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Hypoglycemia in Pregnant Women With
Type 1 Diabetes
Predictors and role of metabolic control
LENE RINGHOLM NIELSEN,
MD
1,2
ULRIK PEDERSEN-BJERGAARD,
MD, DMSC
3
BIRGER THORSTEINSSON,
MD, DMSC
3
MARIANNE JOHANSEN,
MD, DMSC
2,4
PETER DAMM,
MD, DMSC
2,4
ELISABETH R. MATHIESEN,
MD, DMSC
1,2
OBJECTIVE — In pregnancy with type 1 diabetes, we evaluated occurrence of mild and
severe hypoglycemia and analyzed the influence of strict metabolic control, nausea, vomiting,
and other potential predictors of occurrence of severe hypoglycemia.
RESEARCH DESIGN AND METHODS — A prospective observational study of 108
consecutive pregnant women with type 1 diabetes was conducted. At 8, 14, 21, 27, and 33 weeks
of gestation, patients performed self-monitored plasma glucose (SMPG) (eight/day) for 3 days
and completed a questionnaire on nausea, vomiting, hypoglycemia awareness, and history of
mild (managed by the patient) and severe (requiring assistance from others) hypoglycemia.
RESULTS — Forty-nine (45%) women experienced 178 severe hypoglycemic events, corre-
sponding to 5.3, 2.4, and 0.5 events/patient-year in the first, second, and third trimesters,
respectively. The incidence of mild hypoglycemia was 5.5 events/patient-week in early preg-
nancy and decreased throughout pregnancy (P ⬍ 0.0001), regardless of presence of severe
hypoglycemia. Prevalence of nausea and vomiting, mild hypoglycemia, and fraction of SMPG
readings ⱕ3.9 mmol/l did not differ between women with and without severe hypoglycemia.
A1C, median SMPG, and fluctuations in SMPG decreased during pregnancy, with no differences
between women with and without severe hypoglycemia. Logistic regression analysis identified
history of severe hypoglycemia the year preceding pregnancy (odds ratio 3.3 [95% CI 1.2–9.2])
and impaired awareness or unawareness (3.2 [1.2–8.2]) as independent predictors for severe
hypoglycemia.
CONCLUSIONS — In pregnancy with type 1 diabetes, the incidence of mild and severe
hypoglycemia was highest in early pregnancy, although metabolic control was tighter in the last
part of pregnancy. Predictors for severe hypoglycemia were history of severe hypoglycemia and
impaired awareness.
Diabetes Care 31:9–14, 2008
P
regnancy outcome among women
with type 1 diabetes is still signifi-
cantly poorer than in the back-
ground population (1). Optimal glycemic
control is crucial in order to reduce the
risk of congenital malformations, still-
birth, macrosomia, preeclampsia, and
preterm delivery (2–5). However, striving
for near normoglycemia increases the risk
of severe hypoglycemia (6), which is the
major limiting factor for achieving opti-
mal blood glucose control in pregnant
women with type 1 diabetes (7).
Severe hypoglycemia is three times as
frequent in early pregnancy compared
with the period before pregnancy (8), and
the incidence is highest in gestational
week 8 –16 and lower in the second part
of pregnancy (7). Traffic accidents (9) and
death (10) due to severe hypoglycemia in
pregnancy are rare but significant prob-
lems. Pregnancy-induced nausea and
vomiting have been proposed to be con-
tributing factors for severe hypoglycemia
in early pregnancy (7,8). Hypoglycemia
unawareness is a major predictor for severe
hypoglycemia in nonpregnant patients with
type 1 diabetes (11), but its significance
during pregnancy in type 1 diabetes is not
known. It is not known whether the inci-
dence of mild hypoglycemic events or the
occurrence of hypoglycemia awareness
change during pregnancy.
Clinical studies using prospective
evaluation and documentation of mild
and severe hypoglycemic events are lack-
ing in pregnant women using modern in-
sulin treatment with multiple daily
insulin injections and self-monitored
plasma glucose (SMPG) values. With the
purpose to facilitate the development of
clinical approaches that reduce the sever-
ity and frequency of severe hypoglycemia
(12) in pregnant women with type 1 dia-
betes, we thoroughly evaluated the inci-
dence of mild and severe hypoglycemia
during different parts of pregnancy. Fur-
thermore, we analyzed the influence of
strict metabolic control, nausea, vomit-
ing, and other potential predictors on the
occurrence of severe hypoglycemia.
RESEARCH DESIGN AND
METHODS — In a 2-year prospective
observational study, we consecutively in-
cluded all Danish-speaking Caucasian
women with pregestational type 1 diabe-
tes (n ⫽ 121) referred to the Center for
Pregnant Women with Diabetes, Rigshos-
pitalet, before 14 completed gestational
weeks with a single living fetus during the
study period 1 September 2004 to 31 Au-
gust 2006.
Women with psychiatric disorders,
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
From the
1
Department of Endocrinology, Copenhagen University Hospital Rigshospitalet, Copenhagen,
Denmark; the
2
Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark; the
3
Endocrinology Section, Nordsjællands Hospital–Hillerød, Hillerød, Denmark; and the
4
Department of
Obstetrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Address correspondence and reprint requests to Lene Ringholm Nielsen, MD, Department of Endocri-
nology, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. E-
mail: enel@dadlnet.dk.
Received for publication 5 June 2007 and accepted in revised form 23 September 2007.
Published ahead of print at http://care.diabetesjournals.org on 1 October 2007. DOI: 10.2337/dc07-
1066.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/
dc07-1066.
Abbreviations: SMPG, self-monitored plasma glucose; UAE, urine albumin excretion.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
factors for many substances.
© 2008 by the American Diabetes Association.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby
marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Clinical Care/Education/Nutrition/Psychosocial Research
ORIGINAL ARTICLE
DIABETES CARE, VOLUME 31, NUMBER 1, JANUARY 2008 9
Addison’s disease, and glucocorticoid-
treated rheumatoid arthritis (n ⫽ 5) were
excluded, as the medical treatment might
influence the risk of severe hypoglycemia.
If a woman had more than one pregnancy
in the study period (n ⫽ 2), only the first
pregnancy was included. A total of 108
(95%) eligible women accepted to partic-
ipate in the study.
Reporting and classifying
hypoglycemia
At inclusion at a median of 8 gestational
weeks (range 5–13) and at the visits at
gestational weeks 14 (12–16), 21 (20–
23), 27 (25–29), and 33 (31–35), the
women filled in a detailed questionnaire
originally developed for a multicenter
survey of hypoglycemia in nonpregnant
subjects with type 1 diabetes (11,13).
The questions encompassed the num-
ber of hypoglycemic events, state of hy-
poglycemia awareness, blood glucose
level during hypoglycemia, causes of
hypoglycemia, and sociodemographic
data. The questionnaire was expanded
to include questions about pregnancy-
related vomiting and nausea during the
preceding week.
Before the visits at weeks 8, 14, 21,
27, and 33, the women performed SMPG
eight times daily for 3 days (including at
3:00
A.M.). Biochemical hypoglycemia
was defined as an SMPG value ⱕ3.9
mmol/l (12). Based on the SMPG profiles,
the proportions of hypoglycemic values,
hyperglycemic values (ⱖ10.0 mmol/l),
and proportions outside the range of 4.0 –
9.9 mmol/l were calculated for each pa-
tient as a measure of glucose variability.
Mild hypoglycemia was defined as
events with symptoms familiar to the pa-
tient as hypoglycemia and managed by
the patient (14). The number of mild hy-
poglycemic events was assessed in each
questionnaire, whereas the frequency of
mild hypoglycemic events before gesta-
tion was assessed at the first pregnancy
visit.
Severe hypoglycemia was defined as
events with symptoms of hypoglycemia
requiring help from another person to ac-
tively administer oral carbohydrate or in-
jection of glucagon or glucose in order to
restore the blood glucose level (12). Se-
vere hypoglycemic events in the 1-year
period preceding pregnancy (stated as
“previous severe hypoglycemia” in the
following) were reported retrospectively
in the questionnaire at inclusion. To as-
certain severe hypoglycemia during preg-
nancy, the women were asked to contact
the investigators within 24 h after the
event.
When reported, we performed a
structured interview including questions
about date and hour of the event, possible
provoking factor(s), accompanying con-
vulsions or unconsciousness, presence of
nausea or vomiting the preceding 24 h,
time to recovery, and type of treatment.
Plasma glucose values during the hypogly-
cemic events were recorded, if measured.
Events occurring during the early phase of
pregnancy were recorded at the first visit.
The interviews were mainly performed by
telephone, but a few were performed during
clinical visits or hospitalization following
severe hypoglycemia.
Events of severe hypoglycemia were
validated according to Whipple’s triad: 1)
symptoms consistent with hypoglycemia,
2) a blood glucose value ⱕ3.9 mmol/l,
and 3) adequate response to glucose/
glucagon treatment. Events fulfilling all
criteria were classified as definite, those
fulfilling two criteria as probable, and the
remaining as possible (15).
Self-estimated hypoglycemia aware-
ness was derived from the patient’s an-
swer to the question, “Do you recognize
symptoms, when you have a hypoglyce-
mic event” (14). Subjects answering “al-
ways” were classified as having normal
awareness, those answering “usually” as
having impaired awareness, and those an-
swering “occasionally” or “never” as hav-
ing unawareness.
The glycemic threshold for mild hy-
poglycemic events before and during
pregnancy was assessed by the question,
“How low do you believe your blood glu-
cose is, when you recognize a hypoglyce-
mic event?” When the answer was given
as a range, the mean value was used.
Management of diabetes in
pregnancy
Routine SMPG was recommended at least
seven times daily (before and 1.5 h after
each main meal and at bedtime) every day
during pregnancy and at 3:00 A.M. once a
week. The patients registered their SMPG
values in diabetes diaries, which were
evaluated at each clinical visit. The values
were not downloaded electronically from
the glucose monitors. The diet and insulin
dosage were adjusted accordingly. Con-
tinuous glucose monitoring systems were
not generally available and were only
used occasionally in a few of the patients.
The women were instructed to per-
form self-adjustments of insulin dosages
between clinical visits based on the SMPG
of the previous 3 days in order to maintain
preprandial SMPG of 4.0 – 6.0 mmol/l,
1.5-h postprandial SMPG of 4.0 –8.0
mmol/l, and prebedtime SMPG of 6.0 –
8.0 mmol/l. In case of symptoms of hypo-
glycemia and/or SMPG ⱕ3.0 mmol/l, oral
carbohydrate intake was recommended.
If a single premeal SMPG was ⱖ8.0
mmol/l, 1–2 extra units of fast-acting in-
sulin was recommended. In case of SMPG
ⱖ15.0 mmol/l, vomiting, and stomach-
ache, urine ketones should be checked.
They continued their usual insulin regi-
men, four to five injections daily or insu-
lin pump treatment.
The women received oral and written
information about expected changes in
insulin dosage during pregnancy, includ-
ing information about a suspected high risk
of severe hypoglycemia at night between 10
and 16 weeks and the need for an increase
in insulin dosage from week 20. A glucagon
pen (GlucaGen) was prescribed.
All women visited our and/or their
local diabetes clinic at 1- or 2-week in-
tervals throughout pregnancy, where
weight, A1C, and blood pressure were
measured. A1C was measured on a DCA
2000 analyzer by a latex immunoaggluti-
nation inhibition method (DCA 2000;
Bayer). Normal range outside pregnancy
was 4.7– 6.3%, in early pregnancy 4.5–
5.7%, and in late pregnancy 4.4 –5.6%
(16). Blood pressure was measured with a
digital blood pressure monitor after 5–10
min of rest. Normal blood pressure was
defined as ⬍140/90 mmHg. Two 24-h
urine albumin excretions (UAEs) were
performed at inclusion. Microalbumin-
uria was defined as median UAE ⱖ30
mg/24 h and nephropathy as UAE ⱖ300
mg/24 h.
Diabetic retinopathy was diagnosed
with retinal photos at inclusion and at
week 28. Obstetrical ultrasound scanning
was performed on routine basis at inclu-
sion; at weeks 14, 21, 27, and 33; and
when indicated.
Information about insulin type and
dosage and other medications were
drawn from the patients’ medical records.
During the study period, 25 women re-
ceived antihypertensive treatment, mainly
methyldopa (n ⫽ 22). Antidepressive treat-
ment (fluoxetin or paroxetin) was given in
three women. Thyroid dysfunction was
treated with levothyroxine in 16 and with
thiamazole in 2 women, resulting in normal
thyroid function in all 18 women during
pregnancy.
All participants gave written informed
consent. The research protocol was ap-
Pregnant women with type 1 diabetes
10 DIABETES CARE, VOLUME 31, NUMBER 1, JANUARY 2008
proved by the regional committees for eth-
ics and science and by the Danish Data
Protection Agency.
Statistical analysis
Continuous variables were non-normally
distributed and given as median (range).
Discrete variables are given as numbers
and proportions. Differences between
groups were analyzed using
2
test for
categorical variables and Kruskal-Wallis
or Mann-Whitney tests when appropriate
for continuous variables. Changes during
pregnancy were tested assessing the with-
in-subject differences between values at
week 33 and week 8 using nonparametric
tests. The incidence of severe hypoglyce-
mia in the three trimesters was compared
using Poisson regression analysis.
Univariate and multiple logistic re-
gression analysis were conducted with “at
least one severe hypoglycemic event in
pregnancy” as the dependent variable.
With 49 observations, the following five
independent variables were chosen based
on significance in the univariate analyses
or a priori significance based on ref. 8:
duration of diabetes ⬎10 years, previous
severe hypoglycemia, impaired awareness
or unawareness (collapsed due to a low
number of patients with unawareness),
fluctuating SMPG (per 10% increment),
and A1C ⱕ6.5% at inclusion. The results
are expressed as odds ratios (ORs) and
95% CIs.
The associations were considered to
be statistically significant at a two-sided P
value ⬍0.05. All statistical analyses were
performed using SAS (version 9.1; SAS
Institute, Cary, NC).
RESULTS
Severe hypoglycemia
Forty-nine (45%) women experienced
178 severe hypoglycemic events through-
out pregnancy (Table 1). Eighty percent
of the events occurred before 20 weeks
with a peak at 9 weeks (supplemental Fig.
1 [available in an online appendix at
http://dx.doi.org/10.2337/dc07-1066]).
The incidence rates were 5.3, 2.4, and 0.5
events/patient-year in the first, second,
and third trimesters, respectively (P ⬍
0.0001). Thirty-four women had more
than one event, including 11 women with
five or more events (5–31) accounting for
106 (60%) of all events. The first event
occurred before 20 weeks in 95% of the
women. Thirty-three (31%) women expe-
rienced at least one (1–30) severe hypo-
glycemic event the year preceding
pregnancy (1.1 event/patient-year).
There was no difference in weight
gain during pregnancy in women with or
without severe hypoglycemia (15.2 kg
[range 5.6–26.8] vs. 15.0 kg [7.6–34.4]).
There was no difference in the prevalence
of diabetic retinopathy in early pregnancy
(Table 1) or in the number of women with
retinopathy progression during preg-
nancy (11 [22%] vs. 12 [20%]).
Structured interviews about severe
hypoglycemic events were obtained after
167 (94%) of the recorded events. Ac-
cording to Whipple’s triad, 92 events
(55%) were definite, 74 (44%) were prob-
able, and 1 was possible. Median SMPG
was 1.8 mmol/l (range 1.0 –3.9) (n ⫽ 92).
Unconsciousness (30 min [2–360]) oc-
curred at 30 (18%) and convulsions at 13
(8%) events. No traffic accidents or major
injuries were reported.
Eighteen (11%) events were treated
with intramuscular glucagon and seven
(4%) with intravenous glucose. Seven
events required hospitalization ⱖ2 h. Re-
covery time after the event was 30 min
(range 5–360).
At 94 (56%) events, no possible cause
was identified. At 23 (14%) events, the
reason was reported to be excessive insu-
lin dosages, at 38 (23%) events insuffi-
cient caloric intake and/or a postponed
meal (30 –240 min), at 4 (2%) events
vomiting, and at 3 (2%) events planned
physical activity. Five (3%) events were
preceded by recurrent mild hypoglyce-
mic events.
Mild hypoglycemia
The incidence of mild hypoglycemia was
3.4 events/patient-week before preg-
nancy and 5.5, 5.1, 4.2, 3.8, and 3.8
events/patient-week at weeks 8, 14, 21,
27, and 33, respectively, with a significant
decrease from 8 to 33 weeks (P ⬍ 0.0001)
and no difference between women with
and without severe hypoglycemia (Table
2).
Biochemical hypo- and
hyperglycemia
The fraction of biochemical hypoglyce-
mia was stable during pregnancy,
whereas the fraction of SMPG values
ⱖ10.0 mmol/l decreased significantly
from 8 weeks to 33 weeks with a concom-
itant tendency toward a reduction in me-
dian SMPG (Table 2).
Table 1—Baseline clinical data in 108 women with type 1 diabetes according to experience of severe hypoglycemia in pregnancy
Women without severe
hypoglycemia in pregnancy
Women with severe
hypoglycemia in pregnancy
n 59 (55) 49 (45)
Age (years) 31 (21–42) 30 (21–39)
Duration of diabetes (years) 13 (1–36) 19 (2.5–31)*
Gestational age at inclusion (days) 61 (37–94) 62 (42–93)
Last A1C before pregnancy (%) 7.5 (5.9–10.0) 7.0 (5.9–10.9)
BMI before pregnancy (kg/m
2
)
24.1 (17.3–43.8) 24.4 (20.1–32.4)
Insulin type (human insulin/insulin analogs) 32 (54)/27 (46) 28 (57)/21 (43)
Number of daily insulin injections (4/5/CSII) (%) 56/42/2 67/25/8
Diabetic retinopathy 35 (59) 33 (67)
Microalbuminuria/nephropathy 6 (10)/3 (5) 4 (8)/3 (6)
Antihypertensive treatment at inclusion 5 (8) 10 (20)
Systolic blood pressure (mmHg) 119 (95–150) 119 (88–150)
Diastolic blood pressure (mmHg) 70 (55–86) 71 (59–85)
Severe hypoglycemia the year preceding pregnancy 10 (17) 23 (47)†
SMPG threshold for mild hypoglycemic events before pregnancy 3.0 (1.5–4.0) 2.7 (1.5–4.5)*
Data are median (range) or n (%) unless otherwise indicated. *P ⬍ 0.01; †P ⬍ 0.001. CSII, continuous subcutaneous insulin infusion.
Ringholm Nielsen and Associates
DIABETES CARE, VOLUME 31, NUMBER 1, JANUARY 2008 11
Nocturnal hypoglycemia
Ninety-two (52%) severe hypoglycemic
events occurred during sleep, of which 65
(37%) events occurred at night (12:00 –
8:00
A.M.). The year preceding pregnancy,
54% of the reported severe hypoglycemic
events occurred during sleep.
The incidence of mild nocturnal hy-
poglycemia was 1.6, 1.3, 0.8, 0.7, and 0.8
events/patient-week at weeks 8, 14, 21,
27, and 33, respectively, with a significant
decrease from 8 to 33 weeks (P ⬍ 0.001)
and no difference between women with
and without severe hypoglycemia.
Assessment of awareness of
hypoglycemia
A total of 45 (42%) women reported nor-
mal hypoglycemia awareness at inclusion,
56 (52%) reported impaired awareness,
and 7 (6%) reported unawareness. Dur-
ing pregnancy, the women did not report
any significant changes in hypoglycemia
awareness (Table 2). Likewise, the glyce-
mic threshold for perception of warning
symptoms did not change (Table 2).
Predictors of severe hypoglycemia at
inclusion
Univariate analysis showed that women
with severe hypoglycemia in pregnancy
more often had previous severe hypogly-
cemia (OR 4.3 [95% CI 1.8 –10.5]), dia-
betes duration ⬎10 years (3.3 [1.3– 8.2]),
impaired hypoglycemia awareness or un-
awareness (3.9 [1.7–9.0]), and SMPG
readings outside the range of 4.0 –9.9
mmol/l at week 8 (1.6 [1.2–2.1] per 10%
increment).
Throughout pregnancy, there were
no significant differences between
women with and without severe hypogly-
cemia regarding the fraction of biochem-
ical hypoglycemia, self-reported SMPG
threshold for perception of warning
symptoms, median SMPG, A1C, or other
metabolic parameters (Table 2). The drop
in A1C from before gestation to week 8
among women with and without severe
hypoglycemia was comparable (⫺0.5%
[⫺1.8 to 0.4] vs. ⫺0.6% [⫺1.4 to 0.9],
respectively).
Women experiencing severe hypo-
glycemia tended to report nausea or
vomiting less frequently than women
Table 2—Metabolic parameters in 49 women with (ⴙSH) and 59 women without (ⴚSH) severe hypoglycemia in pregnancy with type 1 diabetes
Week 8 Week 14 Week 21 Week 27 Week 33
Median SMPG (mmol/l)
⫺SH 6.4 (4.0–11) 6.8 (4.3–11) 6.7 (4.0–10) 6.8 (3.9–11) 5.9 (4.2–10)*
⫹SH 6.8 (4.0–13) 6.7 (3.9–14) 6.7 (4.6–12) 6.8 (4.9–9) 6.4 (4.1–10)
Biochemical hypoglycemia SMPG
ⱕ3.9 mmol/l (%)
⫺SH 16 (4–44) 13 (0–46) 13 (0–48) 12 (0–50) 15 (0–39)
⫹SH 17 (0–50) 17 (0–54) 14 (0–35) 13 (0–36) 17 (0–46)
SMPG outside the range of 4.0–9.9 mmol/l (%)
⫺SH 34 (8–70) 36 (8–82) 36 (4–59) 29 (0–65) 29 (4–58)†
⫹SH 48 (16–84)‡ 39 (8–81) 36 (0–69) 27 (0–61) 36 (0–58)†
Biochemical hyperglycemia SMPG
ⱖ10.0 mmol/l (%)
⫺SH 16.7 (0–57) 16.7 (0–57) 18.2 (0–48) 14.3 (0–50) 8.3 (0–40)†
⫹SH 21.5 (0–72) 21.7 (0–67) 19.5 (0–65) 12.5 (0–42) 9.1 (0–52)*
Median SMPG at 3:00
A.M.§
⫺SH 5.9 (1.8–14) 6.5 (2.2–18) 6.2 (1.9–14) 5.7 (1.9–13) 5.1 (2.1–16)*
⫹SH 7.9 (2.1–16) 7.0 (2.6–16) 6.3 (3–13) 7.0 (2.9–11) 5.8 (2.7–13)
A1C (%)
⫺SH 6.7 (4.9–8.8) 6.4 (5.2–7.9) 6.0 (4.9–7.1) 5.9 (4.9–6.9) 5.9 (5.0–7.3)†
⫹SH 6.5 (5.2–10.5) 6.3 (5.1–7.8) 6.0 (5.0–7.7) 5.9 (5.0–7.2) 5.9 (4.8–7.2)†
Insulin dosage (IU/kg)
⫺SH 0.76 (0.4–1.2) 0.68 (0.4–1.2) 0.78 (0.4–1.4) 0.90 (0.5–1.7) 1.12 (0.5–1.9)†
⫹SH 0.76 (0.3–1.7) 0.68 (0.3–1.5) 0.73 (0.3–1.2) 0.90 (0.4–1.6) 1.04 (0.5–1.6)†
Self-estimated impaired awareness
⫺SH 25 (43) 25 (49) 28 (54) 25 (46) 26 (47)
⫹SH 36 (75)㛳 33 (73)¶ 35 (85)‡ 34 (81)‡ 31 (72)¶
Number of mild hypoglycemic
events previous week
⫺SH 5 (0–21) 4.5 (0–12) 4 (0–12)§ 3 (0–13) 4 (0–14)*
⫹SH 4 (0–21) 4 (0–14) 3 (0–8) 3 (0–25) 3 (0–15)*
SMPG threshold for mild hypoglycemic events
⫺SH 2.8 (1.5–4.0) 3.0 (1.8–4.5) 3.0 (1.9–4.0) 3.0 (1.9–4.0) 2.8 (1.8–3.8)
⫹SH 2.7 (1.5–4.0) 2.8 (1.6–4.0) 2.7 (1.8–3.8) 2.7 (1.8–4.0) 2.8 (1.9–4.0)
Nausea or vomiting previous week
⫺SH 37 (63) 25 (50) 17 (32) 12 (22) 19 (34)#
⫹SH 27 (56) 14 (30) 11 (26) 9 (21) 11 (25)*
Data are median (range) or n (%). *P ⬍ 0.05, †P ⬍ 0.0001, and #P ⬍ 0.001 between week 33 and week 8. ‡P ⬍ 0.01, 㛳P ⬍ 0.001, and ¶P ⬍ 0.05 between the two
groups. Data were obtained from 85 to 100% of the patients except §where 75% of samples were obtained.
Pregnant women with type 1 diabetes
12 DIABETES CARE, VOLUME 31, NUMBER 1, JANUARY 2008
who did not experience severe hypogly-
cemia (Table 2).
Multiple logistic regression analysis
identified previous severe hypoglycemia
(OR 3.3 [95% CI 1.2–9.2]) and impaired
hypoglycemia awareness or unawareness
(3.2 [1.2– 8.2]) as independent predictors
of severe hypoglycemia.
There was a significant interaction be-
tween impaired hypoglycemia awareness
and previous severe hypoglycemia (P ⬍
0.01). Severe hypoglycemia during preg-
nancy was seen in 21 of 22 (95%) women
with both impaired hypoglycemia aware-
ness and previous severe hypoglycemia
(corresponding to 7.4 events/patient-
year), in 16 of 41 (39%) women with im-
paired hypoglycemia awareness without
previous severe hypoglycemia, in 2 of 11
(18%) women with normal hypoglycemia
awareness and previous severe hypogly-
cemia, and in 10 of 34 (29%) women with
normal hypoglycemia awareness without
previous severe hypoglycemia (corre-
sponding to 1.7 events/patient-year).
Pregnancy outcome
Nine (8%) women developed preeclamp-
sia. Ketoacidosis was not seen. Twenty-
three women (21%) delivered preterm
(⬍37 weeks), mainly between week 34
and 36 due to preeclampsia, large for ges-
tational age infants, or preterm premature
rupture of the membranes. Birth weight
was 3,440 g (range 2,040 – 4,760) in in-
fants of women with severe hypoglycemia
and 3,532 g (2,475–5,620) in infants of
women without severe hypoglycemia
(P ⫽ NS). One neonatal death and no
severe congenital malformations were
registered.
CONCLUSIONS — This prospective
study of 108 women with type 1 diabetes
is based on the distribution of thoroughly
validated prospectively recorded events
of severe hypoglycemia according to a
well-established definition (12), and 95%
of all eligible women participated. Our
findings are in accordance with previous
observations (8,9), which either included
only the first trimester of pregnancy (8) or
twin pregnancies and the same women in
two pregnancies (9). We studied the
whole pregnancy and included only sin-
gleton pregnancies to avoid the potential
bias of complications of twin pregnancies,
and all women were included only once
to secure independent observations.
Structured interviews were obtained
after 94% of all reported events of severe
hypoglycemia, but it cannot be ruled out
that a small degree of underdocumenta-
tion occurred. To ensure a complete reg-
istration of severe hypoglycemia in early
pregnancy, events before the first visit
were included. Subjects with type 1 dia-
betes recall severe hypoglycemic events
well during a 1-year period (14), and thus
the obtained incidence rates are consid-
ered to be reliable.
Women who, at the first pregnancy
visit, are characterized by previous severe
hypoglycemia and impaired hypoglyce-
mia awareness or unawareness have a
three times higher risk of severe hypogly-
cemia in pregnancy compared with
women without these characteristics.
Fluctuating plasma glucose values and a
longer duration of diabetes might also
contribute to a higher risk of severe hypo-
glycemia, whereas the number of mild hy-
poglycemic events per week, a lower A1C,
or the fraction of biochemical hypoglyce-
mia did not predict the risk of severe hy-
poglycemia in these women.
We aimed to investigate whether
many low values recorded by the women
in the routinely used SMPG could identify
women at high risk of severe hypoglyce-
mia. However, that was not the case, pos-
sibly due to insufficient sensitivity of the
method. We cannot exclude that use of
continuous glucose monitoring sys-
tem—a tool that is more sensitive to
record periods of hypoglycemia and fluc-
tuations in glucose values—might have
given other results.
The prevalence of retinopathy in early
pregnancy and the number of women with
retinopathy progression during pregnancy
was comparable in women with and with-
out severe hypoglycemia. Thus, an associa-
tion between severe hypoglycemia and
progression of retinopathy during preg-
nancy was not seen. Likewise, the numbers
of women with microalbuminuria and ne-
phropathy were comparable among
women with and without severe hypoglyce-
mia, but the numbers were too small to
make any conclusions.
Pregnancy-related nausea and vomit-
ing might be contributing factors for se-
vere hypoglycemia in pregnancy (7,8).
Using questionnaires five times during
pregnancy and in interviews after each
event of severe hypoglycemia, we could
rule out that nausea and vomiting are ma-
jor contributing factors for severe hypo-
glycemia in pregnancy.
Self-estimated impaired hypoglyce-
mia awareness or unawareness was asso-
ciated with severe hypoglycemia as
previously described in nonpregnant pa-
tients with type 1 diabetes (11); in partic-
ular, the combination of impaired
hypoglycemia awareness and previous se-
vere hypoglycemia was associated with a
high risk of severe hypoglycemia. How-
ever, preserved hypoglycemia awareness
did not completely protect against severe
hypoglycemia in pregnancy. Noteworthy,
there was no change in hypoglycemia
awareness during pregnancy to explain
the varying risk of severe hypoglycemia.
Hypoglycemia awareness was determined
by the women’s self-estimated under-
standing of awareness, and they had to
distinguish whether they were “always,”
“usually,” “occasionally,” or “never” able
to feel a hypoglycemic event. The same
question was addressed prospectively,
five times in pregnancy, and we noted a
very high agreement in each woman and
in the whole study population indicating
that the women had a good sensation of
their awareness in pregnancy.
A decline in the SMPG threshold for
mild hypoglycemia was seen at onset of
pregnancy in women without severe hy-
poglycemia in pregnancy, but the SMPG
threshold for mild hypoglycemic events
did not change significantly in any of the
groups during pregnancy. This indicates
that other factors than change in hypogly-
cemia awareness account for the lower in-
cidence of severe hypoglycemia in the
second part of pregnancy.
Despite a higher incidence of severe
hypoglycemia in pregnancy, the propor-
tion of events during sleep was compara-
ble before and during pregnancy. More
than one-half of the severe hypoglycemic
events occurred during sleep, of which
37% occurred at night. This is compara-
ble with what was reported in nonpreg-
nant patients with type 1 diabetes (17).
The vast majority of the women expe-
rienced their first event of severe hypogly-
cemia before week 20. This implies that
women who have not experienced severe
hypoglycemia before week 20 have a low
risk of such events in the remaining part
of pregnancy, enabling these women to
strive for an even stricter metabolic con-
trol in the last part of pregnancy.
A declining insulin requirement in
the late first trimester of pregnancy with
type 1 diabetes was previously reported
(18), and overinsulinization has been
suggested as a contributing reason for se-
vere hypoglycemia in early pregnancy
(18). In our study, the insulin require-
ment decreased from week 8 to week 14
and increased from week 14 onwards.
Throughout pregnancy, median SMPG
Ringholm Nielsen and Associates
DIABETES CARE, VOLUME 31, NUMBER 1, JANUARY 2008 13
and A1C decreased, and there was no dif-
ference in insulin dosage or A1C before or
during pregnancy between women with
and without severe hypoglycemia.
Severe hypoglycemia was associated
with more fluctuating plasma glucose in our
study and in the study by Rosenn et al. (7).
This might reflect less compliance with the
diabetes diet and probably overcompensa-
tory caloric intake during hypoglycemia.
We did not record supplementary insulin
injections, but overinsulinization due to fre-
quent supplementary insulin injections
might play a role for the high incidence of
severe hypoglycemia. This is underscored
by the fact that at 14% of the severe hy-
poglycemic events, the women reported
excessive insulin dosages, and in 23% of
the events insufficient calorie intake
and/or a postponed meal were identified
as possible causes of severe hypoglyce-
mia. This suggests that clinicians should
pay more attention to the diet and the use
of supplementary fast-acting insulin dur-
ing pregnancy.
Prolonged periods with low plasma
glucose values increase the risk of severe hy-
poglycemia in nonpregnant patients with
type 1 diabetes (19). In our study, only 3%
of the severe hypoglycemic events were pre-
ceded by recurrent mild hypoglycemic
events. Neither biochemical nor mild hypo-
glycemia were more frequent among
women with severe hypoglycemia. This in-
dicates that other yet unknown factors in-
fluence the predisposition to severe
hypoglycemia in pregnancy.
Early identification of women at in-
creased risk of severe hypoglycemia in
pregnancy is important, since special ed-
ucation and individual modification of
glucose monitoring, diet, and insulin
treatment might be relevant to prevent se-
vere hypoglycemic events. Those identi-
fied as high-risk subjects may benefit
from intensified glycemic analysis in
terms of continuous glucose monitoring
with an alarm to warn the women about
hypoglycemic values (20) and subse-
quent transition to alternative treatment
modalities such as insulin pump (21) or
treatment with a rapid-acting insulin an-
alog (22).
In summary, 45% of women with
type 1 diabetes experienced at least one
severe hypoglycemic event during preg-
nancy. The incidence was highest in early
pregnancy, although the metabolic con-
trol was tighter in last part of pregnancy.
Predictors were previous severe hypogly-
cemia and impaired hypoglycemia aware-
ness or unawareness.
Acknowledgments— This study was sup-
ported by unrestricted grants from Novo Nor-
disk A/S, Bagsværd, Denmark, and the Danish
Diabetes Association.
L.R.N. was supported by a fellowship from
Copenhagen University Hospital Rigshospita-
let, Denmark.
We thank C.S. Laugesen, MD, DMSc, De-
partment of Ophthalmology, Rigshospitalet,
Denmark, for collecting ophthalmological
data.
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