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This chapter should be cited as follows:
Banerjee A, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.416643

The Continuous Textbook of Women’s Medicine SeriesObstetrics Module

Volume 8

Maternal medical health and disorders in pregnancy

Volume Editor: Kenneth K Chen, MD, Alpert Medical School of Brown University, USA Originating Editor: Professor Sandra Lowe

Chapter

Very Advanced Maternal Age and Pregnancy

First published: August 2021

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INTRODUCTION

The average age of childbirth has been rising markedly across the Western world.1 The changing obstetric landscape and multi-morbidity will mean that we will, in time, see these effects across the globe. Advanced maternal age is defined as women >35 years old. Very advanced maternal age (VAMA) and extremely advanced maternal age (EAMA) are defined as women >40 and >45 years old, respectively. Women may choose to delay pregnancy to complete higher education, develop their careers, gain financial security, or for their own personal choice. Numerous studies have demonstrated a continuum for the risk of both the mother and baby with advancing maternal age. VAMA is an independent risk factor for an adverse pregnancy. In this chapter we will review the current literature, highlight the challenges, and suggest pathways to enable us to manage the complexity involved in VAMA women.

EPIDEMIOLOGY

Pregnancy for VAMA has increased in many high-income countries over the past several decades, including those in Europe, the USA, Japan, and the UK.2,3 Birth rates have declined for women aged 20–29 years, remain unchanged for women aged 30–34 years and rose for women aged 35–44 years. In the UK the proportion of maternities in women aged >35 years has increased from 8% (approximately 180,000 maternities) in 1985–87 to 20% (almost 460,000 maternities) in 2006–8. In women aged >40 years this has trebled in the same time, from 1.2% (almost 27,000 maternities) to 3.6% (approximately 82,000 maternities). The US maternal mortality rate for women of VAMA (81.9 per 100,000 live births) is nearly eight times that for women <25 years old (10.6 per 100,000 live births).4 The UK maternal mortality rate for women of VAMA (24 per 100,000 live births) is four times that for women aged 20–24 years (six per 100,000 live births).5

IMPLICATIONS FOR A VAMA PREGNANCY

The implications of VAMA pregnancy include risks to the mother and baby and obstetric outcomes. With a VAMA we have to contend with the fact that our women are more likely to have pre-existing health conditions and require more fertility intervention.6 For VAMA women, maternal age should be combined with other maternal characteristics and obstetric history when determining an individualized adjusted risk for adverse pregnancy complications.7,8 Pregnancy in women of VAMA presents ethical and legal implications to both the individual, her family, and society as a whole. These should preferably be considered prior to pregnancy, particularly as reproductive assistance is often required to achieve pregnancy in this age group. With VAMA there is an increased risk of dying – who would be the next of kin and parent to the baby?

The maternal outcomes include: increased morbidity and mortality, gestational diabetes mellitus, hypertensive disorders, and longer length of stay during the postpartum period.9,10,11 There are worse perinatal outcomes, more preterm delivery, lower birth weight, fetal growth restriction, macrosomia, large for gestational age, perinatal mortality and stillbirth.12,13 Obstetric outcomes include increased risk of miscarriage, cervical incompetence, placental abruption, more elective and emergency Cesarean sections, postpartum hemorrhage, and sepsis.14,15

Cardiovascular disease is reported as a leading cause of mortality in the Western world. Many women whose deaths have been documented in these reports did not know of their underlying cardiac disease prior to pregnancy. Age is a known risk factor for both maternal cardiovascular disease and adverse outcomes in pregnancy.16 A population-based retrospective cohort study found that maternal-age-specific incidence of severe morbidity varied by outcome. EAMA had significantly elevated rates of some of the most severe, potentially life-threatening, morbidities including renal failure, shock, acute cardiac morbidity, serious complications of obstetric interventions, and ICU admission.17

With increasing maternal age there is a continuum of growing risks. Complications described in VAMA occur more commonly during the antenatal period than during the postnatal period, followed by a smaller group having problems during the intrapartum period.14,15 VAMA women have an increased risk of miscarriage (adjusted OR 2.32, 95% CI 1.83–2.93).7 There is an association between increasing maternal age and postpartum hemorrhage in VAMA women (RR 4.94, 95% CI 4.09–5.96).14 There is also an increasing association with maternal age and elective cesarean section in VAMA nulliparous women (RR 8.23, 95% CI 6.23–10.88) versus multiparous (RR 3.73, 95% CI 2.94–4.74). The risk of low birthweight is higher in VAMA (RR 1.43, 95% CI 1.19–1.73). A large retrospective study found that VAMA remained an independent risk factor for gestational diabetes mellitus, even after adjusting for confounding factors (OR 2.80 and 3.14 for women aged 40–44 and >45 years, respectively).15 The risk of placenta previa was also increased (40–44 years, OR 2.56; >45 years, OR 4.83). EAMA women had OR 2.62 (95% CI 1.30–5.27) for iatrogenic prematurity. These risks are summarized in Table 1.

1

Maternal, fetal and obstetric risks in VAMA mothers.

Maternal risks

Obstetric risks

Fetal/neonatal risks

Gestational diabetes mellitus

Pre-eclampsia and other hypertensive disorders

Cardiovascular disease

Increased length of stay

Sepsis

Venous thromboembolism

Cervical incompetence/miscarriage

Premature rupture of membranes

Placenta previa

Placental abruption

Elective/emergency cesarean-section

Postpartum hemorrhage

Chromosomal abnormalities

Stillbirth and fetal loss

Pre-term birth

Macrosomia/large for gestational age

Low birthweight/small for gestational age

NICU admissions

Perinatal mortality

To date, the oldest woman known to have had a successful outcome was a primiparous woman following a donor oocyte in vitro fertilization.18 She delivered by elective cesarean section and became a mother at the age of 68 years.

CONSIDERATIONS AND MEDICAL EVALUATION OF PRE-PREGNANCY COUNSELING

Medical evaluation and counseling prior to pregnancy is essential for the optimal outcome of any pregnancy. This is an opportunity to improve health and mitigate by assessment of pre-pregnancy lifestyle and health, as well as the woman’s suitability to embark on a future pregnancy. All women of VAMA should be offered pre-pregnancy counseling (Table 2). Counseling and work-up may need to be bespoke. It is important to address all psychosocial and physical aspects for every VAMA woman. An open and honest bidirectional conversation balancing the woman’s autonomy and caregiver is important. The VAMA and EAMA groups face different risks, with an increased risk of complications in the latter compared to the former and to younger women (RR 3.32).19

Women with VAMA also require counseling regarding pre-existing medical conditions and the risks that pregnancy may pose to themselves and their fetus. Optimization of pre-existing medical conditions is essential, along with risk stratification and harm minimization strategies.

Favorable outcomes for VAMA are possible for healthy women who have been screened to exclude pre-existing disease. This is also an opportunity to separate low- and high-risk VAMA women as they proceed to a pregnancy, to enable timely investigations and surveillance.

2

Checklist for VAMA pre-pregnancy counseling.

Assessments

Investigations

Actions

  • Routine
  • Screening for metabolic disease and bone health
  • Screening for cardiovascular disease
  • Screening for cancer detection
  • Pre-existing medical conditions
  • Body mass index
  • Urine dipstick for protein and glucose
  • Cervical screening
  • Smoking/alcohol history
  • Lipid profile
  • HbA1c
  • Renal profile
  • Bone profile/vitamin D
  • Liver profile
  • Thyroid function
  • Blood pressure
  • Family history, including any history of sudden cardiac death
  • Echocardiogram
  • Stress test if indicated
  • Disease activity
  • Disease impact
  • Review medication
  • Duration of disease
  • Prognosis
  • Lifestyle modifications
  • Further investigation and management
  • Pharmacotherapy as indicated
  • Optimize underlying condition
  • Modify medications if necessary
  • Ensure period of disease remission/stability
  • Advise re. timing of pregnancy

In vitro fertilization (IVF) pre-pregnancy work-up is even more important in VAMA women. There are situations with increasing age in which embryo transfer should be strongly discouraged, particularly in women with complex multimorbidity as there could be exacerbation of their pre-existing condition and an even higher obstetrical risk.

IVF AND VAMA

The success rates for assisted reproduction techniques in VAMA are all extremely low, including ovulation induction and intra-uterine insemination, being as low as <1% live births per cycle in this group.20 The same review suggested that IVF offers a relatively higher success rate, of around 13.7% per cycle.

A UK national study examined pregnancy complications in EAMA and compared maternal and neonatal outcomes among 233 women aged 48–61 years with 454 women aged 16–46 years. In the latter group, 76% had conceived following IVF or intra-cytoplasmic sperm injection (ICSI) compared with 4% of the former. The older group were more likely to be pregnant for the first time, be overweight or obese, have pre-existing medical conditions, and be carrying a multiple pregnancy.21 Another study found that IVF and the use of donor eggs are individual risk factors for pre-eclampsia in VAMA women.22

As assisted reproductive techniques, particularly the use of donor eggs, continue to improve and become more widely available, more VAMA women will use this route to becoming pregnant. The above findings should be considered when counseling VAMA women about their infertility treatment options and consequences.

ANTENATAL CARE

Once pregnancy is confirmed, the advice should be to book as early as possible and have a maternal health assessment with a qualified health professional, including a full medical history and focused examination (Table 3). Any relevant information from the pre-pregnancy assessment should be made available to the maternity care team at this time. This will aid in stratifying low- and high-risk VAMA women, to facilitate timely investigations and surveillance. Table 3 lists the relevant baseline investigations.

3

Baseline Investigations for VAMA mothers.

Recommendation

Rationale

ECG at booking
(consider echocardiogram if pre-existing history of hypertension or heart disease)

  • Baseline ECG would be beneficial to aid assessment later on in pregnancy

HbA1c and consider an early oral glucose tolerance test (OGTT)

  • To diagnose pre-diabetes/pre-existing (type 2) diabetes mellitus

Renal profile

Urine protein/creatinine ratio

Vitamin D

  • To aid diagnosis and management later on in pregnancy
  • Pregnancy may unmask pre-existing renal disease
  • Opportunity to maintain vitamin D levels

Serial ultrasound measurement of fetal size and assessment of well-being with umbilical artery Doppler from 26–28 weeks of pregnancy

  • There is increased risk of small for gestational age (SGA), pre-eclampsia and intra-uterine growth retardation (IUGR)

Using multivariate logistic regression analysis and adjusting for confounders, the risk for late-onset pre-eclampsia has been shown to increase by 4% with every 1-year increase in maternal age >32 years.23 For all women of VAMA aspirin (75–150 mg once daily nocte) is beneficial. More recent evidence highlights the dose of 150 mg of aspirin in women with risk factors for early onset pre-eclampsia is even more favorable.24

Ongoing care

Regular review and continuity of care in an appropriate maternity care setting is important for VAMA women. VAMA women with any known medical complications and who are deemed as high risk should be seen regularly in a joint obstetric/maternal medicine antenatal clinic. An early OGTT is important to screen for gestational diabetes for all VAMA women. A joint multidisciplinary team meeting with high-risk VAMA woman should be scheduled for 32–34 weeks' gestation to plan the mode and timing of delivery.

VAMA women should be considered for additional fetal monitoring in late pregnancy and the intrapartum period. During the antenatal period surveillance, serial growth scans, cardiotocography and kick charts can be helpful. A low threshold to be reviewed within a maternity setting should be advised if there are any concerns.

Studies of the intrapartum period have shown that there is a higher risk of perinatal mortality at this time. One study found that VAMA was independently associated with risk of anoxic death among primiparous (adjusted OR 5.34, 95% CI 2.34–12.20) and multiparous women (adjusted OR 2.14, 95% CI 0.99–4.60).25 Continuous electronic fetal monitoring should be considered for VAMA women during the intrapartum period.

CARDIAC SYMPTOMS IN VAMA PREGNANCY

The increasing rates of obesity and metabolic syndrome are further accelerating the rate of acquired cardiac disease among VAMA women. The MBRRACE reports have highlighted that cardiac disease is the leading cause of indirect maternal mortality. In the latest report, VAMA women were at increased risk of cardiac disease (RR 2.21, 95% CI 0.46–9.32). VAMA women are also at increased risk of cardiomyopathy and acute coronary syndrome. The incidence of these conditions is increased 3–4-fold with pregnancy, and is even higher in a VAMA pregnancy.26,27 This can easily be missed, particularly if there has been no work-up for maternal health prior to pregnancy. Investigation should not be compromised simply because the woman is pregnant, because most imaging can be performed safely in pregnancy (see chapter on Radiation in Pregnancy).

VAMA women with dyspnea or any chest pain should have a focused and timely set of investigations including an ECG, troponin, cardiac ECHO, and coronary artery/pulmonary imaging if indicated. If symptoms do not resolve, all efforts should be made to make a diagnosis rather than simply to exclude one.

Timing of delivery

The risk of stillbirth increases with increasing maternal age, such that women ≥40 years have the same risk of stillbirth at 39 weeks of gestation as those in their mid-20s at 41 weeks.28,29 For this reason, it is considered appropriate to offer delivery at around at 39–40 weeks in women of VAMA unless there are other obstetric considerations. The timing of delivery should involve shared decision making. There are no specific data regarding VAMA women, although induction of labor in low-risk nulliparous women does not appear to increase the risk of cesarean delivery.30

The timing of delivery should involve shared decision making. One randomized control study showed no increase in emergency cesarean rate or adverse outcome for either mother or neonate when induced at 39 weeks versus expectant care (RR 0.99, 95% CI 0.87–1.14).31One meta-analysis found that VAMA women were more likely to have been offered an induction of labor and elective cesarean delivery.32 The reasons behind this are complex. From a large maternity hospital, retrospective data found an increasing association with maternal age and elective cesarean section in VAMA nulliparous women (RR 8.23, 95% CI 6.23–10.88) versus multiparous (RR 3.73, 95% CI 2.94–4.74).14 This most likely reflects the mother’s preference and health professionals' preferences for a low threshold for risk avoidance.

Intrapartum care

Increasing maternal age is found to be associated with intrapartum complications, including postpartum hemorrhage and emergency cesarean section. EAMA women in one study had an adjusted OR of 2.03 (95% CI 1.50–2.74) for emergency cesarean section.15 EAMA women have approximately eightfold risk for postpartum hemorrhage.33 The incidence of peripartum hysterectomy was 1% in mothers <20 years and 13% in VAMA mothers.34 Delivery should be planned, preferably in a hospital setting where there is access to obstetric services and early critical care within reach if complications arise.

Due to age-related changes in the spine, there may be more technical difficulties while placing a neuraxial block. Performance of neuraxial anesthesia in the VAMA mother may be different regarding the absorption, distribution, and clearance of local anesthetic compared to the pharmacokinetics in a younger woman.18

One cohort study examined risk factors for peripartum hysterectomy using data from Africa, Asia, Europe, and the Americas. The authors speculate that the reason behind the lower threshold for hysterectomy is that VAMA women were thought less likely to have more offspring. There is an increased risk of peripartum hysterectomy at cesarean section in VAMA women when compared to that of a mother aged 20 years (OR 11.73, 95% CI 6.3–21.85 ).34

VAMA was found to have worse perinatal outcomes including preterm delivery, low birthweight babies (RR 1.43, 95% CI 1.19–1.73), higher rates of neonatal intensive care unit admission, and worse Apgar scores14 VAMA have a twofold increased risk of delivery related to perinatal death.25 Surveillance and multidisciplinary working with obstetricians, anesthetists, neonatologists, and midwives is essential at this time.

POSTPARTUM CARE AND LACTATION

There are limited data around outcomes during the postpartum period of a VAMA pregnancy. Postpartum chronic hypertension at around 3 months is associated with advanced maternal age (adjusted OR 1.10, 95% CI 1.01–1.21).35 It is particularly relevant for VAMA women with hypertension during pregnancy or the postpartum period to have a follow-up with their general practitioner. All VAMA women should receive contraception advice and a plan should be in place prior to discharge.

There is a paucity of data of the effect of lobular involution in VAMA and breastfeeding. One meta-analysis found that older maternal age was associated with a higher prevalence of poor sleep quality.36

LONG-TERM CONSEQUENCES

The long-term clinical manifestations for VAMA mothers and children are unfolding at this time.37

During pregnancy, VAMA women are more likely to have complications including pre-eclampsia and intra-uterine growth retardation, resulting in a known increase in cardiovascular disease later in life for both mother and child. The Women’s Health Initiative Study found that women who had their last pregnancy at VAMA were at increased risk of hemorrhagic stroke compared with those whose last pregnancy was at <40 years. The rate for ischemic stroke was 3.8 versus 2.4%, hemorrhagic stroke 1.0 versus 0.5%, and cardiovascular mortality 3.9 versus 2.3%.38 There was also a trend towards a higher rate of acute coronary syndrome among women with their last pregnancy at VAMA, at 3.0 versus 2.5%. One population-based cohort study reviewed all hospitalizations of children up to the age of 18 years of age and born to VAMA women, and found they did not appear to be at increased risk for long-term morbidity.39 More studies are required to determine whether VAMA mothers and their children are at risk long term and, if so, development of strategies for identifying and preventing long-term morbidity is required. Albeit for now, a targeted assessment should be performed on all VAMA women to try and reduce their cardiovascular morbidity risk over the long term.

IMPLICATIONS FOR HEALTH SYSTEMS IN LOW-RESOURCE COUNTRIES

Due to the obstetric shift, more VAMA women will become pregnant worldwide. This has implications for the health of both woman and offspring, as well as broader implications on healthcare resourcing including access to assisted reproductive technologies as well as pregnancy and long-term care. With many competing health priorities, these issues need to be addressed within sociopolitical frameworks. The responsibility for addressing these issues must be shared with the full range of stakeholders, including the VAMA woman and her family, healthcare providers and healthcare delivery organizations.

CONCLUSIONS

Maternal age should be combined with other maternal risk factors and obstetric history when calculating an individualized adjusted risk for adverse pregnancy complications. There is strong evidence of an association between VAMA and adverse maternal outcomes, severe medical and obstetric morbidity during pregnancy.40 The perinatal outcomes and the absolute rate of stillbirth/perinatal death remains low, <10 per 1000 births in most high-income countries. The best outcomes appear to be linked to optimization of pre-existing maternal health prior to pregnancy and ongoing antenatal care with a multidisciplinary team approach.41,42

Given this growing and evolving VAMA population, ongoing education of, and awareness by, healthcare providers are imperative for a satisfactory outcome for both mother and baby.

PRACTICE RECOMMENDATIONS

  • VAMA woman contemplating a pregnancy should be advised to have pre-pregnancy counseling.
  • Pre-pregnancy work-up for VAMA women includes identification and treatment of medical conditions prior to conception.
  • VAMA women require close surveillance throughout pregnancy.
  • VAMA women require follow-up postpartum to optimize long-term health.


CONFLICTS OF INTEREST

The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.

GUIDELINES OF INTEREST

  • Dhanjal MK, Kenyon A. Induction of Labor at Term in Older Mothers. Scientific Impact Paper No. 34, Royal College of Obstetricians and Gynaecologists; London, UK, 2013.
  • Committee Opinion Female Age-Related Fertility Decline, Number 589 The American College of Obstetricians and Gynecologists, Committee on Gynecologic Practice.
  • The Practice Committee of the American Society for Reproductive Medicine.
  • RANZCOG position. Assisted reproductive treatment for women of advanced maternal age.

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Hogan RG, Wang AY, Li Z, et al. Having a baby in your 40s with assisted reproductive technology: The reproductive dilemma of autologous versus donor oocytes. Aust N Z J Obstet Gynaecol 2020;60(5):797–803.

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