Human Placental Lactogen in Relation to Maternal Metabolic Health and Fetal Outcomes: A Systematic Review and Meta-Analysis

Abstract

Human placental lactogen (hPL) is a placental hormone which appears to have key metabolic functions in pregnancy. Preclinical studies have putatively linked hPL to maternal and fetal outcomes, yet—despite human observational data spanning several decades—evidence on the role and importance of this hormone remains disparate and conflicting. We aimed to explore (via systematic review and meta-analysis) the relationship between hPL levels, maternal pre-existing and gestational metabolic conditions, and fetal growth. MEDLINE via OVID, CINAHL plus, and Embase were searched from inception through 9 May 2022. Eligible studies included women who were pregnant or up to 12 months post-partum, and reported at least one endogenous maternal serum hPL level during pregnancy in relation to pre-specified metabolic outcomes. Two independent reviewers extracted data. Meta-analysis was conducted where possible; for other outcomes narrative synthesis was performed. 35 studies met eligibility criteria. No relationship was noted between hPL and gestational diabetes status. In type 1 diabetes mellitus, hPL levels appeared lower in early pregnancy (possibly reflecting delayed placental development) and higher in late pregnancy (possibly reflecting increased placental mass). Limited data were found in other pre-existing metabolic conditions. Levels of hPL appear to be positively related to placental mass and infant birthweight in pregnancies affected by maternal diabetes. The relationship between hPL, a purported pregnancy metabolic hormone, and maternal metabolism in human pregnancy is complex and remains unclear. This antenatal biomarker may offer value, but future studies in well-defined contemporary populations are required.

Full text

Citation: Rassie, K.; Giri, R.; Joham,
A.E.; Teede, H.; Mousa, A. Human
Placental Lactogen in Relation to
Maternal Metabolic Health and Fetal
Outcomes: A Systematic Review and
Meta-Analysis. Int. J. Mol. Sci. 2022,
23, 15621. https://doi.org/10.3390/
ijms232415621
Academic Editors: Francesco
Prattichizzo and Giulia
Matacchione
Received: 10 October 2022
Accepted: 7 December 2022
Published: 9 December 2022
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International Journal of
Molecular Sciences
Review
Human Placental Lactogen in Relation to Maternal Metabolic
Health and Fetal Outcomes: A Systematic Review
and Meta-Analysis
Kate Rassie 1,2, Rinky Giri 2, Anju E. Joham 1,2, Helena Teede 1, 2, † and Aya Mousa 1,*, †
1Monash Centre for Health Research and Implementation (MCHRI), School of Public Health
and Preventive Medicine, Monash University, Level 1, 43-51 Kanooka Grove, Clayton,
Melbourne, VIC 3168, Australia
2Department of Diabetes, Monash Health, 246 Clayton Rd, Clayton, Melbourne, VIC 3168, Australia
*Correspondence: aya.mousa@monash.edu; Tel.: +61-3857-22854
† These authors contributed equally to this work.
Abstract:
Human placental lactogen (hPL) is a placental hormone which appears to have key
metabolic functions in pregnancy. Preclinical studies have putatively linked hPL to maternal and
fetal outcomes, yet—despite human observational data spanning several decades—evidence on the
role and importance of this hormone remains disparate and conflicting. We aimed to explore (via
systematic review and meta-analysis) the relationship between hPL levels, maternal pre-existing and
gestational metabolic conditions, and fetal growth. MEDLINE via OVID, CINAHL plus, and Embase
were searched from inception through 9 May 2022. Eligible studies included women who were
pregnant or up to 12 months post-partum, and reported at least one endogenous maternal serum hPL
level during pregnancy in relation to pre-specified metabolic outcomes. Two independent reviewers
extracted data. Meta-analysis was conducted where possible; for other outcomes narrative synthesis
was performed. 35 studies met eligibility criteria. No relationship was noted between hPL and
gestational diabetes status. In type 1 diabetes mellitus, hPL levels appeared lower in early pregnancy
(possibly reflecting delayed placental development) and higher in late pregnancy (possibly reflecting
increased placental mass). Limited data were found in other pre-existing metabolic conditions. Levels
of hPL appear to be positively related to placental mass and infant birthweight in pregnancies affected
by maternal diabetes. The relationship between hPL, a purported pregnancy metabolic hormone, and
maternal metabolism in human pregnancy is complex and remains unclear. This antenatal biomarker
may offer value, but future studies in well-defined contemporary populations are required.
Keywords:
birthweight; gestational diabetes mellitus; human chorionic somatomammotropin;
human placental lactogen; type 1 diabetes mellitus
1. Introduction
Human pregnancy is defined by complex hormonal and metabolic changes, which
are essential to regulate nutrient availability and ensure the health of the mother and
the growing fetus. In late gestation, a significant increase in maternal insulin resistance
(prioritising the delivery of glucose and amino acids across the placenta for use by the fetus)
is paralleled by a compensatory increase in insulin synthesis and secretion. The endocrine
mechanisms underlying these changes are incompletely understood.
In women with obesity, pre-gestational diabetes (type 1 or 2), or polycystic ovary
syndrome (PCOS); the physiological adaptations of pregnancy exacerbate the existing
states of insulin resistance and/or deficiency underpinning these conditions. During preg-
nancy, gestational diabetes mellitus (GDM), defined as carbohydrate intolerance of variable
severity with first onset or recognition during pregnancy, is also increasingly common.
GDM reflects a failure to sufficiently augment insulin secretion in the face of progressive
Int. J. Mol. Sci. 2022,23, 15621. https://doi.org/10.3390/ijms232415621 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2022,23, 15621 2 of 27
gestational insulin resistance. Maternal diabetes of any type in pregnancy increases the risk
of fetal macrosomia and obstetric complications, and is associated with potential adverse
long-term alterations to the metabolic profile of the mother and offspring [
1
]. GDM during
pregnancy is a significant risk factor for future cardiovascular disease in women—one
recent meta-analysis of observational trials suggested that women with a history of GDM
had a twofold higher risk of future cardiovascular events compared with those who did
not [
2
]. As such, an improved understanding of the mechanisms that alter maternal insulin
resistance—and further insights into biomarkers which can facilitate early identification of
women at risk of GDM—are key priorities.
Human placental lactogen (hPL), previously known as human chorionic somatomam-
motropin, is a polypeptide hormone produced during pregnancy by the syncytiotro-
phoblast cells of the placenta. A member of the somatotropin family, hPL is structurally
homologous to pituitary growth hormone (GH), prolactin (PRL) and placental growth
hormone (GH-V) [
3
]. In humans, hPL binds mainly to the PRL receptor, with lower affinity
for the GH receptor [
4
]. Detection of hPL in maternal plasma occurs at approximately six
weeks of gestation, and its concentration then increases linearly until about the thirtieth
week of pregnancy, reaching peak concentrations of 5000–7000 ng/mL. The secretion rate
of hPL near term is approximately 1 g/day, significantly greater than that of any other hor-
mone [
5
]: indeed, the peak concentration of hPL is at least 25-fold that of PRL [
6
]. Maternal
serum hPL levels are positively correlated with placental mass and are greater in multiple
than singleton gestations [
5
]. hPL was widely used clinically in the 1970s–1980s, prior to
widespread obstetric ultrasound, to assess fetoplacental wellbeing in late pregnancy [
7
,
8
];
but has since fallen from routine clinical use. As a pregnancy-specific hormone, hPL is
rapidly washed from the maternal circulation following delivery of the placenta.
Along with estrogen, progesterone and PRL, hPL promotes third trimester mammary
ductal and alveolar growth for lactogenesis (hence its designation as a ‘lactogenic’ hormone).
However, hPL also has important metabolic roles in carbohydrate and lipid metabolism
and fetal nutrient availability. It has been widely implicated in pregnancy-induced insulin
resistance, maternal beta cell adaptation to pregnancy, and regulation of fetal growth in
pre-clinical studies [
3
,
9
]. As such, altered hPL dynamics have been investigated in the
context of metabolic conditions and outcomes in pregnancy.
The current literature on hPL in relation to maternal metabolism consists primarily
of pre-clinical work and dated observational studies. Clinical research on hPL in human
pregnancy has been relatively limited in recent decades, despite historical data suggesting
that the hormone may have significant diagnostic and therapeutic potential.
In this systematic review, we examine current evidence regarding the relationship
between hPL and maternal metabolic outcomes in pregnancy and postpartum, as well as
key fetal outcomes, in the context of common metabolic conditions. We seek to provide
mechanistic insights and examine the clinical implications of these findings.
2. Materials and Methods
2.1. Protocol and Registration
This review is part of a larger evidence synthesis examining lactogenic hormones in
pregnancy and postpartum, and was conducted following the Preferred Reporting Items
for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines. A protocol for this
review is published [
10
] and was registered with the International Prospective Register of
Systematic Reviews (PROSPERO), CRD42021262771.
2.2. Information Sources and Search Strategy
A systematic search strategy (Supplementary File S1) combining MeSH terms and
text words was developed using the OVID platform, in consultation with expert subject
librarians, and translated to other databases. MEDLINE via OVID, MEDLINE ePub ahead
of print, in-process, in-data review and other non-indexed citations via OVID, CINAHL
plus, and Embase were searched on 8 July 2021 (updated 9 May 2022). Bibliographies of

Int. J. Mol. Sci. 2022,23, 15621 3 of 27
relevant studies identified by the search strategy were also manually searched to identify
additional eligible studies.
2.3. Eligibility Criteria
Selection criteria using a modified version of the Participant, Exposure, Comparison,
Outcome and Study Type (PECOT) framework [
11
] were established a priori. These were
used to determine the eligibility of articles.
Studies were included in the systematic review when the following criteria were
fulfilled: (i) participants were pregnant women and women up to 12 months postpartum;
(ii) endogenous maternal serum hPL was measured and reported at least once during
pregnancy; (iii) a comparison group of any type (or no comparison group) was reported;
and (iv) one of the following key outcomes was reported in relation to hPL:
Maternal:
•
Diabetes status during pregnancy and up to 12 months postpartum (pre-existing
diabetes [type 1 or type 2], impaired glucose tolerance, or GDM; adequately defined)
•
Metabolic indices (continuous measurements) related to maternal glucose/lipid
metabolism (e.g., glucose measurements on oral glucose tolerance test; insulin se-
cretion/sensitivity/resistance indices; beta-cell function) during pregnancy or up to
12 months postpartum
•Obesity/body mass index, gestational weight gain
•Postpartum weight change
•Polycystic ovary syndrome
•Lipid profile
Infant:
•
Birthweight (absolute/centiles, macrosomia), growth restriction or placental mass in
relation to pregnancies affected by maternal GDM or pre-gestational diabetes.
Eligible study types included cross-sectional, longitudinal cohort or case–control
studies, and randomised controlled trials. Narrative and systematic reviews were excluded
from the analysis, but their bibliographies were examined to identify relevant eligible
articles. Commentaries, letters, conference abstracts, and case reports were excluded. Only
full text English articles were included, with no date limits for eligibility. Maternal diabetes
was considered adequately defined if the study clearly referred to type 1 or type 2 diabetes
mellitus (T1DM, T2DM), GDM, or impaired glucose tolerance. If definitions were less
clear (for example, older studies using White’s classification of diabetes in pregnancy),
studies were included only if the information provided was sufficient to confidently deduce
diabetes type. If definition adequacy varied between groups, the study was included only
for the group(s) meeting definition requirements.
Studies were excluded if they were animal,
in vitro
or tissue/cell culture studies;
involved exogenous administration of hPL; involved an intervention or procedure to
manipulate hPL; focused on assisted reproductive technologies; or focused primarily on
women with other pregnancy pathologies (e.g., pre-eclampsia, fetal death).
2.4. Study Selection and Risk of Bias Assessment
Two independent reviewers (KR and RG) screened all abstracts and full texts (Figure 1)
and performed quality assessment, with 10% of studies assessed in duplicate. Quality
appraisal (risk of bias) was conducted on Covidence software, using the Monash Centre
for Health Research and Implementation (MCHRI) Evidence Synthesis Program tool [
12
],
based on the Newcastle-Ottawa Scale for non-randomised studies [
13
]. Quality items were
assessed using a descriptive component approach to evaluate external validity (study de-
sign, inclusion/exclusion criteria, and appropriateness of measured outcomes) and internal
validity (selection, performance, detection, and reporting biases; attrition, confounding,
statistical methodology, and study power). Studies that fulfilled all, most or few criteria

Int. J. Mol. Sci. 2022,23, 15621 4 of 27
were deemed to have low, moderate, or high risk of bias, respectively. Discrepancies were
resolved through discussion and consensus.
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 26
for Health Research and Implementation (MCHRI) Evidence Synthesis Program tool [12],
based on the Newcastle-Ottawa Scale for non-randomised studies [13]. Quality items were
assessed using a descriptive component approach to evaluate external validity (study
design, inclusion/exclusion criteria, and appropriateness of measured outcomes) and
internal validity (selection, performance, detection, and reporting biases; attrition,
confounding, statistical methodology, and study power). Studies that fulfilled all, most or
few criteria were deemed to have low, moderate, or high risk of bias, respectively.
Discrepancies were resolved through discussion and consensus.
Figure 1. PRISMA flowchart.
Figure 1. PRISMA flowchart.
2.5. Data Extraction and Synthesis
Data were manually extracted from all included studies by two independent review-
ers using a purpose-built data extraction form in Microsoft Excel, with 10% extracted in
duplicate. Information was collected on general study characteristics (authors, publication
year and source, country, study design, duration of follow-up), participant characteristics
(baseline age, metabolic conditions, parity, body mass index (BMI), ethnicity), hPL time-
points and values, hPL assay techniques, key maternal outcomes assessed in relation to

Int. J. Mol. Sci. 2022,23, 15621 5 of 27
hPL (unadjusted and adjusted, with consideration of covariates used), key relevant infant
outcomes, and conclusions.
2.6. Evidence Synthesis and Statistical Analysis
Where meta-analysis was possible, Review Manager 5.4.1 software was used. Where
published papers contained insufficient data to be entered into meta-analysis, details were
sought from the authors. Weighted mean differences (WMD) were generated using random
effects models. Statistical heterogeneity was assessed using the I
2
test, with I
2
values of
>50% indicating moderate to high heterogeneity. Sensitivity analyses were conducted to
examine the effects of studies with high risk of bias on the overall results. Sensitivity analy-
sis was also performed with exclusion of studies published prior to the year 2000 (given
that older studies likely reflect a different clinical and therapeutic environment). Where
meta-analysis was not possible, narrative synthesis of results was performed. Data are
presented in summary tables and in narrative format. Forest plots
(Figures A1 and A2a,b)
and funnel plots (Supplementary File S2) were used to present the results of meta-analyses
and publication bias assessments, respectively.
3. Results
3.1. Study Selection and Characteristics
A total of 3922 results were retrieved from the initial database search for the broader
evidence synthesis examining lactogenic hormones. Following removal of duplicates,
2643 and 190
studies were excluded at abstract and full text screening, respectively
(Figure 1)
.
Of note, studies excluded on the basis of unavailable English full text (n= 51) or inadequate
maternal diabetes definition (n= 51) were disproportionately dated, with all published
prior to 1998 and 2000, respectively.
A total of 62 studies met the broader eligibility criteria for inclusion, of which 35 per-
tained specifically to hPL and were included in the current review. Due to methodological
heterogeneity, meta-analysis was only possible for hPL differences in late pregnancy by
T1DM status (four studies) and for hPL differences in early and late pregnancy by GDM
status (three and 10 studies, respectively).
3.2. Risk of Bias of Included Studies
Of the 35 included studies, 12 were deemed high risk of bias, 16 moderate, and seven
low (Tables A1–A5). The main aspects contributing to high risk of bias were the presence
of confounding and selection bias, both of which were present in seven of the 12 studies
deemed high risk of bias. Low-quality statistical analysis and concerns regarding the
accuracy and validity of hormone measurement were also common domains of concern,
each present in six of the 12 high-risk studies.
Based on visual inspection of funnel plots, there was no evidence of publication bias
across any of the outcomes assessed (Supplementary File S2).
3.3. Synthesis of Results
3.3.1. Human Placental Lactogen in Pregnancies Affected by Pre-Gestational
Metabolic Conditions
Twelve studies examined hPL across pregnancy in women with adequately-defined
pre-gestational diabetes mellitus (PGDM) (Table A1). These were all published prior to
1998 and focused on T1DM, with no studies in pregnancies affected by T2DM or PCOS.
(a)
Differences in hPL between T1DM and control pregnancies
Seven of the 12 studies [
14
–
20
] reported measuring early pregnancy (
≤
24 weeks)
hPL in women with T1DM compared with controls, although only six clearly reported
between-group hPL results. Of these, four found hPL to be significantly lower in T1DM
than controls for at least one early pregnancy timepoint [
14
–
17
]. One found hPL to be
higher in T1DM than controls [
18
], while the other found no difference [
20
]. With the

Int. J. Mol. Sci. 2022,23, 15621 6 of 27
exception of one study [
16
], all of these studies lacked sufficient raw published data for
meta-analysis, and their age precluded contacting authors for more details.
Nine studies compared late pregnancy (>24 weeks) hPL between T1DM and controls.
Of these, four [
16
,
18
,
21
,
22
] had available data for meta-analysis (Figure A1). Latest avail-
able pregnancy measurements were used in all cases (all 34–40 weeks). Pooled results
showed significantly higher late pregnancy hPL levels in women with T1DM than controls
(WMD = 1.24
µ
g/mL, 95% CI 0.44 to 2.05, p= 0.003), with no heterogeneity (I
2
= 0%,
p= 0.6). Sensitivity analysis with exclusion of the two studies deemed high risk of bias
did not significantly alter results. Of the five studies without sufficient information for
inclusion in the meta-analysis; two showed significantly higher late hPL levels in T1DM
than control pregnancies [
19
,
23
], two showed no difference [
15
,
20
], and a single small study
showed lower late hPL in T1DM than controls [14].
Two studies which sub-divided T1DM subjects by class (White’s classification, based
on complications and duration) found no difference in hPL values across subgroups of
progressive T1DM ‘severity’ [
17
,
18
]. However, a third study (focused specifically on
diabetic retinopathy) found higher hPL values in the subset of pregnant women with T1DM
with retinopathy, particularly progressive retinopathy, who also had worse glycaemic
control and higher placental mass [19].
(b)
Relationship between hPL and glycaemic measures in T1DM
Five studies [
14
,
15
,
18
,
21
,
22
] examined hPL in T1DM in relation to plasma glucose
(mean and/or prevailing). Botta et al. [
14
] reported that hPL was inversely associated with
blood glucose levels across gestation (both average glucose that day and glucose at the time
of hPL sampling). The remaining studies, of which two had similar methodology [
15
,
18
]
and two sampled hPL serially over 8–24 h [
21
,
22
] reported no relationship between hPL
and glucose.
Two studies examined HbA1c in relation to hPL in T1DM (one in a one-off early preg-
nancy sample, one at serial timepoints); both showing no significant relationship [15,17].
Three studies examined hPL levels relative to the increase in insulin requirements across
pregnancy in T1DM, all reporting no relationship between these two variables [
18
,
20
,
24
].
In contrast, the sole study to use insulin clamp methodology to directly quantify insulin
resistance in early and late pregnancy found that the size of hPL increment across pregnancy
was significantly inversely proportional to late pregnancy insulin sensitivity in women
with T1DM (n= 6) [25].
3.3.2. Human Placental Lactogen in Pregnancies Affected by Gestational Diabetes Mellitus
Seventeen studies examined hPL across pregnancy in women with GDM (Table A2).
(a)
Differences in hPL between GDM and control pregnancies
Five studies [
16
,
18
,
26
–
28
] compared hPL in women with GDM and controls in early
pregnancy (
≤
24 weeks, often prior to GDM diagnosis and recognition). In the three
studies with sufficient data for meta-analysis (Figure A2a), pooled analysis showed no
significant difference in early pregnancy hPL between GDM and control pregnancies
(
WMD = 0.21 µg/mL
, 95% CI
−
0.52 to 0.94, p= 0.6). Statistical heterogeneity was high
(I
2
= 74%, p= 0.02), and small sample sizes universal. Two of the three studies [
16
,
26
]
were deemed high risk of bias; precluding sensitivity analysis. Of the two studies with
insufficient detail for inclusion in the meta-analysis, one reported higher hPL values in
women with GDM than controls [
28
], and the other showed no significant difference
herein [27].
Fourteen studies compared hPL between women with GDM and controls in later
pregnancy (>24 weeks), twelve of which were eligible for meta-analysis, but two were
subsequently excluded due to significant methodological concerns and a suspicion of
erroneous hPL values (see Table A2 footnotes) [
29
,
30
]. All values were third trimester
samples. Pooled analysis of the ten included studies [
16
,
18
,
22
,
26
,
31
–
36
] using the latest
timepoint if multiple were available (Figure A2b), suggested no significant difference in

Int. J. Mol. Sci. 2022,23, 15621 7 of 27
late pregnancy hPL between women with GDM and controls (WMD = 0.47
µ
g/mL, 95% CI
−
0.14 to 1.09, p= 0.1), with moderate heterogeneity (I
2
= 60%, p= 0.008). Sensitivity analyses
with exclusion of older studies and those deemed high risk of bias did not significantly
alter results. The two studies that lacked sufficient detail for inclusion in the meta-analysis
also found no significant difference in late hPL between GDM and controls [37,38].
Three studies examined the clinical utility of hPL as a risk predictor for GDM. Two
studies (one with major methodological limitations, see Table A2 footnotes [
29
]) suggested
it was unlikely to be useful, due to poor classification performance [
28
] or non-significant
predictive capacity [
29
]. Conversely, the third study [
34
] suggested that hPL may be a
promising adjunct to screening glucose challenge tests in predicting the likelihood of a
subsequent abnormal oral glucose tolerance test (OGTT).
(b)
Relationship between hPL and glycaemic measures in GDM
Nine studies examined hPL in relation to cross-sectional or longitudinal glycaemic
parameters in GDM such as plasma glucose or insulin, or markers of insulin sensitivity or
resistance. Overall, none found consistent relationships between hPL and these variables
in women with GDM or controls [18,22,29,30,32,33,36,38,39].
3.3.3. Human Placental Lactogen in Relation to Glycaemic or Insulin-Related Parameters in
Healthy Pregnancies and Postpartum
Four studies [
40
–
43
] examined hPL in relation to glycaemic or insulin-related param-
eters in healthy pregnant women (Table A3). The methodology of these studies varied
considerably, precluding meta-analysis. Benny et al. [
40
] examined hPL dynamics across
a 24 h period in the third trimester, showing a peak after overnight fasting (temporally
coincident with the time of lowest glucose and insulin, and potentially consistent with the
idea of hPL as an insulin-antagonistic hormone). Enzi et al. [
41
] found that maternal hPL
levels at 34 weeks were positively related to the area under the curve (AUC) of both glucose
and insulin, suggesting this confirmed the diabetogenic effects of hPL. This differed from
the findings of two other studies, where hPL was unrelated to prevailing glucose [
42
] or to
2 h OGTT insulin or glucose levels [
43
] in healthy pregnancies. However, higher hPL levels
were associated with higher levels of non-esterified fatty acids in one study [
42
], suggestive
of anti-insulin, diabetogenic properties.
One study [
44
] related hPL to postpartum glycaemia, finding that hPL in late preg-
nancy was not an independent predictor of insulin resistance, beta-cell function or diabetes
risk (all measured at 3 months postpartum).
3.3.4. Human Placental Lactogen in Relation to Body Mass Index or Gestational Weight
Gain in Pregnancy
Four studies [
30
,
41
,
45
,
46
] examined hPL in relation to maternal BMI or gestational
weight gain (GWG) (Table A4). Two studies showed no relationship between hPL and
maternal BMI [
30
] or hPL and GWG (crudely categorised as <20% or >20% ideal body
weight for normal or excessive GWG, respectively) [
41
]. Lin et al. [
45
] described an inverse
relationship between hPL and absolute maternal weight at term, proposed to be a dilutional
effect (more tissue space in larger women). McCarrick et al. [
46
] found that obese women
were over-represented in a group of women with low hPL but normal estrogen levels,
suggesting that obesity may impact on hPL regulation and activity (although many of these
women had other pregnancy complications which may have explained their low hPL levels,
such as toxaemia or intra-uterine growth restriction).
3.3.5. Human Placental Lactogen in Relation to Fetal, Neonatal or Placental Outcomes in
Pregnancies Affected by Maternal Diabetes
Seven studies [
14
,
18
,
20
,
35
,
38
,
47
,
48
] examined hPL in relation to fetal, neonatal or
placental outcomes in pregnancies affected by maternal PGDM/GDM (Table A5). Variable
methodology and lack of reporting detail prevented meta-analysis.

Int. J. Mol. Sci. 2022,23, 15621 8 of 27
One study [
48
] examined hPL in relation to fetal growth/size in the early stages
of T1DM pregnancies (n= 26), and found that hPL at 7–16 weeks could be best related
to menstrual age when the latter was corrected by any ultrasonographically determined
‘growth delay’. Given that hPL reflects functional trophoblastic mass, this suggested that the
observed growth delay in T1DM pregnancies may relate to delayed placental development.
Three studies examined hPL in the late third trimester relative to placental weight at
delivery in pregnancy cohorts affected by (adequately-defined) maternal PGDM/GDM.
One study [
18
] of 38 women found that late pregnancy hPL was strongly positively corre-
lated to placental weight in T1DM (r = 0.8, p< 0.01), GDM (r = 0.6, p< 0.05), and controls
(
r = 0.6
,p< 0.05). In the remaining two studies, one found no relationship (despite a trend
noted) between late pregnancy hPL and placental weight in a small combined cohort of
15 T1DM and 10 control pregnancies [
14
] and the other found that hPL was positively
associated with placental mass in the larger control group (n= 69; r = 0.3, p< 0.01) but not
in the T1DM cohort (n= 40), likely due to low statistical power [20].
Five studies examined hPL in relation to infant birthweight in pregnancies affected by
PGDM/GDM. Two [
14
,
35
] found no relationship between hPL at 36 weeks or at term with
birthweight in a combined cohort of women with T1DM and controls (n= 25) or a combined
cohort of women with GDM, women with premature deliveries and controls
(n= 46)
,
respectively. Conversely, two other studies showed positive relationships between third
trimester hPL and corrected birthweight in T1DM (r = 0.48, p< 0.02) [
20
] or birthweight
in a GDM cohort (r = 0.59, p< 0.05) [
38
]. Finally, Small et al. [
47
] examined hPL in
relation to birthweight ‘class’, finding that a T1DM group with macrosomic infants (mean
birthweight 3.96 kg at 37 weeks) had significantly higher hPL at 34 weeks than matched
T1DM pregnancies without macrosomia (mean birthweight 3.05 kg at 37 weeks).
4. Discussion
To our knowledge, this is the first systematic review of hPL in relation to maternal
metabolic outcomes in pregnancy. Specifically, we explored hPL in healthy pregnancies
and in those with PGDM/GDM, and relationships to maternal metabolic parameters and
fetal growth within these subgroups. Systematic review and meta-analysis suggests altered
hPL dynamics in pregnancies affected by T1DM, but no relationships with GDM were
identified. hPL appears positively correlated with placental mass in PGDM/GDM and
elevated in pregnancies affected by macrosomia. However, hPL levels were not clearly
linked to maternal glycaemic outcomes in PGDM/GDM, despite pre-clinical evidence for
physiological roles in both insulin resistance and maternal beta-cell adaptation to pregnancy.
4.1. hPL in Pre-Gestational (Type 1) Diabetes Mellitus
In pre-gestational T1DM, the results of our review suggest altered hPL dynamics
across gestation (with differential effects in early and late pregnancy). Meta-analysis
comparing early hPL levels in T1DM vs. control pregnancies was not possible due to
a lack of detailed comparative data, but results were broadly suggestive of lower early
hPL levels in pregnancies affected by T1DM. Whilst some authors have speculated that
these low levels may be a direct response to maternal hyperglycaemia [
14
], it should be
noted that experimental evidence showing depression of hPL levels required maternal
blood glucose to be raised dramatically (via rapid intravenous infusion over 30 min to a
mean of 22.2 mmol/L, in the seminal trial) [
49
]. The evidence summarised in our review
suggests that more subtle alterations of plasma glucose, such as may occur in adequately-
controlled maternal T1DM, are unlikely to have a major direct impact on hPL levels.
Overall, the lower levels of hPL observed in early T1DM pregnancy seem more likely to
relate to delayed trophoblastic development [
16
,
48
]. Such a mechanism would be consistent
with the observation that concentrations of other key gestational hormones–such as PRL
and human chorionic gonadotropin (hCG)–may also lag behind normal early pregnancy
reference ranges in T1DM pregnancies, particularly in the context of suboptimal glycaemic
control [50].

Int. J. Mol. Sci. 2022,23, 15621 9 of 27
In the later part of T1DM pregnancy (namely the third trimester), the results of
our review and meta-analysis support higher circulating maternal hPL levels in T1DM
than control pregnancies. The observation of higher hPL levels in T1DM has typically
been attributed to greater placental mass in such pregnancies. Mechanistically, this may
reflect fetal hyperglycaemia with secondary hyperinsulinaemia, leading to macrosomic
stimulation of the placenta [
8
]. Early clinical literature, dating to the era where the hormone
was in routine obstetric use, is in keeping with this: high-normal or high hPL levels
were “expected” in T1DM pregnancy. When levels fell below this, they were likely to
be suggestive of a separate superimposed reason for fetoplacental compromise (such as
toxaemia or late fetal demise, which were common occurrences in T1DM cohorts in that
era) [51].
Together, the results of studies of hPL in T1DM suggest that the relationship between hPL
and maternal metabolism is likely bidirectional. Whilst hPL certainly has metabolic actions,
its concentrations are also likely influenced by an altered maternal metabolic environment
(such as in T1DM), with different mechanisms operational in early vs. late pregnancy.
4.2. hPL in Maternal Glycaemia and Gestational Diabetes Mellitus
Our meta-analysis of studies comparing absolute hPL concentrations between women
with GDM and controls in both early and late pregnancy showed no statistically significant
differences between groups. Similarly, the small number of studies which investigated hPL
as a GDM risk prediction biomarker do not support its predictive utility.
A body of pre-clinical evidence certainly provides theoretical grounds to suggest
that hPL may be immediately relevant to maternal glucoregulation in pregnancy: at high
concentrations, hPL has classically been considered a ‘diabetogenic’ hormone [
8
,
52
] with
insulin-antagonistic and lipolytic effects. Most endocrine texts still describe hPL as a key
contributor to gestational insulin resistance, increasing fetal nutrient availability by sparing
glucose, amino acids and ketones for placental-fetal transport [
53
]. However, rodent and
in vitro
human data have also repeatedly identified a key parallel role for hPL (acting via
the PRL receptor) to induce maternal pancreatic adaptation to pregnancy, increase beta-cell
mass, and potentiate glucose-stimulated insulin secretion [6,54,55].
Despite these roles, the human data synthesised in our review suggests that absolute
maternal hPL concentrations measured in human pregnancy populations may be difficult
to link directly to glycaemic parameters. As such, it seems likely that the
in vivo
metabolic
effects of hPL are likely to be much more complex than suggested by existing pre-clinical
evidence, much of which was accumulated a generation ago. For example, there is increas-
ing acknowledgment of the multifactorial and synergistic nature of late pregnancy insulin
resistance, with important roles for GH-V (a powerful lipolytic hormone), maternal insulin
like growth factor 1 (IGF-1), progesterone, cortisol and tumor necrosis factor (TNF
α
); as
well as a fall in adiponectin [
9
]. As such, the designation of hPL as the “major diabetogenic
stress factor of pregnancy” may be overly simplistic. Similarly, autopsy evidence from
the pancreata of pregnant women indicates that the adaptive beta cell changes of human
pregnancy may be less profound and different in nature to those observed in rodents [56],
which immediately suggests that the extrapolation of findings from sub-primate models
about the insulinogenic properties of the hormone must be approached with caution. Fur-
thermore, circulating serum levels of a hormone do not always tell the whole story: for
example, recent work has suggested that certain PRL receptor polymorphisms may predict
GDM risk, implying that differences in hormone action—at a tissue level—may be just as
important as absolute hormone concentrations [57].
Thus, whilst pre-clinical studies clearly support a key role for hPL in metabolic adapta-
tions to human pregnancy (both as an insulin antagonist and as a stimulus for augmented
insulin secretion); the collated observational data suggest that its measured circulating
concentrations may not provide direct insights into maternal glucose homeostasis.

Int. J. Mol. Sci. 2022,23, 15621 10 of 27
4.3. hPL in Fetal Growth in Pregnancies Affected by Maternal Diabetes
Studies have consistently demonstrated a positive association between hPL and pla-
cental mass (in both diabetic and non-diabetic cohorts) [
14
,
18
,
51
,
58
,
59
] and a positive
association between hPL and infant birthweight has also been demonstrated in several
large general pregnancy cohorts [
60
–
62
]. Our review, which was limited to pregnancies
affected by adequately-defined maternal diabetes, generally supported these findings. Ac-
curate antenatal prediction of fetal macrosomia remains challenging, and current strategies
(including fundal measurements and ultrasound assessment) are resource-intensive. There
is thus a clear requirement for maternal serum biomarkers in improving macrosomia predic-
tion, particularly in women at high risk (such as those with PGDM/GDM). Whilst several
biomarkers have been assessed for their association with birthweight or macrosomia (both
in diabetic and non-diabetic pregnancies), evidence is mixed and uncertainties around
clinical utility persist [
63
]. hPL has recently been largely overlooked in this capacity, but
previous work suggests it may have significant potential if revisited [19,47].
Mechanistically, a direct role for hPL in the regulation of fetal growth is also feasible:
for example, targeted reductions in placental lactogens in sheep pregnancy via modification
of placental gene expression result in significantly reduced fetal weight, possibly mediated
by disrupted IGF-1 and IGF-2 expression [
64
,
65
]. In humans, low levels of hPL in small
for gestational age pregnancies are commonly observed (along with reduced levels of GH-
V) [
62
,
66
,
67
]. The role of hPL in large for gestational age (LGA) pregnancies—particularly
those affected by maternal metabolic disease—is similarly interesting. In general obstetric
populations, significant positive relationships between maternal hPL levels at 34 weeks’ ges-
tation and neonatal body weight, body fat mass and fat cell weight have been reported [
41
],
and other research has demonstrated a 1.6-fold higher expression of hPL genes in the
placentas of LGA newborns compared to those of normal size [
67
]. As such, hPL may
contribute aetiologically to macrosomia, aside from simply reflecting increased placental
mass in LGA pregnancies. Whilst fetal overgrowth in maternal obesity and diabetes is
commonly associated with placentomegaly, it is also possible that the resulting hPL excess
may further stimulate both maternal and fetal beta-cell expansion and increase fetal insulin
production, which would promote glycogenesis, fat deposition and fetal growth [9].
Given the likely positive relationships between hPL and placental mass/neonatal
weight in pregnancies affected by maternal diabetes, as well as a possible aetiological role
in the development of macrosomia; late-pregnancy hPL warrants re-visiting in modern
obstetric populations (both with and without diabetes).
4.4. Strengths and Limitations
As noted above, this is the first review to systematically collate and synthesise the
literature linking hPL to maternal metabolic outcomes in pregnancy and related fetal out-
comes. We employed rigorous, international gold-standard methodology with a protocol
developed a priori to ensure transparency. The review addresses a broad, mechanistic
question that links important aspects of female reproductive and metabolic health; and
sheds light on a hormone which has been overlooked in the endocrine literature in recent
decades. Identification of biomarkers that may aid with GDM risk prediction, or help with
identifying complications in pregnancies affected by maternal diabetes; is a key health
priority–particularly given the accumulating body of evidence linking gestational metabolic
disease (and insulin resistance) to lifetime metabolic and cardiovascular risk in women.
Limitations of the review process include restriction of the search to published English
language articles. In addition, the requirement for clearly defined maternal diabetes
type excluded some older studies (pre-1980s, often referring only to ‘maternal diabetes’).
Inclusion of this literature would have increased the number of included studies–and
possibly numbers for meta-analysis–but would have introduced significant uncertainty
and made results less applicable to modern clinical populations.
Limitations of the literature were substantial and precluded firm conclusions regard-
ing the role of hPL in pregnancy and postpartum in the context of common metabolic

Int. J. Mol. Sci. 2022,23, 15621 11 of 27
conditions. These limitations included heterogeneous methodology and a frequent lack
of detail in data reporting, which contributed to the inability to perform meta-analysis
for many outcomes. Variable study quality was reflected in the risk of bias assessments
(
28 of 35 studies
were deemed to have moderate or high risk of bias). Studies were small
and were all observational in nature, increasing the likelihood of low statistical power
and residual confounding. Measurement of hPL at only one or two timepoints (and often
within a broad gestational age bracket, without subsequent correction for exact gestational
age) was a significant limitation of many studies, given the steep increase in hPL con-
centrations known to occur across normal pregnancy. BMI is also an important potential
confounder in the relationship between hPL and metabolic indices, but BMI reporting in
the included studies was variable, and precluded stratification of meta-analyses based on
BMI. Data (on T1DM, in particular) was dated; and thus reflected a historical therapeutic
environment. Assay methodology for measuring hPL also varied, with older studies using
radioimmunoassay techniques and newer studies favouring enzyme-linked immunoassays.
There were no data relating hPL to maternal metabolic outcomes or fetal parameters in
T2DM or PCOS cohorts, or to lipid profiles; and data on maternal obesity and GWG was
sparse. Finally, the hormonal environment of pregnancy and postpartum is complex, and
studies focusing on absolute levels of a single hormone may overlook other factors such as
hormone synergy, local tissue levels, and receptor polymorphisms.
5. Conclusions
In summary, the findings of our review suggest that in T1DM pregnancies, hPL levels
may be lower than controls in early pregnancy (possibly reflecting delayed placental
development) and higher than controls in later pregnancy (likely in keeping with higher
placental masses), but that absolute hPL concentrations are not clearly linked to maternal
glycaemic outcomes in PGDM or GDM, nor to GDM status/risk. Moreover, hPL is likely
positively related to placental mass and infant birthweight in pregnancies affected by
PGDM or GDM, and may be aetiologically important in the regulation of fetal growth.
Despite having fallen from routine clinical use in recent decades, hPL may warrant renewed
investigation as an antenatal biomarker for the prediction of macrosomia. However, given
the limited available data, small study numbers, and substantial heterogeneity in study
design and methodology, future high-quality studies exploring this hormone in well-
defined contemporary populations are required to clarify these relationships and to inform
future research and clinical practice.
Supplementary Materials:
The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/ijms232415621/s1.
Author Contributions:
K.R. conceptualised and designed the protocol, with oversight from A.E.J.,
H.T. and A.M. K.R. designed the search strategy, conducted the search and obtained full copies
of studies. K.R. and R.G. conducted screening, data extraction and risk of bias assessments. K.R.
tabulated data, interpreted results, and performed statistical analysis with assistance from A.M. K.R.
drafted the manuscript, which was reviewed and approved by R.G., A.E.J., H.T. and A.M. All authors
contributed substantial intellectual input to the manuscript in line with International Committee
of Medical Journal Editors (ICMJE) criteria for authorship and have approved the final version for
publication. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement:
Not applicable.
Data availability statement:
Data sharing is not
applicable to this article as no new data were created or analysed in this study.
Conflicts of Interest: The authors declare no conflict of interest.

Int. J. Mol. Sci. 2022,23, 15621 12 of 27
Appendix A
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 12 of 26
glycaemic outcomes in PGDM or GDM, nor to GDM status/risk. Moreover, hPL is likely
positively related to placental mass and infant birthweight in pregnancies affected by
PGDM or GDM, and may be aetiologically important in the regulation of fetal growth.
Despite having fallen from routine clinical use in recent decades, hPL may warrant
renewed investigation as an antenatal biomarker for the prediction of macrosomia.
However, given the limited available data, small study numbers, and substantial
heterogeneity in study design and methodology, future high-quality studies exploring
this hormone in well-defined contemporary populations are required to clarify these
relationships and to inform future research and clinical practice.
Supplementary Materials: The following supporting information can be downloaded at:
www.mdpi.com/xxx/s1.
Author Contributions: K.R. conceptualised and designed the protocol, with oversight from A.E.J.,
H.T. and A.M. K.R. designed the search strategy, conducted the search and obtained full copies of
studies. K.R. and R.G. conducted screening, data extraction and risk of bias assessments. K.R.
tabulated data, interpreted results, and performed statistical analysis with assistance from A.M. K.R.
drafted the manuscript, which was reviewed and approved by R.G., A.E.J., H.T. and A.M. All
authors contributed substantial intellectual input to the manuscript in line with International
Committee of Medical Journal Editors (ICMJE) criteria for authorship and have approved the final
version for publication. All authors have read and agreed to the published version of the
manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data availability statement: Data sharing is not applicable to this article as no new data were
created or analysed in this study.
Conflicts of Interest: The authors declare no conflicts of interest.
Appendix A
Figure A1. Meta-analysis of hPL levels in T1DM vs. non-diabetic control women in late pregnancy
(>24 weeks)—4 studies.
Figure A1.
Meta-analysis of hPL levels in T1DM vs. non-diabetic control women in late pregnancy
(>24 weeks)—4 studies.

Int. J. Mol. Sci. 2022,23, 15621 13 of 27
Table A1. Studies examining hPL in pregnancies affected by pre-gestational type 1 diabetes mellitus—12 studies.
Author and Year;
Country of Origin Design Participants and
Sample Size
Methodology and
hPL Pregnancy
Timepoints
Metabolic
Parameters
Analysed
Results Authors’ Conclusions Risk of Bias Rating
Botta et al., 1984
[14]
Italy
Longitudinal
observational
n= 15 T1DM
n= 10 controls
hPL sampled at:
12 weeks
16 weeks
20 weeks
24 weeks
28 weeks
32 weeks
36 weeks
T1DM status
Blood glucose
Mean hPL sig lower in T1DM women than
controls at 6 of the 7 timepoints (all other than
16 weeks).
In T1DM women, at 5 of the 7 timepoints, sig
inverse relationship between hPL and mean
blood glucose that day.
In T1DM women, at 4 of the 7 timepoints, sig
inverse relationship between hPL and blood
glucose at the time.
hPL lower in T1DM subjects than controls
across preg
Indication of inverse relationship between hPL
and prevailing blood glucose levels in T1DM,
suggesting that hPL may be influenced by
hyperglycaemia, and that normalising control
may normalise hPL.
Moderate
Braunstein et al.,
1989 [15]
USA
Longitudinal
observational
n= 35 T1DM
n= 31 controls
hPL sampled at:
5–6 weeks
7–8 weeks
9–10 weeks
12–13 weeks
20 weeks
27–29 weeks
35–37 weeks
T1DM status
Blood glucose
HbA1c
Mean hPL sig lower in T1DM women than
controls at 9–10 weeks and 20 weeks (2 of
7 timepoints), at other timepoints no sig
difference.
Mean fasting glucose, mean 1 h post-prandial
glucose and HbA1c at each gestation not related
to hPL in T1DM women.
Finding of lower hPL in T1DM women at
2 timepoints likely due to chance–overall, ‘no
consistent finding’ of differences between
T1DM and control women.
No relationship between glycaemia and hPL in
T1DM at any timepoint.
Moderate
De Hertogh et al.,
1976 [16]
Belgium
Longitudinal
observational
n= 21 T1DM
n= 22 controls
hPL sampled at:
5–8 weeks
9–12 weeks
13–16 weeks
17–20 weeks
21–24 weeks
25–28 weeks
29–32 weeks
33–36 weeks
37–40 weeks
T1DM status
Mean hPL sig lower in T1DM women than
controls at 13–16, 17–20 and 21–24 weeks.
No sig differences at other timepoints, although
three individual T1DM women had very high
(outlying) hPL values in late preg.
hPL lower in T1DM subjects than controls in
early preg, possibly reflecting delayed placental
development.
No significant differences later in preg, although
levels very high in some T1DM individuals.
High
Gillmer et al., 1977
[21]
UK
Cross-sectional n= 11 T1DM
n= 23 controls
hPL sampled every
1–2 h over one 24 h
period in at
34–35 weeks
T1DM status
Blood glucose
OGTT glucose
Mean hPL over 24 h was higher in T1DM than
controls, but did not reach sig (T1DM vs.
controls 5.9 ±1.7 vs. 5.1 ±1.2 µg/mL,
p-value NR).
No sig correlation between mean hPL over 24 h
and mean glucose over 24 h in any group
(T1DM or controls).
In control group, no sig alteration in hPL over
course of OGTT (T1DM women did not
have OGTT).
NS trend to higher hPL in third trimester in
T1DM women than controls.
hPL varied across day in all women, but no
consistent relationship to meals/fasting, etc. No
sig relationship between mean glucose and hPL
in either group, and no hPL alteration with
OGTT in controls.
Moderate

Int. J. Mol. Sci. 2022,23, 15621 14 of 27
Table A1. Cont.
Author and Year;
Country of Origin Design Participants and
Sample Size
Methodology and
hPL Pregnancy
Timepoints
Metabolic
Parameters
Analysed
Results Authors’ Conclusions Risk of Bias Rating
Larinkari et al., 1982
[19]
Finland
Longitudinal
observational
n= 57 T1DM
(n= 42 with no DR,
7 with NPDR, 8
with PDR)
n= 58 early preg
controls
n= 24 later preg
controls
hPL sampled at:
7–13 weeks
14–19 weeks
20–25 weeks
26–31 weeks
32–37 weeks
T1DM status
T1DM control
Mean hPL sig higher in T1DM than controls at
34–36 weeks (10.4 vs. 7.18 µg/mL, p< 0.001).
Other time frames NR.
T1DM patients with DR (n= 15) had higher hPL
than T1DM patients without DR (n= 42) at both
14–19 weeks and 20–25 weeks (NS diff at other
timepoints). This group had had worse
glycaemic control in the first trimester.
T1DM patients with DR in whom retinopathy
progressed during preg (8 of 15, all with worse
control and larger placental masses) all had hPL
values at or above ULN after 28 weeks.
Higher hPL in late preg in T1DM subjects
than controls.
Within T1DM, patients with poor control and
DR had higher hPL in second trimester than
those without DR; and the subset with
progressive DR had markedly elevated hPL
values in the third trimester (in association with
poor control and placentomegaly).
High
Lopez-Espinosa
et al., 1986 [18]
Scotland
Longitudinal
observational
n= 15 T1DM
n= 14 controls
For T1DM,
fortnightly hPL
samples
12–32 weeks and
then weekly until
delivery
For controls, hPL
monthly
T1DM status
T1DM sever-
ity/complications
T1DM duration
Blood glucose
Insulin
requirements
Mean hPL in T1DM sig higher than controls in
2nd trimester (mean ±SEM 1.7 ±0.1 vs.
1.3 ±0.1 µg/mL, p< 0.01), NS diff in early 3rd
trimester (6.4 ±0.4 vs. 5.4 ±0.5, NS), and sig
higher again at 37–40 weeks (8.4 ±0.3 vs.
6.5 ±0.3, p< 0.01).
No differences in hPL between T1DM subjects
with differing T1DM severity/complications
(White’s classes B, C and D).
No relationship of hPL to duration of T1DM.
No relationship of hPL to either plasma glucose
levels or insulin requirements across preg
in T1DM.
hPL appears higher in T1DM than control
patients across late preg.
No apparent relationship between hPL and
T1DM plasma glucose, insulin requirements,
disease duration or severity.
Moderate
Madsen et al., 1983
[23]
Denmark
Cross-sectional n= 42 T1DM
n= 20 controls
One-off hPL sample
at 30–36 weeks T1DM status
Median hPL higher in T1DM than controls in
3rd trimester, 6.9 vs. 6 µg/mL; unclear if sig
(p-value NR).
Median hPL value higher in T1DM than control
women in third trimester, but unclear if sig. High
Pedersen et al., 1998
[17]
Denmark
Cross-sectional n= 79 T1DM
n= 93 controls
One-off hPL sample
at 8–13 weeks
T1DM status
T1DM sever-
ity/complications
HbA1c
hPL value, as MoM for exact gestation, sig
lower in T1DM than controls at 8–13 weeks:
median difference 0.34, p< 0.00001
No differences in hPL between T1DM subjects
with differing T1DM severity/complications
(White’s classes B, C and D).
No relationship of hPL to HbA1c in
T1DM subjects.
hPL sig lower (for gestation) in T1DM than
control preg in first trimester.
Authors suggest that this may reflect delayed
placental development/depressed trophoblast
function in T1DM preg; and/or effect of
hyperglycaemia on hPL secretion. No apparent
relationship between hPL and T1DM
severity/class, nor HbA1c.
Moderate
Persson et al., 1975
[22]
Sweden
Cross-sectional n= 7 T1DM
n= 5 controls
Five samples of hPL
over one 8 h period
at 34–37 weeks
T1DM status
Blood glucose
FFAs/glycerol
Ketones
Insulin
Mean hPL over 8 h sampling period was not sig
different between T1DM vs. controls. More
variability in hPL noted in T1DM.
hPL changes over the sampling period bore no
relationship to changes in glucose, FFAs,
ketones, or insulin over sampling period.
hPL in over 8 h in third trimester not sig
different between T1DM and controls; although
possibly more variable in T1DM.
hPL not clearly related to insulin or glucose
dynamics over an 8 h period in T1DM
or controls.
High

Int. J. Mol. Sci. 2022,23, 15621 15 of 27
Table A1. Cont.
Author and Year;
Country of Origin Design Participants and
Sample Size
Methodology and
hPL Pregnancy
Timepoints
Metabolic
Parameters
Analysed
Results Authors’ Conclusions Risk of Bias Rating
Schmitz et al., 1985
[25]
Denmark
Longitudinal
observational n= 6 T1DM
hPL sampled in
early preg
(~13 weeks) and
late preg
(~34 weeks)
T1DM insulin
sensitivity (glucose
disposal via clamp)
Increase in hPL from early to late preg, ∆hPL,
calculated.
∆hPL inversely proportional to the degree of
insulin sensitivity by late preg, ie those with
larger ∆hPL were less insulin sensitive in late
preg; r = −0.84, p< 0.04.
hPL increase inversely proportional to late preg
insulin sensitivity in small T1DM clamp study
cohort. Authors conclude that hPL seems to be a
major factor causing impaired insulin action in
late gestation.
Moderate
Spellacy et al., 1973
[24]
USA
Longitudinal
observational n= 22 T1DM
Frequent hPL
sampling from early
first trimester to
delivery
T1DM insulin
requirements
Insulin requirement increase across pregnancy
in T1DM was individually variable and not
consistently related to hPL increase.
hPL rise across pregnancy showed no consistent
relationship to rising insulin requirements in
T1DM.
Authors suggest that hPL may not be the key
diabetogenic stress factor of pregnancy as
previously postulated, rather increasing insulin
resistance with gestation likely to be
multifactorial/synergistic.
High
Stewart et al., 1989
[20]
UK
Longitudinal
observational
n= 40 T1DM
n= 69 controls
Frequent hPL
sampling between 6
and 38 weeks in
T1DM subjects
T1DM status
T1DM insulin
requirements
hPL levels in T1DM subjects not sig different
from those of controls across preg, including
when T1DM sub-grouped according to study
site and/or glycaemic control.
Insulin requirement increase across pregnancy
in T1DM not consistently related to hPL.
hPL NS different between T1DM and controls
across gestation, and not related to increase in
insulin requirements across gestation in T1DM.
Authors state that hormonal response of T1DM
women to pregnancy is not different to that of
normal controls to any marked extent, and other
factors likely explain their increasing insulin
requirements and tendency to macrosomia.
Low
Abbreviations: hPL = human placental lactogen, NR = not reported, NS = not significant, sig = significant, SEM = standard error of the mean, MoM = multiples of the median,
DR = diabetic
retinopathy, NPDR = non-proliferative diabetic retinopathy, PDR = proliferative diabetic retinopathy, FFAs = free fatty acids, T1DM = type 1 diabetes mellitus, OGTT = oral
glucose tolerance test, ULN = upper limit of normal, USA = United States of America, UK = United Kingdom. Data are presented as mean
±
SD unless otherwise specified in the table.

Int. J. Mol. Sci. 2022,23, 15621 16 of 27
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 16 of 26
(a)
(b)
Figure A2. (a): Meta-analysis of hPL levels in GDM vs. non-diabetic control women in early pregnancy (≤24 weeks)—3 studies. (b): Meta-analysis of hPL levels in
GDM vs. non-diabetic control women in late pregnancy (>24 weeks)—10 studies.
Table A2. Studies examining hPL in pregnancies affected by gestational diabetes mellitus—17 studies.
Author and
Year; Country
of Origin
Design
Participants
and Sample
Size
Methodology
and hPL
Pregnancy
Timepoints
Metabolic
Parameters
Analysed
GDM
Definition Used Results Authors’ Conclusions
Risk of
Bias
Rating
Al Busaidi et
al., 2004 [27]
Oman
Longitudinal
observational
n = 200, of
which n = 15
developed
GDM
One-off hPL
sample at 11–
13 weeks
GDM status NR
Mean 11–13 week hPL in women who developed
GDM (n = 15) NS diff to that of women with other
preg complications (eg. PIH, IUGR) and/or
control women with no complications
Early (11–13 week) hPL NS different
between GDM women and controls. Early
hPL does not appear to be a useful
biomarker for prediction of GDM risk.
High
Al-Hussein et
al., 2021 [30] †
Cross-
sectional
n = 40 GDM
(20 male
One-off hPL
sample, exact GDM status NR hPL highest in GDM women pregnant with
female fetus, then control with female fetus, then
hPL highest in GDM women carrying
female infants (note groups not matched High
Figure A2.
(
a
): Meta-analysis of hPL levels in GDM vs. non-diabetic control women in early pregnancy (
≤
24 weeks)—3 studies. (
b
): Meta-analysis of hPL levels in
GDM vs. non-diabetic control women in late pregnancy (>24 weeks)—10 studies.

Int. J. Mol. Sci. 2022,23, 15621 17 of 27
Table A2. Studies examining hPL in pregnancies affected by gestational diabetes mellitus—17 studies.
Author and
Year; Country of
Origin
Design Participants and
Sample Size
Methodology
and hPL
Pregnancy
Timepoints
Metabolic
Parameters
Analysed
GDM
Definition Used Results Authors’ Conclusions Risk of Bias
Rating
Al Busaidi et al.,
2004 [27]
Oman
Longitudinal
observational
n= 200, of
which n= 15
developed GDM
One-off hPL
sample at
11–13 weeks
GDM status NR
Mean 11–13 week hPL in women who developed
GDM (n= 15) NS diff to that of women with
other preg complications (eg. PIH, IUGR) and/or
control women with no complications
Early (11–13 week) hPL NS different between
GDM women and controls. Early hPL does not
appear to be a useful biomarker for prediction
of GDM risk.
High
Al-Hussein
et al., 2021 [30] †
Iraq
Cross-sectional
n= 40 GDM
(20 male fetus,
20 female)
n= 40 controls
(20 male fetus,
20 female)
One-off hPL
sample, exact
timepoint NR
(presume
>24–28 weeks
after OGTT)
GDM status
Fasting glucose
HOMA-IR
NR
hPL highest in GDM women pregnant with
female fetus, then control with female fetus, then
GDM with male fetus, then control with male
fetus (all sig).
hPL levels NS related to fasting glucose in all
4 groups.
hPL levels inversely related to HOMA-IR in all
4 groups, but sig only in non-GDM women with
female fetus (r = −0.790, p= 0.001).
hPL highest in GDM women carrying female
infants (note groups not matched for BMI or
other key baseline characteristics).
No clear overall relationships between hPL
and fasting glucose. Suggestion of inverse
relationship between hPL and IR but sig only
in one subgroup.
High
Catalano et al.,
1993 [37]
USA
Cross-sectional
n= 38 women
with abnormal
screening GCT
OGTT
performed twice,
1 week apart, at
27–30 weeks;
hPL sampled
alongside
GDM status
NDDG, but
deemed
abnormal if only
one value
exceeded
thresholds
Study focused on how gestational hormones may
influence OGTT reproducibility. hPL NS diff at
either first or second OGTT in either women with
‘definite’ non-GDM (2 normal results), ‘definite’
GDM (2 abnormal results) or those with
discordant results (one normal and one
abnormal result).
hPL does not appear to be a hormonal factor
influencing OGTT reproducibility. Low
Catalano et al.,
2002 [26]
USA
Longitudinal
observational
n= 5 obese
GDM
n= 4 obese
controls
hPL sampled at:
12–14 weeks
34–36 weeks
GDM status Carpenter-
Coustan
hPL NS diff between GDM women and controls:
in both early preg (mean ±SEM of GDM vs.
controls 0.85 ±0.36 vs. 0.89 ±0.33 µg/mL) and
late preg (GDM vs. controls 7.1 ±1.13 vs.
8.00 ±1.19 µg/mL), p= 0.3 for both.
hPL NS diff between GDM women and control
women in either early or late preg. High
De Hertogh
et al., 1976 [16]
Belgium
Longitudinal
observational
n= 19 GDM
n= 22 controls
hPL sampled at:
5–8 weeks
9–12 weeks
13–16 weeks
17–20 weeks
21–24 weeks
25–28 weeks
29–32 weeks
33–36 weeks
37–40 weeks
GDM status
100 g OGTT. 0,
30, 60, 120, 180
min; thresholds
5.0/8.9/8.3/6.7/
5.5 mmol/L. ≥2
high for dx
Mean hPL sig lower in GDM than control group
at 17–20 weeks only.
At all other timepoints, hPL NS diff between
GDM and controls.
hPL not consistently sig diff between GDM
and control women in serial preg sampling. High
Grigorakis et al.,
2000 [31]
Greece
Cross-sectional n= 15 GDM
n= 26 controls
One-off hPL
sample at
28–32 weeks at
time of OGTT
GDM status ADA Mean hPL NS diff between GDM and controls
(GDM 4.9 ±1.3 vs. controls 4.3 ±1.4 µg/mL).
hPL NS diff between GDM and controls in late
preg. Any contribution of hPL to GDM
pathophysiology ‘likely to be weak’.
Moderate

Int. J. Mol. Sci. 2022,23, 15621 18 of 27
Table A2. Cont.
Author and
Year; Country of
Origin
Design Participants and
Sample Size
Methodology
and hPL
Pregnancy
Timepoints
Metabolic
Parameters
Analysed
GDM
Definition Used Results Authors’ Conclusions Risk of Bias
Rating
Henderson et al.,
1998 [34]
USA
Cross-sectional
n= 257 women,
of whom n= 57
had abnormal
screening GCT;
and n= 25 then
had abnormal
OGTT
(i.e., GDM)
One-off hPL
sample at time
of GCT (exact
timepoint NR
but presume
early
3rd trimester)
GDM status Carpenter-
Coustan
Of women who had an abnormal GCT, hPL sig
higher in women who proceeded to abnormal
OGTT than in those who had a subsequent
normal OGTT; 5.85 ±2.55 µg/mL vs. 3.38 ±1.40,
p= 0.034. NS diff in hPL between women with
normal GCT (4.68 ±1.64 µg/mL), and those who
had abnormal GCT but ultimately went on to
have normal OGTT.
n= 11 women had normal GCT but subsequently
delivered an infant > 4 kg, in them mean hPL at
time of GCT had been similar to the GDM group
(5.83 ±1.29 µg/mL).
hPL in appeared a helpful adjunct to GCT, and
seemed to help with predicting those who
would go on to have positive OGTT.
hPL in normoglycaemic women who
proceeded to deliver macrosomic infants had
retrospectively been similar to that of GDM
women–potential for hPL as a risk predictor for
macrosomia, or of GDM ‘missed’ by OGTT?
Moderate
Kirwan et al.,
2002 [39]
USA
Longitudinal
observational
n= 5 obese
GDM
n= 5 lean
controls
n= 5 obese
controls
hPL sampled at:
pre-conception
10–12 weeks
34–36 weeks
Insulin
sensitivity
Carpenter-
Coustan
Insulin sensitivity measured via clamp in early
and late preg. Late preg insulin sensitivity found
to be NS related to hPL levels (r = −0.24, p= 0.39).
hPL levels in late preg did not appear to be sig
related to the degree of preg-induced insulin
resistance in GDM or non-GDM women (main
sig findings of the trial related to TNF-α,
which did emerge as sig related to
insulin resistance).
Moderate
Kuhl et al., 1975
[36]
Denmark
Cross-sectional n= 11 GDM
n= 9 controls
One-off hPL
sample at 34–35
weeks at time of
OGTT
GDM status
OGTT glucose
At least 2 values
on OGTT that
were >3 SD
above mean of
authors’
previous normal
preg population
Mean fasting hPL NS diff in GDM vs. controls
(6.2 ±2.3 vs. 6.7 ±1.3 µg/mL).
Mean hPL at 3 h of OGTT NS diff in GDM vs.
controls (6.1 ±2.6 vs. 6.2 ±1.1 µg/mL).
No sig alteration in hPL over course of OGTT in
either group.
No difference in shape of hPL curves alongside
OGTT in GDM vs. controls.
hPL NS diff between GDM and controls.
Previous literature suggestive of high late preg
hPL values in T1DM patients may not apply to
mild GDM.
hPL does not appear to be sig altered by minor
physiological fluctuations in plasma glucose,
such as with OGTT.
Moderate
Lopez-Espinoza
et al., 1986 [18]
Scotland
Longitudinal
observational
n= 8 early GDM
on insulin
n= 14 controls
For GDM, hPL
sampled
fortnightly
12–32 wk, then
weekly until
delivery.
For controls,
hPL sampled
monthly
GDM status
Plasma glucose
Insulin
requirements
WHO 1980
Mean hPL higher in GDM than controls in 2nd
trimester (mean ±SEM 2.3 ±0.4 vs. 1.3 ±0.1
µg/mL, p< 0.05). In early and late third
trimester, hPL also showed a trend to being
higher in GDM than controls (early 3rd trimester
6.3 ±0.7 vs. 5.4 ±0.5; late 7.7 ±0.9 vs. 6.5 ±0.6)
but did not achieve sig.
hPL not related to plasma glucose or insulin
requirements in GDM.
Suggestion of higher hPL levels in GDM than
controls across gestation in this study, although
sig only in second trimester.
No apparent relationship between hPL and
either plasma glucose or insulin requirements
in GDM.
Moderate
Luthman et al.,
1994 [38]
Sweden
Cross-sectional n= 12 GDM
n= 12 controls
hPL sampling
across standard
breakfast (0 to
120 min), at
29–38 weeks
GDM status
Plasma glucose WHO 1980
hPL NS diff between GDM and control women at
all timepoints.
hPL levels NS altered by glucose excursions after
standard meal (in either group).
hPL unaltered by meal ingestion, and no
different between GDM and control women, in
third trimester.
Moderate

Int. J. Mol. Sci. 2022,23, 15621 19 of 27
Table A2. Cont.
Author and
Year; Country of
Origin
Design Participants and
Sample Size
Methodology
and hPL
Pregnancy
Timepoints
Metabolic
Parameters
Analysed
GDM
Definition Used Results Authors’ Conclusions Risk of Bias
Rating
Ngala et al.,
2017 [29] †
Ghana
Longitudinal
observational
n= 200 preg
women in 1st
trimester:
n= 50 ‘low risk’
for diabetes and
n= 150
‘standard risk’.
n= 12 later
developed GDM
One-off hPL
sample at
24–28 weeks
GDM status
GDM risk
Fasting glucose,
insulin, IR, BMI,
total
cholesterol, Tg
ADA
When n= 12 GDM compared to all n= 138
non-GDM, NS diff between hPL levels at
24–28 weeks (p= 0.155).
When n= 12 GDM compared to subgroup of
n= 50 women deemed ‘low risk of diabetes’, hPL
sig lower in the GDM women (p< 0.0001).
In multiple logistic regression, hPL at
24–28 weeks did not emerge as a sig predictor of
GDM risk.
All metabolic parameters NS related to
24–28 week hPL in either GDM or
non-GDM women.
hPL NS different between GDM and non-GDM
women at 24–28 weeks, and did not emerge as
a sig predictor of GDM risk.
hPL at 24–28 weeks not linked to other
metabolic parameters including BMI, lipids,
fasting glucose or insulin.
High
Persson et al.,
1975 [22]
Sweden
Cross-sectional n= 8 GDM
n= 5 controls
Five
measurements
of hPL over one
8 h period at
34–37 weeks
GDM status
Blood glucose
FFAs, glycerol
Ketones
Insulin
IVGTT in third
trimester in
at-risk women,
own criteria
Mean hPL over the 8 h sampling period was NS
diff between GDM vs. control women.
hPL changes over the sampling period bore no
apparent relationship to changes in glucose, FFAs,
ketones, or insulin over the sampling period.
hPL in over 8 h in third trimester NS diff
between GDM and controls.
hPL not clearly related to insulin or glucose
dynamics over an 8 h period in GDM
or controls.
High
Rasanen et al.,
2013 [28]
Finland
Case-control n= 90 GDM
n= 92 controls
GDM cases and
controls
identified in late
preg. hPL at
5–13 weeks then
compared
between cases
and controls
GDM status
GDM risk
ADA, but
deemed
abnormal if only
one value
exceeded
thresholds
Median hPL in first trimester sig higher in
women who would go on to get GDM than in
controls (GDM vs. controls 0.34 vs. 0.22 µg/mL,
p< 0.001).
AUC on ROC curve for GDM prediction with
threshold 0.80 ng/mL: sensitivity 28%, specificity
90%, AUC 0.63 (0.55–0.71, p< 0.001), i.e., only
very marginal classification benefit.
First trimester hPL was sig diff between
women who would go on to get GDM and
those who would not (i.e., sig association with
GDM risk, higher hPL in GDM than controls).
However, degree of separation between
distributions of hPL in cases and controls was
not adequate for use as screening test (low
AUC; poor classification performance).
Low
Retnakaran
et al., 2016 [32]
Canada
Cross-sectional n= 105 GDM
n= 290 controls
One-off hPL
sample at
29–30 weeks, at
time of OGTT
GDM status
AUC glucose,
Matsuda index,
HOMA-IR,
fasting insulin,
ISSI-2, and
IGI/HOMA-IR
NDDG
Median hPL NS diff between GDM women and
controls (2.0 vs. 1.9µg/mL, p= 0.1).
No variable showed a sig association with hPL in
either GDM or control women, before or after
adjustment for key covariates.
hPL NS diff between GDM and non-GDM
women at time of OGTT. hPL NS associated
with AUC glucose in either GDM or non-GDM
women. hPL NS associated with other markers
of insulin sensitivity or beta cell function in
either GDM or non-GDM women. Data
suggests that circulating hPL concentrations
may not provide direct insights on maternal
glucose homeostasis.
Moderate

Int. J. Mol. Sci. 2022,23, 15621 20 of 27
Table A2. Cont.
Author and
Year; Country of
Origin
Design Participants and
Sample Size
Methodology
and hPL
Pregnancy
Timepoints
Metabolic
Parameters
Analysed
GDM
Definition Used Results Authors’ Conclusions Risk of Bias
Rating
Samaan et al.,
1985 [35]
USA
Cross-sectional n= 14 GDM
n= 17 controls
One-off hPL
sample at
delivery
GDM status NR
Mean hPL at time of delivery sig higher in GDM
than controls (8.85 ±1.4 vs. 6.8 ±2.1 µg/mL,
p< 0.001).
hPL at time of delivery sig higher in
diet-controlled GDM women than in controls. High
Surmaczynska
et al., 1974 [33]
USA
Cross-sectional n= 13 GDM
n= 33 controls
One off hPL
sample at 30–40
weeks, at time of
OGTT
GDM status
OGTT
O’Sullivan and
Mahan
Mean baseline hPL NS diff between GDM and
controls (mean ±SEM 8.8 ±0.64 vs.
8.4 ±0.45 µg/mL).
Very marginal hPL decrement with 100 g OGTT
seen in overall cohort; magnitude NS diff
between GDM and controls.
hPL at 30–40 weeks NS diff between GDM and
non-GDM women.
hPL dipped slightly with OGTT in cohort
overall, magnitude no diff between GDM and
non-GDM women.
Moderate
Abbreviations: hPL = human placental lactogen, NS = non-significant, sig = significant, NR = not reported, GDM = gestational diabetes mellitus, SEM = standard error of the mean,
IUGR = intra-uterine growth restriction, PIH = pregnancy-induced hypertension, NDDG = National Diabetes Data Group, NGT = normal glucose tolerance, ADA = American Diabetes
Association, GCT = glucose challenge test, OGTT = oral glucose tolerance test, IVGTT = intravenous glucose tolerance test, WHO = World Health Organisation, T1DM = type 1 diabetes
mellitus, BMI = body mass index, IR = insulin resistance, Tg = triglycerides, AUC = area under the curve, ROC = receiver operating characteristic, HOMA-IR = Homeostatic Model
Assessment for Insulin Resistance, ISSI = insulin-secretion sensitivity index, IGI = insulinogenic index, TNF
α
= tumor necrosis factor-alpha, USA = United States of America. Data are
presented as mean
±
SD unless otherwise specified in the table.
†=
The 2017 study by Ngala et al. [
29
] met inclusion criteria for the review, but serious methodological concerns were
raised about this paper during the review process. In particular, the authors’ tabulated hPL values for 24–28 weeks (in
µ
g/mL) are approximately ten times greater than the expected
physiological ranges at this gestation; and it is suspected that an error has occurred with assay methodology or unit conversion. The authors were contacted for comment, but no reply
had been received at the time of manuscript submission. Results of this study need to be interpreted with extreme caution, and the study was omitted from meta-analysis on this basis.
Significant methodological concerns were also raised about the 2021 paper by Al-Hussein et al. [
30
], in which hPL values were presented without any units and with no indication of
gestational age at time of sampling. Again, authors did not reply to an invitation to clarify and the study was excluded from meta-analysis.
Table A3. Studies examining hPL in relation to glycaemic or insulin-related parameters in pregnancy/postpartum—5 studies.
Author and Year;
Country of Origin Design Participants and
Sample Size
Methodology and
hPL Pregnancy
timepoints
Metabolic
Parameters
Analysed
Results Authors’ Conclusions Risk of Bias Rating
Benny et al., 1980
[40]
UK
Cross-sectional
n= 21 women with
normal OGTT in
preg, none obese
(n= 10 Hindi
vegetarians, n= 11
Caucasian
omnivores)
Eleven serial
measures of hPL
over one 24 h
period at
36–39 weeks
Insulin
Glucose
Insulin and glucose sampled serially across 24 h
period, as was hPL. hPL peak (at 0500h after
overnight fast) coincided with nadir of insulin
and glucose.
No direct correlation of individuals’ hPL levels
with insulin or glucose. However, Hindi women
were found to have sig higher mean glucose
than Caucasian women. This was unlikely to be
mediated by hPL because hPL was sig lower in
Hindi than Caucasian women (5.79 ±0.05 vs.
6.11 ±0.05 µg/mL; p< 0.01). Lower hPL in the
Hindi women likely related to sig lower
placental masses.
hPL appeared to peak after overnight fast in
pregnancy, temporally coinciding with time of
lowest glucose and insulin.
Hindi women had higher mean glucose levels in
third trimester than Caucasians, but lower hPL
levels (maybe related to smaller placentas)–so
hPL unlikely to be driving
glycaemic differences.
Moderate

Int. J. Mol. Sci. 2022,23, 15621 21 of 27
Table A3. Cont.
Author and Year;
Country of Origin Design Participants and
Sample Size
Methodology and
hPL Pregnancy
timepoints
Metabolic
Parameters
Analysed
Results Authors’ Conclusions Risk of Bias Rating
Enzi et al., 1980 [41]
Italy
Longitudinal
observational
n= 50 healthy preg
women
One-off hPL sample
at 34–35 weeks
AUC glucose
AUC insulin
hPL at 34/40 positively related to maternal
AUC glucose at 34/40, r = 0.62, p< 0.001.
hPL at 34/40 positively related to maternal
AUC insulin at 34/40, r = 0.31, p< 0.05
hPL at 34 weeks positively related to maternal
AUC insulin and AUC glucose, suggesting
diabetogenic effects.
Low
Fairweather et al.,
1971 [42]
UK
Longitudinal
observational
n= 33 healthy preg
women
hPL sampling:
6–12 weeks
13–19 weeks
20–25 weeks
26–30 weeks
31–32 weeks
33–34 weeks
35–36 weeks
37–38 weeks
39–40 weeks
41–42 weeks
Glucose
NEFAs
NS direct relationship between glucose and hPL
levels at a given time in a given patient.
Positive relationship between hPL and NEFA
levels, r = 0.24, p< 0.01; i.e., higher hPL levels at
at a given time in a given patient tended to be
assoc with higher NEFA levels.
hPL showed NS relationship to glucose levels
within a patient at any given time, but higher
hPL levels tended to be associated with higher
levels of NEFAs.
hPL appears to have anti-insulin, diabetogenic
effects that promote mobilisation of FFAs and
reduce maternal glucose utilisation, sparing
glucose to meet fetal demands.
Moderate
Retnakaran et al.,
2016 [44]
Canada
Longitudinal
observational
n= 301 NGT
n= 60 pre-diabetes
n= 6 DM
(based on OGTT at
3 months
postpartum)
hPL sampled at
time of OGTT in
late second
trimester of preg,
but then analysed in
relation to
postpartum
metabolic status
Maternal diabetes
category at 3 mo
postpartum
Glycaemic markers
at 3 mo postpartum
Risk of pre-DM or
DM at 3 mo
postpartum
hPL in late preg had been no diff between who
went on to be NGT at 3 mo postpartum, those
with pre-diabetes at 3 mo postpartum, and
those with DM at 3 mo postpartum (median
hPL in µg/mL = NGT 2.0 vs. pre-DM 2.0 vs.
DM 1.5, p= 0.312).
On multivariate regression, hPL in late preg not
independently related to any glycaemic markers
(log Matsuda index, log HOMA-IR, log ISSI-2,
log IGI/HOMA-IR, fasting glucose, AUC
glucose) at 3 mo post partum.
On multivariate regression, hPL in late preg not
an independent predictor of the risk of
persistent dysglycaemia at 3 mo postpartum.
hPL in late preg had been no diff between those
with normal glucose tolerance at 3 mo
postpartum and those with postpartum pre-DM
or DM.
hPL in late preg was not an independent
determinant of insulin resistance or beta-cell
function at 3 mo postpartum.
hPL in late preg was not an independent
predictor of the risk of pre-DM or DM at
3 mo postpartum.
Moderate
Scott et al., 1992 [43]
UK Cross-sectional
n= 127 healthy preg
women
(n= 97 European,
n= 30 Asian)
One-off hPL sample
at 29 weeks, at time
of OGTT
2 h insulin on OGTT
2 h glucose on
OGTT
No relationship to hPL in either ethnic group.
No relationship to hPL in either ethnic group.
hPL not related to either 2 h OGTT insulin or 2 h
OGTT glucose in either race in this study. hPL
does not clearly play a role in modifying
insulin action.
Low
Abbreviations: hPL = human placental lactogen, NS = non-significant, sig = significant, AUC = area under the curve, NEFAs = non-esterified fatty acids, FFAs = free fatty acids,
NGT = normal
glucose tolerance, OGTT = oral glucose tolerance test, DM = diabetes mellitus, HOMA-IR = Homeostatic Model Assessment for Insulin Resistance, ISSI = insulin-secretion
sensitivity index, IGI = insulinogenic index, UK = United Kingdom. Data are presented as mean ±SD unless otherwise specified in the table.

Int. J. Mol. Sci. 2022,23, 15621 22 of 27
Table A4. Studies examining hPL in relation to body mass index and/or gestational weight gain in pregnancy—4 studies.
Author and Year;
Country of Origin Design Participants and
Sample Size Methodology
Metabolic
Parameters
Analysed
Results Authors’ Conclusions Risk of Bias Rating
Al-Hussein et al.,
2021 [30] †
Iraq
Cross-sectional
n= 40 GDM
(20 male fetus,
20 female)
n= 40 controls
(20 male fetus,
20 female)
One-off hPL
sampling,
presumably >
24–28 weeks after
OGTT
Maternal BMI Maternal BMI NS rel to maternal hPL level in
any group.
No sig relationship between maternal BMI and
hPL demonstrated in any study subgroup. High
Enzi et al., 1980 [41]
Italy
Longitudinal
observational
n= 50 healthy
preg women
One-off hPL sample
at 34–35 weeks Maternal GWG
Maternal hPL at 34 weeks NS diff between
mothers in excessive GWG group (gained
>20% IBW, mean 16.5 ±1.4 kg, n= 23) and those
in normal GWG group (gained <20% IBW, mean
8.7 ±0.5 kg, n= 27).
Excessive GWG mean hPL 7.7 ±1.5 µg/mL vs.
normal GWG 6.3 ±1.1 µg/mL.
hPL at 34 weeks NS diff between mothers who
had normal GWG and those with
excessive GWG.
Low
Lin et al., 1976 [45]
USA Cross-sectional n= 187 healthy
preg women
One-off hPL sample
near term (within
one week
of delivery)
Maternal weight Maternal weight sig inversely related to
maternal hPL at term (r = −0.28, p<0.01).
Maternal weight at term sig inversely related to
hPL concentration at term. Authors suggest this
might be dilutional effect (?more tissue space in
larger women).
Low
McCarrick et al.,
1979 [46]
USA
Longitudinal
observational
n= 290 preg women
with preg risk
factors (eg prev or
current GDM, PET,
previous losses,
IUGR)
Serial hPL sampling
across third
trimester
33–40 weeks
(approx.
4–5 per woman)
Weight category
Obese women (>72.6 kg at 16 weeks) were
over-represented in “group 3” of the study, n=
44, all of whom had normal estrogen but low
hPL (50% women in that group obese vs. 25%
obese in other groups, p< 0.001).
These women were at an increased risk of preg
complications such as fetal death or SGA (34.1%
had complications) compared to those with
normal hPL and estrogen (group 1, of whom
4.7% had complications) although not as high as
those with both low hPL and low estrogen
(group 2, of whom 71.4% had complications.)
Obese women sig proportionally
over-represented in the group of women with
low hPL but normal estrogen in the study.
Authors conclusion was that obesity may
impact on hPL regulation and activity.
Note that direct impact of the complications
themselves on hPL levels was not considered.
High
Abbreviations: hPL = human placental lactogen, GDM = gestational diabetes mellitus, sig = significant, NS = non-significant, IBW = ideal body weight, BMI = body mass index,
GWG = gestational
weight gain, PET = pre-eclampsia toxaemia, NS = non-significant, sig = significant, SGA = small for gestational age, IUGR = intra-uterine growth restriction,
USA = United States of America. Data are presented as mean ±SD unless otherwise specified in the table. † = Note methodological concerns, see Table A2 footnote.

Int. J. Mol. Sci. 2022,23, 15621 23 of 27
Table A5.
Studies examining hPL in relation to fetal, neonatal or placental outcomes in pregnancies affected by maternal pre-gestational/gestational diabetes—7 studies.
Author and Year;
Country of Origin Design Participants and
Sample Size Methodology Fetal or Placental
Outcomes Results Authors’ Conclusions Risk of Bias Rating
Botta et al., 1984
[14]
Italy
Longitudinal
observational
n= 15 T1DM
n= 10 controls
Serial hPL sampling
across preg
Placental weight
Birthweight
Placental weight positively correlated to week
36 hPL (r = 0.368) across whole cohort, although
not sig (p-value NR).
Birthweight positively correlated to week
36 hPL (r = 0.319) across whole cohort, although
NS (p-value NR).
Late pregnancy hPL positively related to both
placental mass and birthweight across
combined cohort, although short of sig.
Moderate
Lopez-Espinoza
et al., 1986 [18]
Scotland
Longitudinal
observational
n= 15 T1DM
n= 8 GDM
n= 14 controls
Serial hPL sampling
across preg Placental weight
Positively related to pre-delivery (>37 week)
hPL in T1DM (r = 0.8, p< 0.01).
Positively related to third trimester (<37 week)
hPL in GDM (r = 0.6, p< 0.05).
Positively related to pre-delivery (>37 week)
hPL in controls (r = 0.6, p< 0.05).
Late preg hPL levels strongly positively
correlated with placental weight in control,
T1DM and GDM women.
Moderate
Luthman et al., 1994
[38]
Sweden
Cross-sectional n= 12 GDM
n= 12 controls
One-off hPL sample
at 29–38 weeks Birthweight
Positively correlated to third trimester hPL in
GDM cohort (r = 0.59, p< 0.05). No such
relationship found in controls or in overall
cohort.
Late pregnancy hPL positively correlated with
birthweight in the GDM cohort. Moderate
Pedersen et al., 1986
[48]
Denmark
Cross-sectional n= 26 T1DM One-off hPL sample
at 7–16 weeks Early fetal growth
√hPL in early pregnancy related to menstrual
age corrected by 90% of the growth delay
(growth delay = diff in days between menstrual
age and USS CRL age).
√hPL (mg/l) = −0.541 + 0.0142 menstrual age
(days) −0.0128 delay (days).
Authors had previously noted that size of
T1DM pregnancies (by CRL on USS) may lag by
several days behind the age calculated from
LMP. Here, hPL could be best mathematically
related to menstrual age when it was corrected
by this delay. Given hPL reflects functional
placental mass, this suggests that the observed
growth delay in early T1DM pregnancies is
accompanied by a delay in
placental development.
High
Samaan et al., 1985
[35]
USA
Cross-sectional n= 14 GDM
n= 17 controls
One-off hPL sample
at time of delivery Birthweight
Across whole cohort (GDM women, controls;
and a third group of women with preterm birth,
n= 15); NS correlation between maternal hPL
and neonatal weight. Not described for GDM
cohort individually.
NS relationship between hPL at time of delivery
and birthweight across combined cohort of
GDM, preterm birth and control women.
High
Small et al., 1987
[47]
Scotland
Longitudinal
observational
n= 20 T1DM with
macrosomia
(birthweight >90%
for gestation)
n= 20 matched
T1DM without
macrosomia
One-off hPL sample
at 34 weeks Birthweight class
T1DM group with macrosomia (mean
birthweight 3.96 kg at 37 weeks) had sig higher
hPL at 34 weeks than matched T1DM preg
without macrosomia (mean birthweight 3.05 kg
at 37 weeks).
Macrosomia group mean hPL =
8.3 ±2.3 µg/mL vs. non-macrosomia group
mean hPL = 6.5 ±2.3 µg/mL; p< 0.005.
hPL at 34 weeks was sig higher in n= 20 T1DM
women who gave birth to macrosomic infants
than in n= 20 T1DM who gave birth to normal
weight infants. Authors suggested that hPL may
help with detection of macrosomia early in the
third trimester.
Low

Int. J. Mol. Sci. 2022,23, 15621 24 of 27
Table A5. Cont.
Author and Year;
Country of Origin Design Participants and
Sample Size Methodology Fetal or Placental
Outcomes Results Authors’ Conclusions Risk of Bias Rating
Stewart et al., 1989
[20]
UK
Longitudinal
observational
n= 40 T1DM
n= 69 controls
Serial hPL sampling
across preg
Placental weight
Birthweight
hPL at 32 or 36 weeks NS related to placental
weight in T1DM group as a whole, using sig
value of p< 0.01.
hPL at 32 or 36 weeks NS related to birthweight
in T1DM group as a whole, using sig value of
p< 0.01. However, was a positive correlation
between birthweight and 32 week hPL if
p< 0.02 accepted (r = 0.48, p< 0.02).
Both birth and placental weight corrected for
maternal parity, maternal stature, infant sex and
length of gestation.
NS relationship seen between hPL and placental
mass, or hPL and birthweight, in T1DM in this
cohort (using stringent sig threshold of p< 0.01).
Did see a positive relationship between hPL and
birthweight in T1DM group when sig level of
p< 0.02 accepted.
Low
Abbreviations: hPL = human placental lactogen, GDM = gestational diabetes mellitus, sig = significant, NS = non-significant, NR = not reported, GA = gestational age, T1DM = type 1
diabetes mellitus, USS = ultrasound scan, CRL = crown-rump length, LMP = last menstrual period, USA = United States of America, UK = United Kingdom. Data are presented as mean
±SD unless otherwise specified in the table.

Int. J. Mol. Sci. 2022,23, 15621 25 of 27
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