newborns. The strength of our study is that we report the experience of a single tertiary center. Another strength is that is that we included all patients aged over 45 years who were admitted with a diagnosis of pregnancy, not just those who resulted in birth so we can give the overall results of VAMA pregnancies.
 

Conclusion

The use of ART in VAMA is a risk factor for APO. However, despite increased APO, higher live birth rates were detected. This may be a result of more attentive perinatal care. Prospective studies with a larger number of patients are needed to predict and prevent pregnancy complications in this extreme population.
 

1-Wang J.,  Sauer M. V. . In vitro fertilization (IVF): a review of 3 decades of clinical innovation and technological advancement. Therapeutics and clinical risk management, 2(4), 2006;355–364.
2-Sauer M. V. . Reproduction at an advanced maternal age and maternal health. Fertility and sterility, 103(5), 2005;1136–1143.
3- Smithson S. D., Greene N. H., Esakoff T. F. Pregnancy outcomes in very advanced maternal age women. American journal of obstetrics & gynecology MFM, 2022;4(1),
4- Leader J., Bajwa A., Lanes A., Hua X., Rennicks White R., Rybak N., et al. The effect of very advanced maternal age on maternal and neonatal outcomes: A Systematic Review. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC, 40(9), 2018;1208–1218.
5. Callaway LK, Lust K, McIntyre HD. Pregnancy outcomes in women of very advanced maternal age. Aust N Z J Obstet Gynecol 2005;45:12-6.
6. Dildy GA, Jackson GM, Fowers GK, Oshiro BT, Varner MW, Clark SL. Very advanced maternal age: pregnancy after age 45. Am J Obstet Gynecol 1996;175:668-74.
7-Yogev Y., Melamed N., Bardin R., Tenenbaum-Gavish K., Ben-Shitrit G.,Ben-Haroush, A. Pregnancy outcome at extremely advanced maternal age. American journal of obstetrics and gynecology, 203(6), 2010;558.e1–558.e5587.
8-Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 2002;346:725–30.
9- Schieve LA, Ferre C, Peterson HB, Macaluso M, Reynolds MA, Wright VC. Perinatal outcome among singleton infants conceived through assisted reproductive technology in the United States. Obstet Gynecol 2004;103:1144–53.
10-Moaddab A., Laurence B.M., Haleh S.H., Amir A.S., Amy S., Sara E. A. et al. "Effect of advanced maternal age on maternal and neonatal outcomes in assisted reproductive technology pregnancies." European Journal of Obstetrics & Gynecology and Reproductive Biology 216 (2017): 178-183.
11- Balasch, J. Gratacós, E. Delayed childbearing: effects on fertility and the outcome of pregnancy. Current opinion in obstetrics & gynecology, 24(3), 2012;187–193.
12-Montan S. Increased risk in the elderly parturient. Current opinion in obstetrics & gynecology, 19(2), 2007; 110–112.
13-Jackson S., Hong C., Wang E. T., Alexander C., Gregory K. D., Pisarska M.D. Pregnancy outcomes in very advanced maternal age pregnancies: the impact of assisted reproductive technology. Fertility and sterility, 103(1), 2015; 76–80.
14- ESHRE Guideline Group on RPL, Bender Atik, R., Christiansen, O. B., Elson, J., Kolte, A. M., Lewis, S., Middeldorp, S., Mcheik, S., Peramo, B., Quenby, S., Nielsen, H. S., van der Hoorn, M. L., Vermeulen, N., & Goddijn, M. (2023). ESHRE guideline: recurrent pregnancy loss: an update in 2022. Human reproduction open, 2023(1), hoad002.
 
15- ACOG Practice Bulletin No. 227: Fetal Growth Restriction: Correction. (2021). Obstetrics and gynecology, 137(4), 754.
 
16- Helewa, M. E., Burrows, R. F., Smith, J., Williams, K., Brain, P., & Rabkin, S. W. (1997). Report of the Canadian Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of hypertensive disorders in pregnancy. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 157(6), 715–725.
17- Dagklis, T., Akolekar, R., Villalain, C., Tsakiridis, I., Kesrouani, A., Tekay, A., Plasencia, W., Wellmann, S., Kusuda, S., Jekova, N., Prefumo, F., Volpe, N., Chaveeva, P., Allegaert, K., Khalil, A., & Sen, C. (2023). Management of preterm labor: Clinical practice guideline and recommendation by the WAPM-World Association of Perinatal Medicine and the PMF-Perinatal Medicine Foundation. European journal of obstetrics, gynecology, and reproductive biology, 291, 196–205.
 
18-Lang M., Zhou M., Lei R., Li W. Comparison of pregnancy outcomes between IVF-ET pregnancies and spontaneous pregnancies in women of advanced maternal age. The journal of maternal-fetal & neonatal medicine: The official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 36(1), 2023; 2183761.
19. Cunningham FG, Leveno KJ. Childbearing among older women the message is cautiously optimistic. N Engl J Med 1995;333:1002–4.
20. Kenny LC, Lavender T, McNamee R, O'Neill SM, Mills T, Khashan AS. Advanced maternal age and adverse pregnancy outcome: evidence from a large contemporary cohort. PLoS One 2013;8:e56583
21- Magnus M.C., Wilcox AJ., Morken N.H., Weinberg C.R., Haberg S. E. Role of maternal age and pregnancy history in risk of miscarriage: Prospective register based study. BMJ (Clinical research ed.), 364, 2019;l869.
22- Wilcox A.J., Weinberg C.R., O'Connor J.F., Baird D. D., Schlatterer J. P., Canfield R. E., et al. Incidence of early loss of pregnancy. The New England journal of medicine, 319(4), 1988;189–194.
23- Sugai S, Nishijima K, Haino K, Yoshihara K. Pregnancy outcomes at maternal age over 45 years: a systematic review and meta-analysis. Am J Obstet Gynecol MFM. 2023 Apr;5(4):100885. doi: 10.1016/j.ajogmf.2023.100885.
 
24-Osmundson, S. S., Gould, J. B., Butwick, A. J., Yeaton-Massey, A., & El-Sayed, Y. Y. (2016). Labor outcome at extremely advanced maternal age. American journal of obstetrics and gynecology, 214(3), 362.e1–362.e3627. https://doi.org/10.1016/j.ajog.2015.09.103
 
25-Lodge-Tulloch N. A., Elias F. T. S., Pudwell J., Gaudet L., Walker M., Smith, G. N., et al. Caesarean section in pregnancies conceived by assisted reproductive technology: a systematic review and meta-analysis. BMC pregnancy and childbirth, 21(1), 2021;244.
26. Conway DA, Patel SS, Liem J, Fan KJ, Jalian R, Williams J 3rd, et al. The risk of cytogenetic abnormalities in the late first trimester of pregnancies conceived through assisted reproduction. Fertil Steril 2011;95:503–6.
27. Carolan M, Frankowska D. Advanced maternal age and adverse perinatal outcome: a review of the evidence. Midwifery 2011;27:793–801.
28- Zhou, Y., Yin, S., Sheng, Q., Yang, J., Liu, J., Li, H., Yuan, P., & Zhao, Y. (2023). Association of maternal age with adverse pregnancy outcomes: A prospective multicenter cohort study in China. Journal of global health, 13, 04161. https://doi.org/10.7189/jogh.13.04161
 
29. Chan BC, Lao TT. Effect of parity and advanced maternal age on obstetric outcome. Int J Gynaecol Obstet 2008;102:237–41.
30. Santi E., Nencini G., Cerni A., Greco P., Spelzini F., Tormettino B., et al. The PLART study: incidence of preterm labor and adverse pregnancy outcomes after assisted reproductive techniques-a retrospective cohort study. Archives of gynecology and obstetrics, 300(4), 2019;911–916.
31. Cavoretto P, Candiani M, Giorgione V, Inversetti A, Abu-Saba M, Tiberio F et al Risk of spontaneous preterm birth in singleton pregnancies conceived after IVF/ICSI treatment: meta-analysis of cohort studies. Ultrasound Obstet Gynecol 51(1):2018;43–53
32. Pandey S., Shetty A., Hamilton M., Bhattacharya S., Maheshwari A. Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Human reproduction update, 18(5), 2012;485–503.
33. O'Leary CM, Bower C, Knuiman M, Stanley FJ. Changing risks of stillbirth and neonatal mortality associated with maternal age in Western Australia 1984–2003. Paediatr Perinat Epidemiol 2007;21:541–9.
34. Ates S, Batmaz G, Sevket O, Molla T, Dane C, Dane B. Pregnancy outcome of multiparous women aged over 40 years. Int J Reprod Med 2013; 287519.
35. Schimmel MS, Bromiker R, Hammerman C, Chertman L, Ioscovich A, Granovsky-Grisaru S, et al. The effects of maternal age and parity on maternal and neonatal outcome. Arch Gynecol Obstet 2015;291:793–8.
36. Marozio L, Picardo E, Filippini C, Mainolfi E, Berchialla P, Cavallo F, et al. Maternal age over 40 years and pregnancy outcome: a hospital-based survey. J Matern Fetal Neonatal Med 2019;32:1602–8.
37. Arya S, Mulla ZD, Plavsic SK. Outcomes of women delivering at very advanced maternal age. J Womens Health (Larchmt) 2018;27:1378–84.
38. Kanmaz A. G., İnan A. H., Beyan E., Ögür S.,  Budak A. Effect of advanced maternal age on pregnancy outcomes: a single-centre data from a tertiary healthcare hospital. Journal of obstetrics and gynaecology: the journal of the Institute of Obstetrics and Gynaecology, 39(8), 2019;1104–1111.
39. Qin J., Liu X., Sheng X., Wang H., Gao S. Assisted reproductive technology and the risk of pregnancy-related complications and adverse pregnancy outcomes in singleton pregnancies: a meta-analysis of cohort studies. Fertility and sterility, 105(1), 2016;73–85.e856.
40- Lei L.L., Lan Y.L., Wang S.Y., Feng W., Zhai Z.J.. Perinatal complications and live-birth outcomes following assisted reproductive technology: a retrospective cohort study. Chin Med J (Engl). 2019;132(20):2408-2416.
41. McDonald S., Murphy K., Beyene J., Ohlsson A. Perinatal outcomes of singleton pregnancies achieved by in vitro fertilization: a systematic review and meta-analysis. J Obstet Gynaecol Can 2005;27:449–459
42- Rademaker D, Hukkelhoven CWPM, van Pampus MG. Adverse maternal and perinatal pregnancy outcomes related to very advanced maternal age in primigravida and multigravida in the Netherlands: A population-based cohort. Acta Obstet Gynecol Scand. 2021 May;100(5):941-948. doi: 10,1111/aogs.14064
43- Okun, N., Sierra, S., GENETICS COMMITTEE, & SPECIAL CONTRIBUTORS (2014). Pregnancy outcomes after assisted human reproduction. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC, 36(1), 64–83. https://doi.org/10.1016/S1701-2163(15)30685-X
 
 
 

	File/Dsecription
	Figure-1 Flowchart of the study group
	Table 1 Distribution of pregnancy complications and results between women with VAMA who conceived with ART compared with spontaneous conceptions