DOI: 10.1111/tog.

12710 2021;23:38–47
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Very advanced maternal age

a b
Alice Howell MBBS MA MSc MRCOG,* Margaret Blott MBBS FRCOG
a
Specialist Registrar (ST4), Royal Free London NHS Foundation Trust, London NW3 2QG, UK
b
Consultant Obstetrician, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
*Correspondence: Alice Howell. Email: alice.howell6@nhs.net

Accepted on 14 July 2020. Published online 21 December 2020.

Key content Learning objectives

 Increasing fertility options have led to increased birth rates among  To understand the maternal implications, complications and risks
women over the age of 45 years. of pregnancy in women of very advanced maternal age, to aid
 Most women aged 45 years or older conceive via assisted counselling this group of women prior to and during pregnancy.
reproductive technologies, which are associated with increased  To understand the fetal complications associated with pregnancy
risks to both mother and fetus. in women of very advanced maternal age, including stillbirth and
 Multiple pregnancies are disproportionately common in this group preterm labour.
of women as a result of multiple embryo transfer. The maternal  To establish an evidence-based approach to the antenatal
and fetal risks are increased significantly in multiple pregnancies. management and care of women of very advanced maternal age.
 A maternal age of 45 years or more is associated with
Keywords: antenatal care / assisted conception / medical disorders
complications in early pregnancy and the antenatal period and
in pregnancy / multiple pregnancy / pre-eclampsia
with significant obstetric complications.
 Fetal complications are increased in this group; in particular there
is an increased risk of multiple births, increased rates of preterm
birth and higher perinatal mortality rates.

Please cite this paper as: Howell A, Blott M. Very advanced maternal age. The Obstetrician & Gynaecologist 2021;23:38–47. https://doi.org/10.1111/tog.12710

Introduction Assisted reproductive technologies

Since the mid-1970s, the average age of childbearing has Spontaneous conception in women of vAMA is rare, but
steadily increased in England and Wales.1 Assisted more common in parous women.4,5 Conception using
reproductive technology (ART) is an available choice in autologous embryos is also rare; the live birth rate is 2.9%
many countries and has given older women the possibility of in a cycle for women aged 45 years. For women aged 46 years
having a baby. and older, the live birth rate was so low, it was reported as
In 2018, there were 2366 live births to women aged being 0%.6
45 years or older in England and Wales, compared with In 2016, Fitzpatrick et al.3 conducted a UK cohort study to
1619 births in 2008.2 Of women having a baby who are describe the characteristics, management and outcomes of
aged 48 years or more, 53% are primiparous compared women of vAMA, focusing on women aged 48 years and
with 44% of younger women.3 Medical literature uses the over. It showed that 78% of the women delivering had
term ’very advanced maternal age’ (vAMA) to refer to conceived using ART.3 Of these, 51% had assisted conception
women who are aged 45 years or more at the time performed outside the UK, 91% reported using egg donation
of delivery. and 21% had used donor sperm. Of these women, 40% had
Although the relationship between advancing maternal age one embryo transferred, 45% had two embryos transferred
and increased risks of adverse maternal and infant outcomes and 15% had three or more embryos transferred. Just under
is well established, most studies have only reported outcomes half of those who had multiple embryos transferred went on
in women older than 35 years or older than 40 years. This to have a multiple pregnancy.
review aims to establish an evidence-based approach to the ART is associated with an increased risk of ovarian
care of women aged 45 years or more using studies that hyperstimulation syndrome, miscarriage, ectopic pregnancy,
specifically assess the risks in this group of pregnant women pregnancy-induced hypertension, pre-eclampsia, venous
and their babies. thromboembolism (VTE), genetic and chromosomal

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 Howell and Blott

disorders, structural abnormalities, fetal growth restriction Table 1 shows a summary of the risks for women of vAMA,
(FGR), stillbirth and preterm labour.7–10 These risks also from the current evidence, comparing conception with ART
increase with maternal age and multiple pregnancies. and spontaneous conception.
Pre-eclampsia complicates just 1.1% of natural conception
pregnancies and 12.6% of oocyte donation conceptions in
Early pregnancy complications
women of vAMA.10 Among oocyte donation pregnancies, the
risk of pre-eclampsia is the same among primiparous and Miscarriage rates increase with increasing maternal age. In
multiparous women, but as maternal age increases, the risks women of vAMA, the overall risk of miscarriage is 53%.14
increase. Guesdon et al.11 demonstrated that in women of Rates of miscarriage beyond the first trimester are also
vAMA undergoing oocyte donation with singleton increased.15 There is currently no intervention for the
pregnancies, the risk of gestational hypertension was 5.5% prevention of miscarriage in this group. The management
in women aged 45–49 years, rising to 19.2% above the age of of women of vAMA with both sporadic and recurrent
50 years. In the same study, babies born to women aged miscarriage is no different to younger women and has been
45–49 years had a 14.3% risk of FGR compared with 30.7% covered elsewhere.16
in women aged above 50 years. The risk of an ectopic pregnancy in women with vAMA is
Studies demonstrate women of vAMA who conceive by three times the overall risk of ectopic pregnancy in all
ART have a 23.3% risk of delivering a baby before 36 weeks women, with studies17 demonstrating a 6.9% risk of ectopic
of gestation compared with a 9.3% risk in vAMA women pregnancy in women aged 44 years or older. Conception by
who conceive spontaneously,9 independent of parity. Babies ART is not protective against ectopic pregnancy. It is likely
conceived by ART had a 22.1% risk of being born with a low that age-related changes associated with exposure of risk
birth weight (<2500 g), while babies conceived factors are directly related to maternal age.18
spontaneously have a 7.4% risk. Studies in this area are Management of ectopic pregnancies should follow local
often limited in information as to whether the embryo was protocols based on national guidelines.16,19 Clinicians should
autologous or donated. be aware there is some evidence that women aged 40 years
Women of vAMA who become pregnant as a consequence and older with ectopic pregnancies are twice as likely to need
of ART should, like all women, have a risk assessment at a blood transfusion than younger women.20 A VTE
booking; they should be offered low-dose aspirin (150 mg) reassessment after miscarriage or ectopic pregnancy should
from 12 weeks of gestation until delivery.12 They should also be performed, following findings from the most recent
be assessed for VTE, since women who have conceived with confidential enquiry into maternal deaths in the UK.13
ART are at increased risk, particularly in the first trimester.
The most recent review of maternal deaths in the UK
Multiple pregnancy
recommends clear pathways for women to access early
prescriptions and support for thromboprophylaxis to Women of vAMA are more likely to have a multiple
ensure compliance.13 pregnancy than younger women.2,3,21 Figure 1 shows the
rates of multiple births in women of vAMA and all women in
the UK from 1938–2018. In 2018, women of vAMA in the UK
Table 1. Summary of the risks from the current evidence for women
had a multiple pregnancy rate of 79.3/1000 compared with
of very advanced maternal age, comparing conception with assisted 15.4/1000 in all women.2
reproductive technologies (ART) and spontaneous conception Since 1993, women of vAMA have consistently recorded
the highest multiple pregnancy rate, secondary to increasing
Pregnancy Pregnancy
conceived by ART conceived availability of ART and the number of embryos transferred.
and oocyte spontaneously In January 2009, the Human Fertilisation and Embryology
Condition donation (%) (%) Authority (HFEA) recommended elective single embryo
transfer in an effort to reduce the overall national multiple
birth rate through ART to 10%. Clinics are not to exceed a
Maternal pre-eclampsia 12.6 1.1
maximum multiple birth rate;2 however, women of vAMA
Delivery before 23.3 9.3 are often the group that receives more than one embryo. Half
36 weeks of gestation of women aged 48 years and older who had a double embryo
Risk of baby being born 22.1 7.4
transfer went on to have a multiple pregnancy. This is higher
with low birth weight than reported rates in double embryo transfers in a younger
(<2500 g) population, likely associated with the use of donated ova.3
Clinicians should be aware that patients travelling abroad
for ART are more likely to undergo multiple embryo transfer.

ª 2020 Royal College of Obstetricians and Gynaecologists 39

 Very advanced maternal age

Figure 1. Rates of multiple births in women of very advanced maternal age (vAMA) and all women, 1938–2018.2HFEA = Human Fertilisation and
Embryology Authority; IVF = in vitro fertilisation.

Women of vAMA with multiple pregnancy have increased Table 2 shows a summary of the evidence, risks and
rates of fetal and maternal complications compared with recommendations for fetal, neonatal and maternal morbidity
women of vAMA with singleton pregnancies11,22–24 and and mortality in women of VAMA with twin and
younger women with multiple pregnancies.25 singleton pregnancies.
In women of vAMA, the risks associated with a multiple
pregnancy as a result of ART are different to a singleton
Maternal complications, risks and
pregnancy conceived spontaneously or by ART. Twin
recommendations
neonates born to women of vAMA will sustain more
adverse outcomes than singletons.22–26 After ART they are Pregnancies in women of vAMA have increased risks of pre-
56–65% more likely to be born before 37 weeks of existing medical conditions, GDM, gestational hypertension,
gestation.23,25,26 Birth before 32 weeks of gestation is also pre-eclampsia, abnormal placentation, ICU admission,
significantly increased.25 Twin infants are four times more caesarean delivery, postpartum haemorrhage (PPH), blood
likely to need intubation and are 1.5–3 times more likely to transfusion and prolonged admission to hospital.3,5,21,24,28–31
be admitted to neonatal intensive care.23,26 They are less likely to smoke cigarettes.3
Maternal complications associated with ART and multiple Fitzpatrick et al.3 found that 44% of women aged 48 years
pregnancy are worse in women of vAMA.23–25 They are or older had a reported pre-existing medical condition
significantly more likely to suffer life-threatening compared with 28% of younger women. There is little
complications, such as bleeding requiring a blood evidence to suggest which pre-existing medical conditions
transfusion and maternal admission to the intensive care have the best and worst outcomes, but women over the age of
unit (ICU);25 10–42% of women develop gestational 40 years are three times more likely to die than women in
hypertension,23,25 26–32% develop pre-eclampsia,23,25 their early 20s.13 We recommend early referral to a high-risk
10–35% develop gestational diabetes mellitus (GDM),22,25 antenatal clinic or maternal medicine clinic.
and 79.0–91.8% had a caesarean section delivery.22,25 Care must be individualised. Many of the studies looking
Antenatal care should be in line with guidance published at outcomes in women of vAMA have not separated
by the National Institute for Health and Care Excellence primiparous from multiparous women, multiple from
(NICE) on multiple pregnancy,27 but individualised singleton pregnancies, pregnancies conceived spontaneously
according to obstetric factors. Fetal surveillance should be from those conceived with ART, or pregnancies in women
offered and recommended in line with the NICE twins and with or without pre-existing co-morbidities.
triplets guideline.27 We recommend early discussions
between clinician and patient about the mode of delivery, Obesity
in light of the increased risk of preterm delivery. There is Women aged 48 years or more are more likely to be
currently no effective intervention proven to decrease the risk overweight or obese than younger women.3 Pregnant
of preterm delivery. women who are obese are at greater risk of pre-eclampsia,

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 Howell and Blott

Table 2. Summary of the evidence, risks and recommendations for

Diabetes
fetal, neonatal and maternal morbidity and mortality in women of very Maternal age is known to be a risk factor for the development
advanced maternal age with twin and singleton pregnancies of GDM. Studies have demonstrated rates of 12.6–21.0% in
women of vAMA,3,21,28–31 rising to 28% in women aged
Risk in Risk in
twins singletons 50 years and above and 35.1% in twin pregnancies conceived
Condition (%) (%) Recommendation by ART.24 Women of vAMA are nine times more likely to
require insulin to treat GDM than younger women.3 We
recommend offering screening at 16–18 weeks of gestation,
Delivery 56–65 8–14 Ensure that women are
in addition to screening at 26–28 weeks of gestation. Should a
before being cared for in a
37 weeks of specialist multiples clinic woman screen positive, her care should follow national
gestation with a neonatal intensive guidance.33 Care may need to be shared between a diabetes
care unit that can provide specialist multidisciplinary care, a multiples clinic and a
Delivery 22.67 2 appropriate levels of care
lead consultant.
before for babies born
34 weeks of prematurely
gestation Have early discussions about Hypertensive disease
steroids and the location of Pre-eclampsia, severe or early onset pre-eclampsia and
Delivery 8.2 1.3 birth
before
eclampsia are more common in women of vAMA than in
32 weeks of younger women.3,24,28–31 Fitzpatrick et al.3 found that 6% of
gestation women aged 48 years and older developed pre-eclampsia or
eclampsia compared with 2% of younger women. Meyer24
Admission to 36 8
neonatal
found that 32% of vAMA with multiple pregnancy conceived
intensive care by ART developed pre-eclampsia or eclampsia compared
with 6.2% of younger women who conceived a twin
Fetal growth 18.6 7.6 Scans as recommended by pregnancy by ART.
restriction the NICE twins and triplets
guideline27 Despite these figures, most maternal outcomes are good
and there is some evidence that women of vAMA are not at
Maternal 10–42 14 Regular blood pressure greater risk of complications from hypertension solely based
hypertensive monitoring in the third
on their age.34 Older women without pre-existing
disease trimester
hypertension have been shown to have favourable
Maternal pre- 26–32 4–12 Advise low-dose aspirin outcomes, with rates of severe pre-eclampsia being
eclampsia 150 mg from 12 weeks of significantly higher in women above 50 years of age in
gestation until delivery
whom there are higher rates of pre-existing hypertension.34,35
GDM 10–35 8.0–23.8 Advise glucose tolerance When pre-existing maternal health is documented, it seems
test at 16–18 weeks of that the main predictor of outcomes is maternal health and
gestation, as well as at 26– not maternal age.
28 weeks of gestation to
screen for GDM
Pre-pregnancy counselling should be offered to all women
with pre-existing hypertension, including a review of anti-
Caesarean 79.0– 50 Early discussions about the hypertensive medications, an up-to-date echocardiogram,
section 91.8 mode of delivery renal function tests and renal imaging.
delivery

Hypothyroidism
GDM = Gestational diabetes mellitus; NICE = National Institute for Hypothyroidism is more common in women of vAMA.30 The
Health and Care Excellence.
relationship between pre-existing hypothyroidism and
adverse pregnancy outcomes is well established.
GDM and caesarean birth than women with a normal body Surveillance of thyroid function and treatment with
mass index (BMI). There is also a higher risk of fetal neural levothyroxine is an effective management strategy.
tube defects associated with obesity.32 The management of
women with vAMA who are overweight or obese is no Venous thromboembolism
different to that of younger overweight or obese women and Evidence that maternal age affects rates of VTE is conflicting:
has been covered elsewhere.32 In our experience, the early Fitzpatrick et al.3 found that rates of thrombotic events were
initiation of high dose folic acid (5 mg) is often missed in the same in women across all age groups; however, previous
this group. large studies have shown that women over the age of 35 years

ª 2020 Royal College of Obstetricians and Gynaecologists 41

 Very advanced maternal age

have a 70% increase in VTE in the postpartum period.36 Postpartum haemorrhage

Current guidance in the UK simplifies risk and states that age PPH has been shown to be the most statistically significant
greater than 35 years is a risk factor for VTE antenatally complication affecting women of vAMA, whether they are
and postnatally.37 primiparous or multiparous, having a singleton or multiple
Thrombophrophylaxis is recommended for women of pregnancy, conceived spontaneously or by ART. PPH affects
vAMA with additional risk factors. The duration of one in four women of vAMA.3 Women with multiple
prophylaxis should be based on individual risk factors, in pregnancies, pre-eclampsia and those receiving
keeping with national guidance.37 Admission alone increases thromboprophylaxis are at particular risk. Women of
VTE risk 12-fold.37 Following the confidential enquiry into vAMA are almost four times more likely to need blood
the death of a woman in the UK, it was advised that VTE products following a PPH than younger women.3 Plans and
reassessment occurs at every opportunity; the woman was precautions to minimise the risk of PPH should be discussed
over the age of 40 years with a pregnancy as a result of ART. with the mother in the antenatal period, including the
She collapsed immediately after a caesarean section following investigation and treatment of anaemia and the role of
a 10-day admission for pre-eclampsia.13 prophylactic uterotonics in the management of the third
stage of labour.40
Previous uterine surgery
Women aged 48 years or older have a 26% risk of having had Caesarean section
previous uterine surgery, not including a caesarean section, Caesarean section rates are high in women of vAMA, but
compared with 7% of younger women.3 The type of uterine only in primiparous women.3 Primiparous women of vAMA
surgery was not specified in the study. In our experience, are eight times more likely to deliver by caesarean section
women of vAMA are more likely to have undergone uterine than women aged 30–34. Women of vAMA who conceived
surgery related to fibroids. We advise early referral to a high- by ART are six times more likely to deliver by caesarean
risk antenatal clinic to discuss options and risks regarding section.5 Of women of vAMA with multiple pregnancy who
mode of delivery. Women may have access to previous conceive by ART, 91.8% deliver by caesarean section.24 These
medical records or operation notes and should be studies do not separate emergency from elective caesarean
encouraged to share these with her consultant team. The sections, but in Fitzpatrick’s large UK study, in which 78% of
management of delivery following myomectomy may be women aged 48 years or older had a caesarean section, the
influenced by the operation performed and if the cavity has indications were as follows: maternal age (21%), fetal
been breached, many women are advised at the time of the compromise (19%), maternal compromise (14%), failure to
myomectomy to request caesarean sections for any progress (14%), abnormal presentation (10%), previous
future deliveries. caesarean section (9%) and maternal request (5%). These
figures indicate that most, but not all caesarean sections are
Placental complications performed electively.
Women of vAMA are three times more likely to have Women should be offered and supported in their decision-
placenta praevia.3 In primiparous women, this may be as a making. Discussions should be initiated early on in antenatal
result of ART, multiple pregnancy or damage to the care. Women should be made aware of the national guidance
endometrium during previous uterine surgery.38 In when requesting a caesarean section.41 It is recommended
multiparous women, a previous caesarean section may be that intrapartum care takes place in a maternity unit with
a contributing factor.3 All women should be advised to facilities for emergency caesarean delivery and access to
have a fetal anomaly ultrasound scan between 18 and appropriately skilled clinicians.
21 weeks of gestation and those involved in scanning
should be aware of the increased risk of placenta praevia in Admission to hospital and intensive care
women of vAMA. The investigation and management of Women of vAMA have a 30% risk of antenatal hospital
placenta praevia and placenta accreta is covered by admission21 and are 33.5 times more likely to be admitted to
national guidelines.39 ICU than younger women.3 A study of singleton pregnancies
Women of vAMA are three times more likely to have a demonstrated that women aged 40 years or older had
placental abruption than younger women.3 It is difficult to significantly elevated rates of renal failure, shock, cardiac
predict and no effective prevention treatments are currently morbidity and serious complications following obstetric
available. Women of all ages are advised to report all vaginal interventions contributing to increased admission to ICU.42
bleeding to their antenatal care provider. Placental abruption We recommend that care is offered in a place with
is a clinical diagnosis and there are no sensitive or reliable appropriate intensive care support for both mother and
diagnostic tests available. Ultrasound has limited sensitivity neonate(s), that high-risk women of vAMA are seen in a
in the identification of retroplacental haemorrhage.38 high-risk anaesthetic clinic at 30–32 weeks of gestation and

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 Howell and Blott

Table 3. A summary of maternal complications, risks and recommendations in women of very advanced maternal age (vAMA)

Maternal complication Risk Recommendation

Pre-existing medical 44% (of women aged 48 years or older) Early referral to a high-risk antenatal clinic or maternal medicine
complication clinic

Gestational diabetes mellitus 12.6–21.0% Offer screening at 16–18 weeks of gestation in addition to screening
35.1% (in twin pregnancies conceived by at 26–28 weeks of gestation
assisted reproductive technology) Women of vAMA are nine times more likely to require insulin

Hypertensive disease 6–32% Pre-pregnancy counselling should be offered to all women with pre-
existing hypertension, including a review of antihypertensive
medications, an up-to-date echocardiogram, renal function tests
and renal imaging
Advise low-dose aspirin 150 mg from 12 weeks of gestation until
delivery
Regular blood pressure monitoring in the third trimester

Previous uterine surgery 26% (of women aged 48 years or older) Early referral to a high-risk antenatal clinic

Placenta praevia Three times more likely to have placenta Fetal anomaly ultrasound scan between 18 and 21 weeks of
praevia than younger women gestation
Those involved in scanning should be aware of the increased risk of
placenta praevia in women of vAMA

PPH 25% Plans and precautions to minimise the risk of PPH should be
Women of vAMA are almost four times discussed. Investigate and treat anaemia
more likely to need blood products than Discuss the role of prophylactic uterotonics in the management of
younger women the third stage of labour

Antenatal hospital admission 30% Thrombophrophylaxis is recommended for women of vAMA with
additional risk factors
Admission alone increases venous thromboembolism risk 12-fold

Admission to intensive care unit 33.5 times more likely to be admitted than Consider offering care in a place with appropriate intensive care
younger women support for both mother and neonate(s)
High-risk women of vAMA to be seen in a high-risk anaesthetic clinic
at 30–32 weeks of gestation
On-call consultant anaesthetist should be made aware when a
woman of vAMA is admitted to the unit

PPH = postpartum haemorrhage.

that the on-call consultant anaesthetist be made aware when

Effect on fetal and neonatal morbidity
a woman of vAMA is admitted to the unit.
and mortality
In the UK, if the mother is not married then a father only
has parental responsibility if he is named on the child’s birth Little is known about the long-term effect of being born when
certificate. Women of vAMA are as likely to be single as your mother is of vAMA. Some studies have suggested that
women of other ages,3 but they are more likely to be using women are more likely to have stable careers and finances,
donated sperm or embryos. Owing to the increased risks with one large study showing that increasing maternal age is
discussed, it is advised that the mother has a will in place associated with children having fewer hospital admissions,
prior to delivery, to clarify the legal status of the donor or any fewer unintentional injuries, better language and fewer social
co-parent and to confirm who will be legally and financially and emotional difficulties.43
responsible for the child in the case of maternal illness
or death. Perinatal morbidity
Table 3 shows a summary of maternal complications, risks Many studies demonstrate that children born to women of
and recommendations in women of vAMA. vAMA have increased perinatal morbidity; they are more

ª 2020 Royal College of Obstetricians and Gynaecologists 43

 Very advanced maternal age

often born before 37 weeks of gestation,3,921,22,28,30,44 discussed.52 There is currently no consensus on the
admitted to the neonatal intensive care unit (NICU),29,30 management of later pregnancy for these women. In
more often born small for gestational age (SGA),28,34,45–47 or addition to serial growth scans for women of vAMA, we
born with a birthweight of less than 2500 g.3,29,48 recommend asking women to monitor fetal movements
Fitzpatrick et al.3 found that women aged 48 years and until delivery and informing them to sleep in the right or
above are twice as likely to deliver spontaneously before left lateral position. An induction of labour can be offered,
37 weeks of gestation and 4.5 times more likely to deliver particularly beyond 37 weeks of gestation. Clinicians and
prematurely because of iatrogenic intervention. Women of women of vAMA must be able to discuss balancing the
vAMA are twice as likely to have a SGA baby28 and have a benefits and risks of remaining pregnant and waiting for
32% chance of having a baby with a birthweight of less than spontaneous labour against the benefits and risks of
2500 g.3 The high rate of babies born with a weight below induction of labour and elective caesarean section.
2500 g was shown to be associated with prematurity rather
than FGR.3 One in six babies born to women of vAMA need Trisomy and congenital anomalies
admission to NICU.30 Appropriate plans for care need to be The risk of Down syndrome (trisomy 21) is directly related to
made; such plans may involve a transfer of care, in liaison maternal age if a pregnancy is conceived spontaneously. In
with the neonatology team. The increased risk of neonatal donor embryos, it is related to the age of the donor. The
admission means that having premature and SGA babies can incidence of trisomy 21 at term is 1:1350 for a 25-year-old
have significant long-term and short-term economic and woman (or donor). This increases to 1:35 at the age of
psychosocial effects on the mother and family.21,29,30 45 years and 1:25 at the age of 49 years.57 The live birth rate
Studies have shown that singleton pregnancies are likely to of cases of trisomy 21 to women of vAMA is significantly
have less perinatal morbidity than multiples;35 however, there lower than 1:35, probably owing to the use of younger donor
is currently a paucity of studies looking at how maternal embryos and, possibly, the availability of legal termination of
complications and risk factors lead to iatrogenic preterm pregnancy services.
delivery, neonatal admissions, lower birthweight and In the UK, the combined test is part of a national screening
perinatal morbidity and mortality. programme. An older woman is more likely to have a screen-
positive result than a younger woman because she starts with
Perinatal mortality a higher age-specific risk of Down syndrome. The test is more
Although many studies report adverse perinatal outcomes in likely to detect a Down syndrome pregnancy in an older
women of vAMA, the absolute rate of stillbirth and perinatal woman than in a younger woman. In women of vAMA who
death is between 1.00 and 1.87%3,5,49 compared with 0.55% have conceived with their own embryos, there is a 95%
in younger women.49,50 detection rate for Down syndrome (higher than in any other
Perinatal mortality rates are 2.0–3.8 times higher in babies age group).58
born to women of vAMA3,9,49–52 and, as with women of all Using a cut-off of 1 in 150 at term as a screen-positive
ages, prematurity and SGA babies account for a significant result, one in four women of vAMA will screen positive.58
number of stillbirths and early neonatal deaths in the UK. A screen-positive result requires careful counselling.
Clinicians must be aware that primiparous women and Invasive diagnostic testing (amniocentesis or chorionic
black women are the highest risk group for stillbirth and that villous sampling) can be offered; it gives accurate results
obesity and additional medical comorbidities are additional but has a small risk of miscarriage. Non-invasive prenatal
risk factors for stillbirth.50,53 While women should be testing (NIPT) may be an alternative to invasive testing; it
encouraged to address factors such as obesity, the only way detects 99% of Down syndrome cases and has no risk of
to prevent antepartum stillbirth is to offer timed delivery in miscarriage; some women may prefer this option. A small
the form of an induction of labour or an elective caesarean risk of false-positive results means it is recommended that
section.53–55 There is some evidence that women aged any positive NIPT result is confirmed with invasive
44 years and older benefited from delivery by 38 weeks of diagnostic testing if the woman is considering termination
gestation to reduce stillbirth.56 of pregnancy on the basis of trisomy. There is currently no
We recommend that all women of vAMA are advised to national guidance on the role of NIPT in antenatal care
take low-dose aspirin from 12 weeks of gestation, have and screening.
their pregnancy associated plasma protein-A (PAPP-A) There is a significant association between congenital
measured, have serial assessment of fetal size and umbilical anomalies and trisomy; however, Fitzpatrick et al.3 found
artery Doppler from 26–28 weeks of gestation and regular similar rates of congenital anomalies between women
blood pressure monitoring in the third trimester.46 High- aged 48 years and older and younger women (1.9%
risk cases must be identified and the potential versus 1.5%). This should be reassuring to women
consequences of early delivery and prematurity of vAMA.

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 Howell and Blott

Preconception advice regarding:

- Individualised risks to mother and fetus
- Folic acid 400 μg or 5 mg depending on risk factors
- Medication review
- Optimising body mass index
- Benefits of single embryo transfer
Women with pre-existing hypertension:
- Anti-hypertensive medication review
- Up-to-date echocardiogram
- Renal function tests
- Renal imaging

Immediate venous thromboemolism risk assessment once pregnant:

Clear pathway for women to access prescriptions and support for
thromboprophylaxis to ensure compliance

Low threshold for referral to early pregnancy unit in light of increased

rates of miscarriage and ectopic pregnancy
Venous thromboembolism reassessment after miscarriage or ectopic pregnancy

Booking appointment to establish:

- Method of conception
- Previous uterine surgery. If so, for early referral to a high-risk antenatal clinic to
discuss options and risks regarding mode of delivery
- Risk assessment for venous thromboembolism
- Advise low-dose aspirin (150 mg) from 12 weeks of gestation until delivery

Multiple pregnancy diagnosed in first trimester Singleton pregnancy

- Early referral to multiples clinic (or high-risk antenatal clinic) with a dedicated - Early referral to a high-risk antental clinic or
consultant lead in a hospital with a neonatal intensive care unit that can provide maternal medicine clinic if required
appropriate levels of care for babies born prematurely - PAPP-A measured and noted
- Venous thromboembolism risk assessment at every appointment or admission (significant if less than 0.4 multiples of the median)
- Advise low-dose aspirin (150 mg) from 12 weeks of gestation until delivery - Request serial growth scans at 28, 32 and 36 weeks’ gestation
- PAPP-A measured and noted (significant if less than 0.4 multiples of the median) Venous thromboembolism risk assessment at every
appointment or admission

Screening for gestational diabetes mellitus with a glucose

tolerance test at 16–18 weeks Screening for gestational diabetes mellitus with a glucose
tolerance test at 16–18 weeks

Early discussion regarding risk of preterm delivery,

mode of delivery, place of delivery and the role of steroids and Screening for gestational diabetes mellitus with a glucose
magnesium sulphate tolerance test at 26–28 weeks if screen negative at 16–18 weeks

Screening for gestational diabetes mellitus with a glucose Regular blood pressure monitoring and urine analysis, increasing
tolerance test at 26–28 weeks if screen negative at 16–18 weeks in frequency in the third trimester of pregnancy
Venous thromboembolism risk re-assessment if
hypertensive disease develops or admission required

Regular blood pressure monitoring and urine analysis, increasing

in frequency in the third trimester of pregnancy
Early discussion regarding risk of preterm delivery, mode of
Venous thromboembolism risk re-assessment if
delivery and place of delivery
hypertensive disease develops or admission required

Women with additional risk factors (e.g. high body mass index,
Women with additional risk factors (e.g. high body mass index, multiple pregnancy, hypertensive disease, placenta praevia)
multiple pregnancy, hypertensive disease, placenta praevia) should be referred to high-risk obstetric
should be referred to high-risk obstetric anaesthetic clinic at 30–32
30 32 weeks ‘gestation
anaesthetic clinic at 30–32
30 32 weeks ‘gestation

Timing of delivery with multiple pregnancy to be guided by fetal Aim to deliver by 38 weeks’ gestation to
surveillance and maternal risk factors. No current evidence on reduce risk of stillbirth
optimum timing of delivery.

Figure 2. Suggested additional considerations in the antenatal care of women of very advanced maternal age (vAMA).

ª 2020 Royal College of Obstetricians and Gynaecologists 45

 Very advanced maternal age

6 Gunnala V, Irani M, Melnick A, Rosenwaks Z, Spandorfer S. One

Conclusion thousand seventy-eight autologous IVF cycles in women 45 years and
older: the largest single-center cohort to date. J Assist Reprod Genet
The number of women of vAMA becoming pregnant is 2018;35:435–40.
increasing, but the rate of multiple births in this group 7 Royal College of Obstetricians and Gynaecologists (RCOG). The
management of ovarian hyperstimulation syndrome. Green-top guideline
appears to be beginning to decrease, in part because of HFEA no. 5. London: RCOG; 2016. .
multiple birth policy. However, many women are seeking 8 Richardson A, Taylor M, Teoh J, Karas T. Antenatal management of singleton
ART abroad, where multiple embryo transplant is pregnancies conceived using assisted reproductive technology. Obstet
Gynaecol 2019;22:34–44.
more common. 9 Sydsjo G, Lindell Pettersson M, Bladh M, Skoog Svanberg A, Lampic C,
Multiple birth, primiparity and pre-existing maternal Nedstrand E. Evaluation of risk factors’ importance on adverse pregnancy
hypertension appear to be the most significant risk factors and neonatal outcomes in women aged 40 years or older. BMC Pregnancy
Childbirth 2019;19:92.
in women of vAMA and pre-pregnancy counselling has an 10 Dior U, Laufer N, Chill H, Granovsky-Grisaru S, Ya. Increased incidence of
important role to play in the care of these women. preeclampsia in mothers of advanced age conceiving by oocyte donation.
Most women with vAMA have successful pregnancy Arch Gynecol Obstet 2018;297:1293–9.
11 Guesdon E, Vincent-Rohfritsch A, Bydlowski S, Santulli P, Goffnet F, Le Ray
outcomes; however, clinicians must be aware of the women C. Oocyte donation recipients of very advanced age: perinatal complications
of vAMA with higher risks, as well as the preventative and for singletons and twins. Fertil Steril 2017;107:89–96.
surveillance strategies available for women during 12 National Institute for Health and Care Excellence (NICE). Hypertension in
pregnancy: diagnosis and management. London: NICE; 2019. .
their pregnancies. 13 Knight M, Bunch K, Tuffnell D, Jayakody H, Shakespeare J, Kotnis R, et al.
Caring for a woman with multiple risk factors can be Saving lives, improving mothers’ care. Lessons learned to inform maternity
complex and maintaining continuity of care can be care from the UK and Ireland Confidential Enquiries into Maternal Deaths
and Morbidity 2014–16. Oxford: University of Oxford, National Perinatal
challenging. Figure 2 shows a flow chart summary of the Epidemiology Unit; 2018.
suggested additional recommendations in the antenatal care 14 Magnus M, Wilcox A, Morken N, Weinberg C, H
aberg S. Role of maternal
of women of vAMA. We advise women to have a named age and pregnancy history in risk of miscarriage: prospective register based
study. BMJ 2019;364:I869.
consultant obstetrician who oversees her care and develops a 15 Khalil A, Syngelaki A, Maiz N, Zinevich Y, Nicolaides K. Maternal age and
personalised care plan with her59– this may be an expert in adverse pregnancy outcome: a cohort study. Ultrasound Obstet Gynaecol
multiple pregnancy, maternal medicine or high-risk 2013;42:634–43.
16 National Institute for Health and Care Excellence (NICE). Ectopic pregnancy
obstetrics. As risk factors develop, reviewing the and miscarriage: diagnosis and initial management. Clinical guideline
personalised care plan at each antenatal visit can ensure CG154. London: NICE; 2012.
good communication. This will ensure a high standard of 17 Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal
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Disclosure of interests 19 Royal College of Obstetricians and Gynaecologists (RCOG). Diagnosis and
There are no conflicts of interest. management of ectopic pregnancy. Green-top guideline no. 21. London:
RCOG; 2016.
20 San Lazaro Campillo I, Meaney S, O’Donoghue K. Ectopic pregnancy
Contribution to authorship hospitalisations: a national population-based study of rates,
AH instigated, researched and wrote the manuscript. MB management and outcomes. Eur J Obstet Gynecol Reprod Biol
edited the manuscript. Both authors read and approved the 2018;231:174–9.
21 Simchen M, Yinon Y, Moran O, Schiff E, Sivan E. Pregnancy outcome after
final version of the manuscript. age 50. Obstet Gynecol 2006;108:1084–8.
22 Khatibi A, Nybo Andersen A, Gissler M, Morken N, Jacobsson B. Obstetric
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