RCP Endocrinology Update
Endocrine Testing – yes or no?
Pregnancy
Dr Maralyn Druce
12-12:30
Pregnancy and Endocrine Testing
Urine Home Pregnancy Test
• Usually positive 13-14 days after fertilization
= approx date that period missed / due
• 25% positive 2 days before missed period
• 40% positive 1 day before missed period
Blood Pregnancy Test
• Usually positive 9-10 days after fertilization
*****
Ultrasound
• Definitive
• Earliest is transvaginal at >5 weeks
False negative results:
• Test performed too early in
the pregnancy
• Certain drugs such as
diuretics, promethazine,
and tranquilizers
False positive results:
• Samples that have protein,
blood, or excess pituitary
gonadotropin
• Certain types of antibodies
with fragments of the hCG
molecule.
Levels lower than expected:
• Miscalculation of dating
• Miscarriage / blighted
ovum
• Ectopic pregnancy
Levels higher than expected:
• Miscalculation of dating
• Molar pregnancy
• Multiple pregnancy
False negative results:
• Test performed too early in
the pregnancy
• Certain drugs such as
diuretics, promethazine,
and tranquilizers
48-72h
False positive results:
• Samples that have protein,
blood, or excess pituitary
gonadotropin
• Certain types of antibodies
with fragments of the hCG
molecule.
Levels lower than expected:
• Miscalculation of dating
• Miscarriage / blighted
ovum
• Ectopic pregnancy
Levels higher than expected:
• Miscalculation of dating
• Molar pregnancy
• Multiple pregnancy
False negative results:
• Test performed too early in
the pregnancy
• Certain drugs such as
diuretics, promethazine,
and tranquilizers
72-96h
False positive results:
• Samples that have protein,
blood, or excess pituitary
gonadotropin
• Certain types of antibodies
with fragments of the hCG
molecule.
Levels lower than expected:
• Miscalculation of dating
• Miscarriage / blighted
ovum
• Ectopic pregnancy
Levels higher than expected:
• Miscalculation of dating
• Molar pregnancy
• Multiple pregnancy
False negative results:
• Test performed too early in
the pregnancy
• Certain drugs such as
diuretics, promethazine,
and tranquilizers
False positive results:
• Samples that have protein,
blood, or excess pituitary
gonadotropin
• Certain types of antibodies
with fragments of the hCG
molecule.
>4days
Levels lower than expected:
• Miscalculation of dating
• Miscarriage / blighted
ovum
• Ectopic pregnancy
Levels higher than expected:
• Miscalculation of dating
• Molar pregnancy
• Multiple pregnancy
Pregnancy and Endocrine Testing
what is this *really* about?
Pregnancy and Endocrine Testing
Endocrine
Disease
caused or
affected by
pregnancy
Endocrine
Testing
impacted by
pregnancy
Endocrine
disease affects
offspring
Pregnancy and Endocrine Testing
Endocrine
Disease
caused or
affected by
pregnancy
Endocrine
Testing
impacted by
pregnancy
• Diabetes Mellitus
• Thyroid
Dysfunction
• Diabetes
Insipidus and
Pituitary
dysfunction
Endocrine
disease affects
offspring
Pregnancy and Endocrine Testing
Endocrine
Disease
caused or
affected by
pregnancy
Endocrine
Testing
impacted by
pregnancy
• Diabetes Mellitus
• Thyroid
Dysfunction
• Diabetes
Insipidus and
Pituitary
dysfunction
Endocrine
disease affects
offspring
Maternal Endocrine Adaptations
Glucose Management
• Hyperplasia and hypertrophy of the beta cells in the islets of
Langerhans probably as the result of stimulation by oestrogen and
progesterone
• During early pregnancy, the glucose requirements of the fetus lead to
enhanced transport across the placenta by facilitated diffusion and
maternal fasting hypoglycaemia may be present
• Basal insulin secretion is normal, however there is hypersecretion of
insulin in response to a meal.
• As pregnancy progresses, the levels of hPL rise, as do the levels of
glucocorticoids, as well as (sometimes) BMI, leading to the insulin
resistance seen in the last half of pregnancy
700,000 women
in the UK give
birth every year
5% of these have
diabetes mellitus
87.5% have
gestational
diabetes mellitus
7.5% Type 1 DM
5% Type 2 DM
Significance
• Original GDM criteria were developed to identify risk
of diabetes after pregnancy
• Hyperglycaemia due to diabetes mellitus impacts on
pregnancy risk and fetal outcomes
• Risks include: miscarriage, pre-eclampsia and preterm
labour
• Stillbirth, congenital malformations, macrosomia, birth
injury, perinatal mortality and postnatal adaptation
problems (such as hypoglycaemia) are more common
in babies born to women with pre-existing diabetes.
• During pregnancy, pre-existing diabetic retinopathy
can worsen rapidly in the mother
Hyperglycaemia, even non-diagnostic of gestational
diabetes mellitus is linked to adverse fetal outcomes
HAPO study NEJM (2008) 358: 19; 1991-2002
https://www.guidelines.co.uk/duk/diabetes-in-pregnancy
NICE guidance:
For patients with pre-existing diabetes mellitus
• Emphasise information-giving, preconception
care and planning for patients known to have
diabetes
• Aim for pre-pregnancy HbA1c <6.5% (as long
as no troublesome hypos) with insulin if
needed
• CBG before and one hour after every meal
NICE guidance:
Who to ‘screen’ for GDM?
Assess for risk factors:
• BMI above 30 kg/m2
• previous macrosomic baby weighing 4.5 kg or
above
• previous gestational diabetes
• family history of diabetes (first-degree relative
with diabetes)
• minority ethnic family origin with a high
prevalence of diabetes.
• Glucose level and HbA1c can’t be used to ‘predict
risk’
NICE recommendations:
For the patient at risk
• Diagnose gestational diabetes if the woman has either:
– a fasting plasma glucose level of 5.6 mmol/litre or above
or
– a 2-hour plasma glucose level of 7.8 mmol/litre or above
• Treat and retest to target
• Self-monitoring of glucose (point of care testing)
• Various tests during pregnancy including endocrine and
non endocrine (retinal screening, renal monitoring)
• all women diagnosed with pre-existing diabetes, or
with gestational diabetes, should test glucose levels
before breakfast and 1 hour after every meal during
pregnancy
Pregnancy and Endocrine Testing
Endocrine
Disease
caused or
affected by
pregnancy
Endocrine
Testing
impacted by
pregnancy
• Diabetes Mellitus
• Thyroid
Dysfunction
• Diabetes
Insipidus and
Pituitary
dysfunction
Endocrine
disease affects
offspring
Thyroid biochemistry in Pregnancy
• Thyroid Gland enlarges
by ~ 18% during
pregnancy ?due to HCG
• This may account for the
increase in thyroglobulin
during pregnancy
• Rising synthesis of
oestrogen induces
hepatic synthesis of TBG
• Enhanced sialyation of
TBG – reduces clearance
rate.
• Increased TBG →total T3
and T4; free T3 and T4
unaffected but change
for other reasons.
Trimester-specific reference ranges
Where possible establish a lab- and population-specific range
Where not possible use the following:
Hypothyroidism in Pregnancy
Overt hypothyroidism
• Adverse pregnancy outcomes
– Gestational hypertension more common (36% vs 25% in
SCH vs 8% in normal)
– Higher risk of caesarian section, placental abruption,
anaemia, PPH, preeclampsia
• Adverse fetal outcomes
– Miscarriage, growth restriction, prematurity, stillbirth,
neurodevelopmental delay
Subclinical hypothyroidism
• Adverse pregnancy and fetal outcomes (NEJM paper and
others) but less dramatic and intervention unproven
Hypothyroidism in pregnancy:
Questions
• Which patients with subclinical disease should be
treated, at what point and to what targets? Does
this differ in pregnancy compared to the nonpregnancy state?
• Should there be universal screening for
subclinical hypothyroidism in pregnancy? Or
targeted screening or none?
• How should the antibody-positive patient with
normal TFTs be managed in pregnancy?
Preliminary question:
Treating hypothyroidism in pregnancy
• Cochrane Review 2010 (Reid, Middleton et al)
• 3 x RCT with moderate bias involving 314 women
• Treatment of hypothyroidism uncontroversial and
standard practice even from previous non-RCT
studies
• Subclinical hypothyroid treatment showed effects
on preterm birth. Effect on neurodevelopmental
outcomes not included in data however NEJM
paper at least showed association if not effect of
intervention (but another reason to treat)
Therefore: should we be screening for
TFTs in pregnancy?
•
•
•
•
•
Cochrane review 2015
Data from >26,000 women
Compared universal screening with case-finding
Case finding may diagnose up to 80% of all cases
More women in screening group diagnosed with
dysfunction and treated
• However, no difference in outcomes (although not
all secondary outcomes included in data and still
open to debate)
Still controversial:
Testing and treating thyroid
autoantibodies in euthyroid women
• Small study showed
treatment reduced 3
fold increased
miscarriage and 2 fold
increased preterm birth
• Not replicated in other
studies
• Trials ongoing
Hyperthyroidism in pregnancy
• Differential diagnosis: ‘trimester-appropriate’ TFTs,
gestational thyrotoxicosis
• Endocrine test interpretation important
• Risks include risks to mother; miscarriage, IUGR and
stillbirth; and effects of antibodies on fetal thyroid
• Once diagnosed treat conventionally but….
Issues:
• Safety of antithyroid drugs
• Cannot use RAI in pregnancy and surgery only in
trimester 2
A word on treatment:
Antithyroid drugs
• Conflicting evidence
• JCEM 2012 Yoshihara et al – methimazole assoc
with congenital malformations eg aplasia cutis,
omphalocoele
• JCEM 2013 Andersen et al – both antithyroid
drugs associated with fetal anomalies but the
spectrum may differ: Danish registry study
• EJE review 2014 meta-analysis implied use of
either agent in the first trimester led to 2-3%
birth defects; best outcomes if stopped by 6/40
Andersen JCEM 2013
Caveat:
Thyroid status not
accounted for
Pregnancy and Endocrine Testing
Endocrine
Disease
caused or
affected by
pregnancy
Endocrine
Testing
impacted by
pregnancy
• Diabetes Mellitus
• Thyroid
Dysfunction
• Diabetes
Insipidus and
Pituitary
dysfunction
Endocrine
disease affects
offspring
Diabetes Insipidus
DI: Endocrine testing in pregnancy?
• 24 hour urine volume
• Serum sodium, osmolalities (pregancyrelevant ranges)
• Exclude other causes
• May require clinical diagnosis rather than
biochemical
• Water deprivation test avoided in pregnancy
(safety)
Suspected hypopituitarism
Increased risk in pregnancy of:
• Apoplexy / Sheehan’s syndrome
• Lymphocytic hypophysitis
NB primary adrenal failure in pregnancy – rare
and symptoms often mimic pregnancy
symptoms
Caveats regarding endocrine testing
Basal tests are unlikely to perturb patient
• Interpretation may need trimester specific ranges
or may limit the use of some basal tests
altogether
• Specific issues of protein-bound hormones
Dynamic tests need consideration re safety AND
utility
• SST – trimester specific responses proposed
• ITT, glucagon test etc better avoided
Other ‘endocrine’ tests – functional imaging,
venous sampling, nuclear medicine all limited
Pregnancy and Endocrine Testing
Endocrine
Disease
caused or
affected by
pregnancy
Endocrine
Testing
impacted by
pregnancy
• Prolactinoma
Endocrine
disease affects
offspring
• Suspected
functioning
tumour –
pituitary and
other
Pregnancy and Endocrine Testing
Endocrine
Disease
caused or
affected by
pregnancy
Endocrine
Testing
impacted by
pregnancy
• Prolactinoma
Endocrine
disease affects
offspring
• Suspected
functioning
tumour –
pituitary and
other
Prolactinoma in pregnancy
• Appreciable prolactinomas are diagnosed before
pregnancy as they impact fertility
• Women with prolactinomas who are pregnant or
who wish to become pregnant should be guided by
endocrine input re prolactin-lowering and
treatment planning
• Pregnancy may be associated with appreciable
increase in size of prolactinoma (could impact
vision)
• Prolactin in pregnancy not a guide to size of
tumour so endocrine testing is pointless
Pregnancy and Endocrine Testing
Endocrine
Disease
caused or
affected by
pregnancy
Endocrine
Testing
impacted by
pregnancy
• Prolactinoma
Endocrine
disease affects
offspring
• Suspected
functioning
tumour –
pituitary and
other
Functioning tumours
• Cushing’s syndrome
– Issue is clinical diagnosis. Associated with infertility if
precedes pregnancy. Recognition during is confounded by
physiological changes of pregnancy
– -Cortisol excess from pituitary or adrenal tumour – the
problem of measurement of total cortisol in pregnancy
– Alternatives may include UFC or salivary cortisol although
validation less accurate
• Acromegaly – placental GH production (GH2) makes IGF1
measurements unreliable
• Phaeochromocytoma – rare but important. Mentioned
because you should think of it in antenatal hypertension.
Outcomes better if diagnosed antenatally. Urinary or
plasma metanephrines as in non-pregnant state, but
imaging options limited
Pregnancy and Endocrine Testing
Endocrine
Disease
caused or
affected by
pregnancy
Endocrine
Testing
impacted by
pregnancy
Endocrine
disease
affects
offspring
• Hyperparathyroid
Pregnancy and Endocrine Testing
Endocrine
Disease
caused or
affected by
pregnancy
Endocrine
Testing
impacted by
pregnancy
Endocrine
disease
affects
offspring
• Hyperparathyroid
Hyperparathyroidism
• Clinical presentation as per non pregnant and indeed may be
asymptomatic – testing is via calcium levels then for cause
• Maternal complications as per non pregnant
• 25% increase in pre-eclampsia
• 80% fetal complication rate – early miscarriage, IUGR,
preterm labour, fetal death, post partum calcium
dysregulation
• Rare so no value in screening but case finding important
• Placenta breaks down PTH, may be a calcium rebound after
delivery
• Avoid bisphosphonates for fetal skeleton, safety of cinacalcet
unproven
Pregnancy and Endocrine Testing
Endocrine
Disease
caused or
affected by
pregnancy
Endocrine
Testing
impacted by
pregnancy
Endocrine
disease affects
offspring
Pregnancy and Endocrine Testing
YES or NO?