The Journal of Maternal-Fetal & Neonatal Medicine

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Impact of advanced maternal age on neonatal

morbidity: a systematic review

Inês Rodrigues, Henrique Soares, Gustavo Rocha & Inês Azevedo

To cite this article: Inês Rodrigues, Henrique Soares, Gustavo Rocha & Inês Azevedo (2023)
Impact of advanced maternal age on neonatal morbidity: a systematic review, The Journal of
Maternal-Fetal & Neonatal Medicine, 36:2, 2287981, DOI: 10.1080/14767058.2023.2287981

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
2023, VOL. 36, NO. 2, 2287981
https://doi.org/10.1080/14767058.2023.2287981

REVIEW ARTICLE

Impact of advanced maternal age on neonatal morbidity:

a systematic review
Ine^s Rodriguesa, Henrique Soaresa,b, Gustavo Rochab and In^es Azevedoa,b
a
Faculty of Medicine, University of Porto, Porto, Portugal; bDepartment of Neonatology, Centro Hospitalar Universit�ario de S~ao Jo~ao,
Porto, Portugal

ABSTRACT ARTICLE HISTORY

Objective: This systematic review aimed to understand the impact of advanced maternal age Received 7 April 2022
(AMA) on the neonatal morbidity, based on the available scientific evidence. Revised 5 November 2023
Methods: A systematic search was conducted on 22 November 2021, using the PubMed and Accepted 21 November 2023
Scopus databases to identify studies that compared the morbidity of neonates delivered to
KEYWORDS
AMA mothers with that of neonates delivered to non-AMA mothers. Advanced maternal age;
Results: Sixteen studies that evaluated the effect of AMA on the neonatal morbidity were neonate; neonatal intensive
included in this review. Nine of these studies found some association between AMA and care; respiratory distress
increased neonatal morbidity (with two of them only reporting an increase in asymptomatic syndrome; necrotizing
hypoglycemia, and one only reporting an association in twins), six found no association enterocolitis; neonatal
between AMA and neonatal morbidity and one study found a decrease in morbidity in preterm outcome
neonates. The studies that found an increase in overall neonatal morbidity with AMA considered
older ages for the definition of AMA, particularly �40 and �45 years.
Conclusion: The current evidence seems to support a lack of association between AMA and the
neonatal morbidity of the delivered neonates. However, more studies focusing on the neonatal
outcomes of AMA pregnancies are needed to better understand this topic.

Introduction that AMA was not associated with an increase of neo­

natal morbidity, or mortality, in preterm neonates
In the most developed countries there is a trend in
delayed childbearing over recent decades [1]. In these [14,15].
The objective of this systematic review was to
countries, advanced maternal age (AMA) became
increasingly common and has been associated with a gather all the scientific evidence on the effect of AMA
wide range of adverse obstetric, perinatal, and neo­ on the neonatal morbidity, in order to draw conclu­
natal outcomes [2–6]. sions and to assess the need for further studies. More
Most of the published literature reports on the specifically, this review aims to assess if neonates born
obstetric and perinatal data, with relatively few studies to mothers of AMA present higher morbidity than
assessing the effect of AMA on the morbidity and those born to non-AMA mothers.
mortality of the neonates resulting from these preg­
nancies. Higher number of perinatal complications and Methods
a higher number of admissions to neonatal intensive
care units (NICUs) have been described in the term A systematic review was conducted according to the
and near-term infants [7]. In preterm infants, especially Preferred Reporting Items for Systematic Reviews and
very low birth weight (VLBW) infants, according to Meta-Analyses (PRISMA) guidelines for the search, with
some studies, AMA is associated with an increased no limit of time. PubMed and Scopus databases were
incidence of respiratory distress syndrome (RDS), systematically searched, on 22 November 2021 using
necrotizing enterocolitis (NEC), retinopathy of the following terms: maternal age, advanced maternal
prematurity (ROP) and periventricular leukomalacia age, very advanced maternal age, delayed childbear­
(PVL) [8–13]. On the other hand, other studies found ing, neonatal morbidity, neonatal outcome, pregnancy

CONTACT In^es Rodrigues inesrodriguesmed@gmail.com Faculty of Medicine, University of Porto, Porto, Portugal
� 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the
posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
2 I. RODRIGUES ET AL.

outcome, respiratory distress syndrome, transient tach­ Data were extracted from the selected studies using
ypnea of the newborn, pneumothorax, bronchopulmo­ a pre-determined model. Extracted data included:
nary dysplasia, patent ductus arteriosus, necrotizing author name, study year(s) and country(ies), study
enterocolitis, intraventricular hemorrhage, periventricu­ design, sample size, maternal age ranges considered
lar venous infarction, periventricular leukomalacia, for the study, gestational ages of the included neo­
retinopathy of prematurity, sepsis, pneumonia, menin­ nates, mean birth weight when available, the assessed
gitis, jaundice (Table 1). outcomes and the main findings of the study.
After removing duplicates, two independent authors
(GR and IR) screened the abstracts of 1083 articles.
Study quality assessment
Disagreements were solved upon discussion with a
third element (IA). At the end of this process, 26 articles The quality of the studies included in this review was
were included. After an additional search, using the assessed by two independent authors (GR and HS),
same methodology for the selection process, seven
more articles were included. Thus, a total of 33 articles
were eligible for full-text review, after which 16 articles
were included in this systematic review. The selection
process flowchart can be seen in Figure 1.
All studies prior to 22 November 2021 that met the
inclusion criteria were included. The inclusion criteria
were studies comparing the morbidity of neonates
born to mothers of AMA with that of neonates born to
mothers of non-AMA. Morbidity was defined as one or
more of the following outcomes: RDS, pneumothorax,
bronchopulmonary dysplasia (BPD), NEC, intraventricular
hemorrhage (IVH), periventricular venous infarction
(PVI), PVL, ROP, sepsis, pneumonia, meningitis, transient
tachypnea of the newborn (TTN), seizures or convul­
sions, jaundice, and any metabolic disturbance.
Exclusion criteria included: studies that included
only mothers with advanced age with hypertensive
disorders or diabetes; studies that only included mul­
tiple gestations; articles written in languages other
than English, Portuguese, French, or Spanish; studies
that did not evaluate the outcomes defined for this
review, namely studies that only assessed congenital Figure 1. PRISMA flow diagram of the selection process for
anomalies. Review manuscripts were also excluded. the systematic review.

Table 1. Queries used for search in PubMed and Scopus.

PubMed search query (“advanced maternal age” OR “AMA” OR “very advanced maternal age” OR “delayed childbearing”) AND (“neonatal
morbidity” OR “neonatal outcome�” OR “pregnancy outcome�” OR “newborn morbidity” OR “newborn complication�”
OR “perinatal outcome�” OR “perinatal morbidity” OR “Pregnancy outcome” [MeSH])
Scopus search query TITLE-ABS-KEY ((“advanced maternal age” OR “AMA” OR “very advanced maternal age” OR “delayed childbearing”) AND
(“neonatal morbidity” OR “neonatal outcome�” OR “pregnancy outcome�” OR “newborn morbidity” OR “newborn
complication�” OR “perinatal outcome�” OR “perinatal morbidity”))
Additional search terms � “advanced maternal age” AND (“respiratory distress syndrome” OR “RDS”)
� “maternal age” AND pneumothorax
� advanced maternal age AND bronchopulmonary dysplasia
� advanced maternal age AND patent ductus arteriosus
� advanced maternal age AND necrotizing enterocolitis
� advanced maternal age AND intraventricular hemorrhage
� maternal age AND periventricular venous infarction
� “maternal age” AND “retinopathy of prematurity”
� “maternal age” AND “periventricular leukomalacia”
� “advanced maternal age” AND sepsis
� “advanced maternal age” AND pneumonia
� “advanced maternal age” AND meningitis
� “maternal age” AND transient tachypnea of the newborn
� “advanced maternal age” AND jaundice
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3

using the STROBE (Strengthening the Reporting of Risk of bias across studies
Observational Studies in Epidemiology) [16] guidelines
The major biases found were: most studies had a
and a GRADE (Grading of Recommendations Assessment,
retrospective design; AMA definition was not uni­
Development and Evaluation) [17] level was attributed to
formly used in all studies; definitions of the neonatal
each included article.
morbidities were different among the various studies
and lack of definitions of the outcomes were found in
Results some studies; the main objective of some studies was
Sixteen studies that evaluated the effect of AMA on not to evaluate specific morbidities of the newborn;
the neonatal morbidity were included in this system­ different epochs and countries across the different
atic review. A summary of the studies and their main studies including some old articles not translating the
findings can be seen in Table 2. In this set of studies, current neonatal practices; most studies did not ana­
eight were retrospective cohort studies, six were retro­ lyze all neonatal outcomes, and some articles analyzed
spective case–control studies, one was a prospective only one or two outcomes.
case–control study, and one was a prospective cohort
study. The oldest study included in this systematic Discussion
review was from 1991 and the most recent was from
2021. There are several studies and meta-analysis showing
The studies differed in the definition of AMA. Most that a wide range of adverse obstetrical and perinatal
defined AMA as �35 or �40 years. Four studies outcomes are associated with women of AMA [7,25–
assessed the neonatal outcomes of only preterm or 32]. Most of the adverse outcomes can be explained
VLBW infants, the others also included infants deliv­ through the physio-pathological changes due to aging
ered at term. in the female reproductive system and aging-associ­
Four of the 16 studies found an association ated comorbidities. But AMA can also be an independ­
between AMA and overall increase in neonatal mor­ ent risk factor according to current evidence [32].
bidity [3,5,6,18], two of which considered AMA a This systematic review aimed to gather all the sci­
maternal age �45 years and the other two considered entific evidence on the effect of AMA on the neonatal
AMA a maternal age �40 years. One study also found morbidity and mortality, more specifically, to assess if
an increase in neonatal morbidity but only in twins, neonates born to mothers of AMA present higher
when comparing a maternal age �50 years to a mater­ prevalence of morbidities, during the neonatal period,
nal age of 45–49 years [2]. Other two studies found than those born to non-AMA mothers.
that AMA had an impact, not in the overall morbidity
of the neonate, but specifically an increase in the inci­ RDS
dence of cystic periventricular leukomalacia (cPVL) [8]
and RDS [13], for maternal ages �35 and �32 years, RDS occurs mainly in very preterm infants with imma­
respectively. The studies by Canto et al. [19] and ture lungs and surfactant deficiency and is the most
Romero-Maldonado et al. [20] found an increase in the common cause of respiratory failure in preterm
incidence of asymptomatic hypoglycemia in neonates infants [33].
delivered to mothers �40 and �35 years, respectively, In this systematic review, 11 studies evaluated the
but no increase in the overall neonatal morbidity. In impact of AMA on the incidence of RDS. The study of
the later, the increase in hypoglycemia was Dani et al. [13] that included 63,537 newborns and
presumptively associated to an increased incidence compared a maternal age �32 years to a maternal age
of gestational diabetes mellitus in AMA pregnan­ <32 years, concluded that AMA was a risk factor for
cies [20]. RDS. Shrim et al. [18] included 1108 neonates and
Six of the studies found no association between found that a maternal age �40 years was associated
AMA and neonatal morbidity, including two studies with higher incidence of RDS when comparing with a
that focused only on preterm or VLBW infants maternal age of 20–39 years. The study by Çetin et al.
[4,15,19,21–24]. Lastly, the results of one study showed [5] included 989 neonates and found an increase in
that in preterm neonates, morbidity might even the incidence of RDS in neonates delivered to mothers
decrease with increasing maternal age, specifically a of �40 years when comparing to a maternal age of
decreased incidence of mortality, NEC, and neonatal 18–40 years. The other eight studies [4,8,19–24] did
sepsis [14]. not find an association between AMA and RDS.
 4

Table 2. Summary of findings.

Sample Gestational age Mean birth
Study Time period Study design GRADE size Maternal age (years) (weeks) weight (g) Outcomes evaluated Conclusions
Haines et al. 1991, 1985–1989 Retrospective Moderate 22,689 <20; 20–34 (control); >35 Not mentioned Not mentioned RDS, necessity for intubation, seizures, The outcome of infants born to
Hong Kong [23] cohort study or intracranial hemorrhage, NICU mothers >35 years was similar to
admission the outcome of infants born to
mothers between 20 and 34 years.
Dani et al. 1999, 1 February 1995– Prospective Moderate 63,537 <32 (control); �32 Not mentioned Not mentioned RDS, TTN Maternal age �32 is a risk factor
Italy [13] 31 January cohort study for RDS.
1996
I. RODRIGUES ET AL.

Romero-Maldonado January– Retrospective Moderate 420 18–34 (control); �35 Not mentioned 1790.2 NICU admission, RDS, TTN, pneumonia, No statistically significant differences
et al. 2002, December case–control pneumothorax, IVH, NEC, patent were found in the neonatal
Mexico [20] 1999 study ductus arteriosus, hyperglycemia, morbidity between the two groups,
hypoglycemia, hypocalcemia, except for a higher incidence of
hyperbilirubinemia, sepsis asymptomatic hypoglycemia in the
AMA group.
Shrim et al. 2010, 2001–2007 Retrospective Moderate 1108 20–39 (control); 40–44; �45 Not mentioned 3363.2 RDS, NICU admission, perinatal and Babies born to mothers �40 years had
Canada [18] cohort study neonatal mortality higher rates of RDS, NICU
admission, and neonatal mortality.
Yogev et al. 2010, 2000–2008 Retrospective Moderate 5487 20–29; 30–39; 40–44; �45 Not mentioned Not mentioned NICU admission, metabolic NICU admission and metabolic
Israel [3] case–control (study group) complications (including complications were significantly
study hyperbilirubinemia, hypoglycemia, higher among neonates born to
hypocalcemia, and erythrocythemia), mothers �45.
neonatal death
Kanungo et al. 2011, 2003–2008 Retrospective Moderate 12,326 Age groups: 15–20; 21–25; <33 1357.1 Survival without any major morbidity; In preterm neonates, as maternal age
Canada [14] cohort study 26–30; 31–35; 36–40; BPD; IVH grade 3 or 4; PVL; ROP increased by 5 years, survival
41–54 stage 3, 4, or 5; NEC stage 2 or 3; without major morbidity improved
neonatal sepsis by 5% and mortality, NEC, and
sepsis reduced by 8%, 11%, and 9%
respectively.
Canto et al. 2012, January 2000– Retrospective Moderate 682 20–29 (control); �40 �32 3267.8 Perinatal death, NICU admission, Only hypoglycemia was significantly
Spain [19] December cohort study hypoglycemia, jaundice, RDS, sepsis, higher for the AMA group, but the
2007 asphyxia, convulsion, NEC neonatal outcome overall was not
affected by maternal age.
Çetin et al. 2015, 1 January 2007– Retrospective Moderate 910 �18; 18–40; �40 Not mentioned 2846.1 RDS, neonatal sepsis, AMA pregnancies were associated with
Turkey [5] 31 January case–control hyperbilirubinemia, NEC, an increase short-term neonatal
2015 study convulsions, hypoglycemia, morbidity, except for NEC incidence,
hypocalcemia, NICU admission which was similar between the
groups.
Cakmak Celik et al. 1 January 2008– Retrospective Moderate 254 21–35 (control); �40 >20 Not mentioned NICU admission, TTN, RDS When adjusting for confounders,
2017, Turkey [22] 31 August case–control maternal age was not associated
2010 study with neonatal morbidity.
Çakmak et al. 2019, June 2016– Retrospective Moderate 1202 <35 (control); �35 Not mentioned 3100.9 RDS, sepsis, NICU admission There was no difference in neonatal
Turkey [4] December case–control (subdivided in 35–40 morbidities between the two
2017 study and >40) groups of maternal age.
Rocha et al. 2019, 1 January 2015– Retrospective Moderate 499 <35 (control); �35 24–30 960.8 RDS, pneumothorax, NEC, IVH, PVI, Maternal age �35 was associated with
Portugal [8] 31 December cohort study cPVL, ROP, sepsis, pneumonia, higher incidence of cPVL in preterm
2016 meningitis infants.
Sydsj€
o et al. 2019, 2007–2013 Retrospective Moderate 109,130 �39 (control); 40–44; �45 Not mentioned Not mentioned Child’s health at delivery, survival Women �45 years were more likely to
Sweden [6] case–control have an unhealthy neonate, and
study those infants were more likely to
die within the first 4 weeks.
Tseng et al. 2019, August 2010– Retrospective Moderate 536 20–34 (control); �35 Not mentioned 1068.2 RDS, NEC stage �2, IVH grade 3 or 4, In VLBW infants, AMA did not affect
Taiwan [21] November cohort study BPD, PDA, cPVL, sepsis, ROP, neonatal morbidity.
2014 neonatal mortality
(continued)
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5

Transitory tachypnea of the newborn

AMA—advanced maternal age; BPD—bronchopulmonary dysplasia; IVH—intraventricular hemorrhage; NEC—necrotizing enterocolitis; NICU—neonatal intensive care unit; PDA—patent ductus arteriosus; PVI—peri­
similar between groups of maternal
twins born to older mothers, but

preterm infants did not differ by

Adverse neonatal outcomes in very
Neonatal outcomes are poorer for
Neonatal outcomes did not differ
TTN is a benign condition that typically appears within

according to maternal age.

the first two hours of life in term and late preterm
Conclusions

neonates and is characterized by tachypnea and signs

maternal age group.

age in singletons.
of respiratory distress [34]. Although it is usually a self-
limited condition, admission to a neonatal unit is fre­

ventricular venous infarction; (c)PVL—(cystic) periventricular leukomalacia; RDS—respiratory distress syndrome; ROP—retinopathy of prematurity; TTN—transient tachypnea of the newborn.
quently required [35]. Infants born by C-section are at
risk of TTN [36] and AMA has been associated to an
increase in the number of prelabor C-section [37].
In this review, the studies by Dani et al. [13],
hypoglycemia, ventilatory support,
mechanical ventilation or support,

Composite severe neonatal morbidity

encephalopathy, seizures, death

Infant mortality, BPD, severe brain

injury (IVH � grade 3 or cPVL),
Romero-Maldonado et al. [20], and Cakmak Celik et al.
NICU admission, sepsis, need for

(IVH, NEC, asphyxia, perinatal

phototherapy, RDS, need for
Outcomes evaluated

NEC, IVH, hypoxic-ischemic

[22] evaluated the effect of AMA on the incidence of

death), NICU admission,

severe ROP, severe NEC

TTN and no association was found in any of the

perinatal mortality

studies.

BPD
BPD is a disease resulting from the interference of sev­
eral prenatal and postnatal factors in the development
Not mentioned
Mean birth
weight (g)

of the lower respiratory tract of extreme preterm

infants and it can lead to lifelong lung disease [38].
3313.0

1194.0

In this systematic review, three studies [14,15,21]

evaluated the effect of AMA on BPD and none found
Gestational age

Not mentioned

an association between the two.

(weeks)
[37–41]

�22

NEC
18–34 (control); 35–39; �40

NEC is a gastrointestinal condition affecting mainly

Maternal age (years)

premature neonates that can have serious effects and

45–49 (control); �50
<35 (control); >35

for many years it has been a major cause of morbidity

and mortality in NICUs worldwide [39,40].
In this systematic review, nine studies evaluated the
impact of AMA on the incidence of NEC. The study by
Kanungo et al. [14] that included 12,326 neonates
Sample
size

7607

with a gestational age <33 weeks, concluded that the

220

657

incidence of NEC decreased by 11% as maternal age

Moderate

Moderate
GRADE

increased by five years. The study by Çetin et al. [5]

Low

associated AMA with an increased incidence of NEC.

The study by Schwartz et al. [2] analyzed 657 neonates
Prospective case–
control study

cohort study

cohort study
Study design

and compared those born to mothers �50 years with

Retrospective

Retrospective

those born to mothers of 45–49 years and showed an

increase in composite severe neonatal morbidity,
including NEC, but only in twins. The other six studies
31 December
1 January 2011–

April 2011–June

[8,15,19–21,24] found no association between AMA

Time period
February–July

and NEC.
2019

2018

2012
Table 2. Continued.

Neonatal sepsis
Miremerg et al. 2020,

Schwartz et al. 2020,

Nourkami-Tutdibi

Despite maternal intrapartum prophylaxis, which

Europe [15]
et al. 2021,
Israel [24]

reduced its rates, early-onset sepsis (EOS) remains a

Israel [2]

severe problem, especially for preterm neonates

Study

[41,42]. Risk factors include prematurity, low birth

6 I. RODRIGUES ET AL.

weight, chorioamnionitis, premature prolonged rup­ consensual that infants at risk should have their
ture of membranes, resuscitation, and low APGAR plasma glucose concentrations measured [47]. There is
score [42]. a high incidence of hypoglycemia in asymptomatic
In this review, eight studies assessed the effect of neonates, although its significance is unclear [48].
AMA on the incidence of neonatal sepsis. In the study In this review, five studies evaluated the effect of
by Kanungo et al. [14], in preterm neonates, as mater­ AMA on asymptomatic hypoglycemia, and all found
nal age increased by five years, the incidence of sepsis an association. The study by Romero-Maldonado et al.
decreased by 9%. The study by Çetin et al. [5] showed [20] that included 420 neonates, showed a higher inci­
an increase in sepsis incidence with AMA. The other dence of asymptomatic hypoglycemia in neonates
six studies [4,8,19–21,24] found no association. Two delivered to mothers �35 years, when comparing to
studies [8,20] evaluated the effect of AMA on the inci­ neonates born to mothers of 18–34 years. The authors
dence of pneumonia and one [8] evaluated the effect associate this to the higher incidence of gestational
on meningitis and no association was found. diabetes in AMA pregnancies. The study by Canto
et al. [19] included 682 neonates and found higher
PVL and IVH incidence of hypoglycemia in neonates born to moth­
ers �40 years compared with neonates born to moth­
PVL is caused by dysregulation of cerebral blood flow
ers of 20–29 years. The study by Yogev et al. [3] that
causing ischemia of the periventricular white matter
included 5487 neonates found a higher incidence of
and it is a major cause of cerebral palsy in premature
metabolic complications (including hypoglycemia) in
neonates [43,44]. cPVL is the most severe form of the
neonates delivered to mothers �45 years when com­
disease [43].
In preterm infants, particularly in extremely preterm paring to neonates delivered to younger mothers. The
neonates, IVH remains a clinically significant problem, study by Çetin et al. [5] also found an association
increasing the risk of adverse neurological out­ between AMA and increased incidence of asymptom­
comes [45]. atic hypoglycemia, and Schwartz et al. [2] found this
In this review, four studies evaluated the effect of association but only in twins.
AMA on PVL. The study by Rocha et al. [8] that
included 499 neonates with a gestational age of 24– Jaundice and metabolic complications
30 weeks found that a maternal age �35 years was
associated with higher incidence of echographic cPVL, In the neonatal period, jaundice is the most common
when compared with a maternal age <35 years. In this morbidity, frequently requiring intervention [49].
multicenter study, the main objective was not to assess Another metabolic complication frequently observed
cPVL and a confirmatory diagnosis by magnetic reson­ in neonates is hypocalcemia, with risk factors includ­
ance was not performed. The other three studies ing infants of diabetic mothers, preterm infants, and
[14,15,21] found no association between AMA and PVL. perinatal asphyxia [50].
Seven studies [2,8,14,15,20,21,24] assessed the Five studies included in this systematic review
effect of maternal age on IVH and only Schwartz et al. studied the effect of AMA on jaundice or other meta­
[2] found an increase in incidence, but only in twins. bolic complications. The study by Yogev et al. [3] con­
cluded that metabolic complications were significantly
higher among neonates born to mothers �45 years.
ROP Çetin et al. [5] showed that AMA was associated with
ROP is a leading cause of childhood blindness. It only higher rates of hyperbilirubinemia and hypocalcemia.
occurs in preterm infants and is caused by a prolifer­ The other three studies [19,20,24] found that these
ation of retinal blood vessels [46]. outcomes were not associated with AMA.
In this review, four studies evaluated the effect of
AMA in the incidence of ROP and none of them found
NICU admissions
any association [8,14,15,21].
A systematic review and meta-analysis by Lean et al.
[7] including 63 cohort studies and 12 case–control
Asymptomatic hypoglycemia
studies, reported an increase in NICU admission
It is common in healthy newborns to temporarily pre­ among infants of AMA women.
sent low plasma glucose levels [47]. There is no uni­ Ten of the studies included in this review evaluated
form definition of neonatal hypoglycemia but it is the effect of maternal age on the rate of NICU
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 7

admissions. The studies by Çetin et al. [5] and Shrim are associated with women of AMA, and these include
et al. [18] associated a maternal age �40 years with a increased risks for miscarriage, chromosomal abnor­
higher rate of NICU admissions. The study by Yogev malities, stillbirth, fetal growth restriction, preterm
et al. [3] found the same association but for a mater­ birth, pre-eclampsia, gestational diabetes mellitus and
nal age �45 years. Schwartz et al. [2] also found an cesarean section [7,25–32]. The effect of age on preg­
association between the two variables, but only in nancy outcome was investigated in a meta-analysis of
twins. The other six studies [4,19,20,22–24] found no 75 studies by Lean et al. [7], the largest and most
association between AMA and NICU admissions. comprehensive systematic review investigating AMA
and pregnancy outcome up today. In this meta-ana­
lysis, AMA significantly increased the risk of stillbirth
Mortality
with a population attributable risk of 4.7%; similar
Although the objective of this systematic review was trends were seen for risks of fetal growth restriction,
not to evaluate the effect of AMA on neonatal mortal­ neonatal death, NICU admission, and gestational dia­
ity, eight of the included studies assessed this out­ betes mellitus. The relationship between AMA and
come. Shrim et al. [18] found an increase in mortality stillbirth was not related to maternal morbidity or
with AMA. Kanungo et al. [14] found a decrease of 8% assisted reproductive therapies. The authors concluded
in mortality of preterm neonates as maternal age that stillbirth risk increases with increasing maternal
increased by five years. The other six studies age, and that this is not wholly explained by maternal
[2,3,15,19,21,24] found no association between the comorbidities and use of assisted reproductive thera­
two variables. pies; they propose that placental dysfunction may
mediate adverse pregnancy outcome in AMA.
Overall morbidity Despite the evidence on the effect of maternal age
on maternal and perinatal outcomes [7,25–32], the stud­
Overall, nine studies [2,3,5,6,8,13,18–20] in this review ies focusing on the neonatal outcomes are not as many
found some association between AMA and neonatal and the results are more heterogenous. More studies
morbidities, with two of them only reporting an focusing on neonatal outcomes are needed to under­
increase in asymptomatic hypoglycemia [19,20] and stand this effect, particularly paying attention to the
the study by Schwartz et al. [2] only reporting a signi­ role of gestational age and the cutoff of maternal age.
ficative association in twins, which is an important
finding, but does not fully support the association
between AMA and neonatal outcomes. Six studies Strengths and limitations
[4,15,21–24] found no association between AMA and There have been a lot of studies and some systematic
neonatal morbidity and one study [14] found a pro­ reviews reporting the effects of maternal age on
tective effect of AMA in preterm neonates. maternal and perinatal morbidity [7,25–32]. However,
The studies that found an increase in overall neo­ this systematic review focuses on neonatal outcomes
natal morbidity with AMA [3,5,6,18] considered older and complications such as RDS, TTN, BPD, NEC, sepsis,
ages for the definition of AMA, particularly �40 and PVL, and ROP, thus bringing some new insight into
�45 years. This might suggest that higher maternal this topic.
ages have a higher impact on the morbidity of the Most of the studies included were retrospective
neonates. On the other hand, two of the studies that and of moderate evidence, thus, there is a great risk
found no effect of AMA only evaluated the outcomes of bias associated with these studies, limiting its con­
for preterm or VLBW infants [15,21]. Adding to the clusions. The fact that the studies included were quite
fact that the study by Kanungo et al. [14] found a pro­ variable in terms of what is considered AMA, the dif­
tective effect of maternal age on the outcomes of pre­ ferent outcomes evaluated in each study, the gesta­
term neonates, we might theorize that the effect of tional ages included and the inclusion or not of twin
AMA might be different according to gestational age. pregnancies, also limited the conclusions reached in
According to these results, although there seems to this systematic review.
be a lack of association between AMA and neonatal
morbidity, this relationship is not yet clearly under­
Conclusion
stood. Our findings on neonatal morbidity contrast
with those reported for antenatal and perinatal out­ The current evidence seems to support a lack of asso­
comes. A wide range of adverse pregnancy outcomes ciation between AMA and neonatal morbidity.
8 I. RODRIGUES ET AL.

However, more well-designed prospective studies 40 years or older. BMC Pregnancy Childbirth. 2019;
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