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Diabetes in Pregnancy:

Detection, Intervention, Prevention

Michael Shannon, MD

Chair, Providence Endocrinology/Diabetes CAT

Diabetes in Pregnancy: Outline

Prevalence, Pathophysiology and Complications of

diabetes in pregnancy

Risk factors and screening of diabetes in pregnancy

Treatment of diabetes in pregnancy: nutrition, insulin

therapy, and newer technologies

Prevention of postpartum diabetes & recurrence (if

time allows)

Diabetes in Pregnancy

Approximately 200,000 pregnancies each

year are complicated by diabetes (up to 9.2%

of all pregnancies, CDC 2014)

Includes:

Type 1 (DM1)

Type 2 (DM2)

Gestational Diabetes Mellitus: any degree of

glucose intolerance, with onset or first

recognition during pregnancy (87% of cases)

13% DM at conception

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Diabetes in Pregnancy: Pathophysiology

The hypoglycemic potency of insulin is diminished

[in pregnancy] as insulin resistance supervenes (N

Freinkel “Banting Lecture” 1980)

Possible candidates that increase across gestation –

hCG, E/P, human placental lactogen

Growth hormone-like activity is seen in the placenta

but unclear if contributor; other associations are

seen with leptin, IGFBP-1, and triglycerides

HD McIntyre et al, Diabetes Care 2018

Diabetes in Pregnancy: Pathophysiology

Diabetes in Pregnancy: Complications

There are two distinct groups of complications

Congenital malformations

These are related to 1st trimester hyperglycemia

Seen in pre-pregnancy diabetics only; not seen in

GDM, diabetic fathers, or pre-diabetics

Complications related to fetal macrosomia

Mostly related to fat deposition after 24-28 weeks

This 2nd-3rd trimester hyperglycemia causes birth

injury and possibly increased adult BMI, DM risk

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Infant Malformations Occur

Before the Seventh Gestational Week Anomaly

Ratio of incidence

Gestational age after ovulation in weeks

Caudal regression 252 3

Situs inversus 84 4

Spina bifida, hydrocephalus 2 4

Anencephalus 3 4

Renal anomalies 5

Agenesis 6 5

Cystic kidney 4 5

Ureter duplex 23 5

Heart anomalies

4 Transposition great vessels 5

Ventricular septal defect 6

Atrial septal defect 6

Anal/rectal atresia 3 6

JL Mills et al. Diabetes 1979

Diabetes in Early Pregnancy Trial Prevalence of Major Fetal Complications

Mills JL et al. NEJM. 1988

0

1

2

3

4

5

6

7

8

9

10

No Diabetes Early-entry diabetes Late-entry diabetes

9.0%

4.9%

2.1%

Prevalence

rate (%)

No Diabetes

Diabetes <21 days postconception

Diabetes >21 days postconception

Diabetes in Early Pregnancy (DIEP) Pregnancy Loss by A1C Status

JL Mills et al, NEJM 1988

0

5

10

15

20

25

30

35

40

45

–3 –2 –1 0 1 2 3 4 5 6 7 8 9

A1C: Standard deviation from control mean

Diabetes

No diabetes

Pregnancy

loss %

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Fetal Macrosomia

Fetal macrosomia is closely related to glucose

levels in the 2nd, and especially the 3rd, trimester

Fetal macrosomia associated with adverse effects:

Shoulder dystocia and brachial plexus injury

Hepatomegaly and cardiomegaly

Neonatal hypoglycemia, other organ failure, NICU stay

Increased rate of C-sections

Best theorized with the Pedersen hypothesis

Fetal hyperinsulinemia

Maternal Glucose and Macrosomia Modified Pedersen Hypothesis

Fetus

Fetal pancreas stimulated

Mother

Pla

cen

ta

Insulin

Maternal hyperglycemia

Extra Glucose Stored as Fat:

Macrosomia and Insulin Resistance

Fetal Macrosomia

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Fetal Macrosomia

Macrosomia and Child Obesity

The neonatal environment and macrosomia may also

give “imprinting” on future obesity risk

A study of multi-ethnic women from 1990s and

measured offspring weight assessed 5-7 yrs later

Increasing maternal blood sugars was associated

with greater macrosomia and later childhood obesity

Even without macrosomia, however, maternal high

blood sugars nearly doubled the risk of childhood

obesity at age 5-7

TA Hillier et al, Diabetes Care 2007

At age 17, children of mothers with DM in pregnancy are

more likely to be overweight (whether GDM or pre-preg)

Zvi Laron et al, ADA 2013

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Obesity and Macrosomia: Cycle of

Maternal and Infant Consequences

Fetal/Neonatal

Macrosomia

Childhood

Obesity

Adult Obesity

and Diabetes

Obesitogenic and Diabetogenic Environment

Pregnancy with

GDM or DM2

Can glycemic control in pregnancy break obesity cycle?

Macrosomia and Child Obesity

The neonatal environment and macrosomia may also

give “imprinting” on future obesity risk

A study of multi-ethnic women from 1990s and

measured offspring weight assessed 5-7 yrs later

Increasing maternal blood sugars was associated

with greater macrosomia and later childhood obesity

Even without macrosomia, however, maternal high

blood sugars nearly doubled the risk of childhood

obesity at age 5-7

Successfully treated sugars greatly reduced

childhood obesity

TA Hillier et al, Diabetes Care 2007

Diabetes in Pregnancy

Approximately 200,000 pregnancies each

year are complicated by diabetes in

pregnancy (about 7-8% of all pregnancies)

Includes:

Type 1 (DM1)

Type 2 (DM2)

Gestational Diabetes Mellitus: any degree of

glucose intolerance, with onset or first

recognition during pregnancy (87% of cases)

13% DM at conception

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Diabetic Pregnancies in the Past

Infant

mortality (%)

Mean maternal blood glucose (mg/dL)

Adapted from Jovanovic L, Peterson CM. Diabetes Care. 1980

Joslin <1922

Joslin 1924–38

Essex 1951–55

Pedersen 1969

Karlsson 1972

Joslin 1956–75

Tyson 1976

Martin 1979

Essex 1973 Karlsson 1972

Tyson 1979

100

50

0

0 100 200 DKA

Jovanovic 1980

What’s a Woman with Diabetes to Do?

Do women plan their pregnancies?

85 women with preconception DM; most women (79%) knew

should optimize their glucose before conception but fewer than

half (41%) of their pregnancies were planned

More planned pregnancies with higher income, private

insurance, education, happily married, and seeing an

endocrinologist

Most unplanned pregnancies were not contraceptive failures,

but may have been consciously or subconsciously intended.

Women who felt that their doctors discouraged pregnancy were

more likely to have an unplanned pregnancy than were women

who had been reassured they could have a healthy baby.

EV Holing et al, Diabetes Care 1998

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Preconception DM Care Possible Contraindications to Pregnancy

Coronary artery disease (heart attacks/stents)

Active, untreated severe diabetic retinopathy

Kidney insufficiency

Kidney function < 1/3 normal

Very large amounts of protein in urine

Very high blood pressure despite

treatment

Severe gastroparesis

American Diabetes Association, Diabetes Care

Who To Screen for GDM?

Increasing Rates of GDM

Source: CDC

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Increasing Rates of GDM

Source: DS Feig et al, Diabetes Care 2014

Increasing Rates of DM2 in Youth

Gestational Diabetes: Risk Factors

Overweight / obesity

Age

High risk ethnic group

Others: previous child > 9 pounds,

polycystic ovary syndrome, hypertension,

family history of gestational diabetes

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GDM: Age

Source: CDC

GDM: Body Mass and Ethnicity

Source: CDC

Who and How To Screen for GDM?

Screen almost all patients at 24-28 weeks

Screen high risk individuals at first prenatal visit and then retest at 24-28 weeks if negative on first screen

Patients for Early GDM

Testing Considerations

Maternal age >35 years

Previous infant >4kg

Previous GDM

Strong FH of Type II or

GDM

Obesity or PCOS

ADA Position Statement, Diabetes Care 2007

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ACOG: Screening and Diagnosis of GDM

Initial Screen: 50 g OGTT, test 1 hr glucose

If >140 or > 130 mg/dl requires further test

My option = consider > 180 mg/dl diagnostic

Diagnostic: fasting 100 g OGTT, at least 2+

Fasting glucose: 95 mg/dl

1 hour glucose: 180 mg/dl

2 hour glucose: 155 mg/dl

3 hour glucose: 140 mg/dl

Why not ADA/IADPSG Criteria?

One Step Approach recommended by IADPSG and one of two choices per ADA

Diagnostic: one or more elevated with 75 g

Fasting glucose: 92 mg/dl

1 hour glucose: 180 mg/dl

2 hour glucose: 155 mg/dl

Treatment of Diabetes in Pregnancy

Testing – well-timed, recorded, and lots of it

Treatment foundation is medical nutrition therapy

In patients who are not controlled by diet or pre-

existing diabetes, insulin is preferable (ADA)

ADA recommends insulin for optimal control

in Type 1 and Type 2 diabetics

ACOG has endorsed the use of oral agents

(metformin, glyburide, acarbose) and insulin

No oral DM agent is “approved” in pregnancy

All of this is better with diabetes educators!

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Self-Monitored Blood Glucose: SMBG Goals and Testing Frequency

Goals Timing

Fasting 60–95 mg/dL Test on waking

Premeal 60–95 mg/dL Test before each meal

1-hour postprandial 100–120 mg/dL Test 1 hour after each meal

Frequency

Preexisting

diabetes

7X/day =1 fasting + 2 premeal + 3 postprandial +

1 nighttime (2-4 AM) if hypoglycemia

The perfect is the enemy of the good (Voltaire)

Medical Nutrition Therapy

Treatment foundation is medical nutrition therapy

and intensive insulin therapy

Carbohydrate control at meals: 30 grams for

breakfast, 45-60 with lunch and dinner

15 gram snacks between meals

Post meal walking/exercise may reduce sugars

All of this requires diabetes educators!

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Oral Medications

Insulin is recommended as the standard treatment by

the ADA (ADA recommends discontinuing non-

insulins and starting insulin)

ACOG in Aug 2013 endorsed use of some orals

Glyburide is pill that stimulates insulin production in

pancreas; one good trial of this in 2000; can have lows’

Fifth International Workshop states caution in its use

Metformin has had some successful trials; many stay

on it (especially fertility docs); it does cross placenta

Limited trials on other diabetes drugs in pregnancy

Insulins “Approved” in Pregnancy

These are Category B by FDA in old system

Short acting insulins:

Regular insulin

Lispro (Humalog) insulin

Aspart (Novolog) insulin

Long acting insulins:

NPH insulin

Detemir (Levemir) insulin

Initiating Insulin Therapy in Pregnancy

If not controlled by diet, initiate stepwise insulin -> do

not let patients starve themselves away from insulin!

Give insulin for abnormal sugars

May only need at certain times (not all meals)

Need to analyze blood sugar readings to make

more specific interventions

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Initiating Insulin Therapy in Pregnancy

If not controlled by diet, initiate stepwise insulin -> do

not let patients starve themselves away from insulin!

Give insulin for abnormal sugars

High fasting sugars = bedtime long acting (NPH or

detemir)

Abnormal postprandial glucose with regular insulin

or rapid-acting insulin (lispro or aspart) imme-

diately before the meal with elevations

May only need at certain times (not all meals)

NPH

Insulin Algorithm Human Insulins (NPH/Regular)

4:00 16:00 20:00 24:00 12:00 8:00

NPH

Plasma

insulin

NPH

Breakfast

Regular

Lunch

Regular

Dinner

Regular

24:00

NPH

15

0600 0800 1800 1200 2400 0600

Time of day

20

40

60

80

100 B L D

Insulin Algorithm

With Category B Analog Insulin

Detemir (Levemir)

Lispro (Humalog) or Aspart (Novolog)

Normal pattern

U/mL

Carbohydrate Counting in Pregnancy

Carbohydrate counting

during pregnancy is essential

Detailed counting and carbo-

hydrate ratios with insulin

(i.e. 2 units per 15 grams)

Often different ratios as

different meals (more with

breakfast carbohydrates)

Harm reduction…

Optimizing Insulin in Pregnancy

Patients may do well with adjusting their own with

guidance: i.e. go up 2 units of bedtime insulin for

every two days your fasting sugars are > 90

Patients can use carbohydrate ratio dosing: i.e. take 3

units for every 15 grams (exchange) of carbohydrates

Patients can take VERY large doses of insulin… my

highest was 900 units per day

Where possible, insulin pens are a lot easier to teach

(for providers) and learn (for patients)

Patients will have (mostly) increasing insulin needs in

pregnancy -> the moving dartboard

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Newer Technology for

Diabetes in Pregnancy

Insulin Pumps

Insulin pumps can benefit many

pregnant diabetics; about 28% of

all DM1 patients have pumps, and

pregnancy may be a good time to

initiate pump usage

Patients should already be able to

manage frequent blood sugar

checks, count carbohydrates, and

give multiple daily insulin

injections (may need to show

insurance plans)

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Insulin Pump in Pregnancy - Data

2007 study of CSII showed no benefit

2016 Cochrane Review compared CSII vs MDI in

pregnancy – key findings

No evidence to support the use of one particular form

of insulin administration over another

Only a few trials appropriate for meta-analysis, a

small number of women included and questionable

generalisability of the trial population.

D Farrar et al, Cochrane Database of Systematic Reviews, 2016

Patient-Driven CGM

Patients can often utilize personal continuous

glucose monitoring for their sugars, especially

those with type 1 diabetes

Can pick up patterns in mealtime dosing and

basal rates -> also can separate out basal and

bolus problems with their interpretation

Sensors are not perfect and require calibration

and interpretation but newer technology is

(obviously, CDEs) an improvement

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Questions and Thanks to WADE

A hospital is no place to be sick.

Samuel Goldwyn (1882-1974)

What to expect at the hospital for delivery

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At the time of delivery…

Very little insulin is needed during active labor, and

some people need an IV with glucose to avoid ketones

RIGHT after pregnancy, insulin needs will drop

dramatically -> often reset almost all the way to pre-

pregnancy levels (plus some weight)

Go over postpartum insulin dosing with your doctor

After Delivery:

Patients with GDM can stop medications, and if

preexisting DM, usually can reduce or stop insulin

If GDM, need a 75 gram 2-hour glucose tolerance test

6-12 weeks after (this catches “unmasked” DM)

In 5-15 years, about half of women with GDM will

develop DM2 (about 7x normal population)

66% will have GDM in any subsequent pregnancy

(risks: can modify body weight, can’t change aging!)

Prevention: Future GDM

Weight loss: obese women who lost at least 10 pounds

between pregnancies reduced GDM risk by one third

Bariatric surgery in one study (of 700 women) reduced

the risk of gestational diabetes by three-quarters

Exercise may reduce gestational diabetes (mixed data)

Few studies on roles of specific dietary factors

How can I prevent or delay getting type 2 diabetes later in life?

You can do a lot to prevent or delay type 2 diabetes.

Reach and maintain a reasonable weight. Even if you stay above your ideal

weight, losing 5 to 7 percent of your body weight is enough to make a big

difference. For example, if you weigh 200 pounds, losing 10 to 14 pounds can

greatly reduce your chance of getting diabetes.

Be physically active for 30 minutes most days. Walk, swim, exercise, or go

dancing.

Follow a healthy eating plan. Eat more grains, fruits, and vegetables. Cut

down on fat and calories. A dietitian can help you design a meal plan.

Remind your health care team to check your blood glucose levels regularly.

Women who have had gestational diabetes should continue to be tested for

diabetes or pre-diabetes every 1 to 2 years. Diagnosing diabetes or pre-

diabetes early can help prevent complications such as heart disease later.

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Prevention: Future Type 2 Diabetes

Reach and maintain a reasonable weight. Even if you stay above

your ideal weight, losing 5 to 7 percent of your body weight is

enough to make a big difference.

Physically active for 30 minutes most days. Walk, swim,

exercise. (Accountability partner…)

Healthy eating plan. Eat more grains, fruits, and vegetables. Cut

down on fat and calories.

Check your blood glucose levels regularly. Women who have

had gestational diabetes be tested for diabetes or pre-diabetes

every 1 to 2 years; also recommend before next conception

How can I prevent or delay getting type 2 diabetes later in life?

You can do a lot to prevent or delay type 2 diabetes.

Reach and maintain a reasonable weight. Even if you stay above your ideal

weight, losing 5 to 7 percent of your body weight is enough to make a big

difference. For example, if you weigh 200 pounds, losing 10 to 14 pounds can

greatly reduce your chance of getting diabetes.

Be physically active for 30 minutes most days. Walk, swim, exercise, or go

dancing.

Follow a healthy eating plan. Eat more grains, fruits, and vegetables. Cut

down on fat and calories. A dietitian can help you design a meal plan.

Remind your health care team to check your blood glucose levels regularly.

Women who have had gestational diabetes should continue to be tested for

diabetes or pre-diabetes every 1 to 2 years. Diagnosing diabetes or pre-

diabetes early can help prevent complications such as heart disease later.