Medical Disorders of Pregnancy

Hassan A Shehata MRCOG MRCPI

Consultant Obstetrician, Gynaecologist & Obstetric PhysicianEpsom & St. Helier University Hospitals NHS Trust

St. Helier’s Hospital – 3 October 2006

CEMACH 2002-2004 Breakdown of direct causes

CEMACH 2002-2204 Breakdown of indirect causes

CEMACH 2002-2004 Leading Causes of Death

Diabetes - Classification

Diabetes in pregnancy

Pre-existing diabetesGestational diabetes

(GDM)

IDDMType I

NIDDMType II

Pre-existing diabetes True GDM

Effect of pregnancy on DM• Normal pregnancy

– Fall in fasting BG– Rise in post-prandial BG– Insulin resistance & relative glucose intolerance– Glucose tolerance decrease with increasing

gestation due to hPL, glucagon & cortisol– Renal threshold for glucose falls

• Rise in insulin requirements x 2• Deterioration in nephropathy

(reversible)• Two fold risk of progression of

retinopathy

CEMACH 2006• Women in UK with pre-existing (type 1 or type 2)

diabetes are poorly prepared for pregnancy

• The recent CEMACH report highlighted the fact that across the country, only 1 in 3 women were documented as receiving any kind of preconception counselling or having a preconception HbA1c measurement

• The level of uptake of folic acid supplements before conception was very poor (39%) which is particularly concerning given the increased risk (3.4-fold) of neural tube defect

• Even amongst those take folic acid, few were prescribed the higher dose (5mg) as recommended by the National Service framework (NSF) Diabetes

Type 2 DM• Previous reports of type 2 diabetes being perceived as far less

common in women of childbearing age as well as less serious condition

• However, it has become increasingly apparent that both these perceptions are mistaken

• The prevalence of type 2 diabetes in young people is increasing and accounts for over a 1/4 of pregnant women with pre-existing diabetes and in some parts of the country including London this rises to 45%

• Over-representation of black, Asian and other minority groups (49% compared with only 9% of women with type 1 diabetes) and a strong association with social deprivation

• It is now clear that adverse pregnancy outcomes are as common in women with type 2 diabetes as those with type 1 diabetes

• Risk of perinatal mortality and congenital malformation are equivalent and babies of women with type 2 diabetes are more likely to be large in size for gestational age and delivered pre-term

Feto-maternal blood glucose relationships

• Glucose crosses the placenta by a process of facilitated diffusion

• Fetal plasma glucose levels are similar to those of the mother

• Fetal insulin secretion occurs from 10 weeks gestation

• There is a brisk fetal insulin response to raised plasma glucose levels in diabetic pregnancy

• Sustained fetal hyperglycaemia secondary to maternal hyperglycaemia can result in fetal -cell hyperplasia

HbA1c

• Level is raised in diabetes

• Reflects diabetic control over the previous 2 or 3 months

• Estimation has proved a valuable additional aid to be on the look-out for major congenital abnormalities

Effect of pre-existing DM on pregnancy

• Increased risk of congenital abnormalities

• Increased perinatal mortality– late “unexplained”

intrauterine death• Increased risk of pre-

eclampsia• Increased perinatal

morbidity– Prematurity– Macrosomia

Congenital Abnormalities• 2 - 4 fold increase ie. 10% risk• Directly related to glycaemic

control

• Correlated with HbAIC

• Very small risk if HbAIC < 50% above upper limit of normal

• Sacral agenesis• CHD• Skeletal / NTD

Perinatal Mortality

• IUD is rare• Related to fetal acidaemia• Related to maternal BG• Cannot predict with

– biophysical profile– CTG

– Umbilical artery Doppler

Perinatal Morbidity

Modified Pederson Hypothesis

M acrosom ia O rganom egaly

Jaundice

Polycythaem ia Hypoglycaem ia RDS

Fetal Hyperinsulinaem ia

Fetal pancreatic beta cell hyperplasia

Fetal hyperglycaem ia

M aternal Hyperglycaem ia

Management of DM in Pregnancy

• Pre-pregnancy counselling• Combined clinic (single physician +

obstetrician)• HBGM with meter• Aim for normoglycaemia

– fasting 4-6 mmol/l– 1 hr pp 4-8 mmol/l– 2 hrs pp 4-7 mmol/l

• Diet +/- Insulin• Monitor control of IDDM with HbA1C

• Glucagon kit for IDDMs• Screen for retinopathy

Pre-pregnancy counselling (PCC)

• Optimize glycaemic control– Risk of major congenital

malformations is increased x 3/4.– Risk correlates with HbA1C.

• Assess presence / severity of complications– Hypertension– Retinopathy– Nephropathy

• Stop oral hypoglycaemics

PCC……Contraindications to pregnancy in DM

• Ischaemic Heart Disease

• Untreated proliferative diabetic retinopathy

• Hypertension and severe renal impairment (Cr > 250)

• Severe gastroparesis

Obstetric Management

• Ultrasound– to detect congenital abnormalities– to assess fetal growth / polyhydramnios

• Screen for pre-eclampsia• Timing of delivery

– Risk of IUD vs. risk of RDS– Risk of macrosomia and shoulder dystocia

vs. CS– 38 - 40 weeks

• Caution with steroids and beta-sympathomimetics

Intrapartum and postpartum care

• Continuous FHR monitoring• IV dextrose and variable IV insulin• BG 5-8 mmol/l• Halve rate of insulin post partum• Pre-pregnancy insulin SC dose when

eating• Prophylactic antibiotics if CS• Neonatal BG 4 hours• Feed neonate early

Recommendations

• Plan pregnancyPlan pregnancy• Pre-pregnancy counsellingPre-pregnancy counselling• Tertiary centre / joint clinic / Tertiary centre / joint clinic /

diabetes nurse specialist / diabetes diabetes nurse specialist / diabetes midwife/ dieticianmidwife/ dietician

• Monitor using post-prandial BGsMonitor using post-prandial BGs• Basal bolus insulin regimenBasal bolus insulin regimen• Monitor fetus and time deliveryMonitor fetus and time delivery• Post-pregnancy counsellingPost-pregnancy counselling

Hyperthyroidism

• Prevalence in pregnancy is up to 0.2%

• Grave’s disease - up to 90% of cases

• Untreated - dangerous for mother & baby

Hyperthyroidism - Clinical Features

• Many of the typical features are common in normal pregnancy

• Discriminatory features include weight loss, tremor, a persistent tachycardia, lid lag and exophthalmos

• If thyrotoxicosis occurs for the first time in pregnancy, it usually presents late in the first or early in the second trimester.

Normal ranges for TFT in pregnancy

Gestation f T4 (pmol/ l)

f T3 (pmol/ l)

TSH (mu/ l)

nonpreg 11- 23 4- 9 0- 4

1st trim 11- 22 4- 8 0- 1.6

2nd trim 11- 19 4- 7 0.1- 1.8

3rd trim 7- 15 3- 5 0.7- 7.3

Hyperthyroidism - Effect of Pregnancy

• Thyrotoxicosis often improves during pregnancy especially in the second and third trimesters.

• Exacerbations may occur in the first trimester, possibly related to hCG production, and in the puerperium

Hyperthyroidism - Effect on Pregnancy• If severe and untreated, it is associated with

inhibition of ovulation and infertility

• Higher incidence of miscarriage, placenta abruption, pre-term delivery and PET

• Neonatal hyperthyroidism, prematurity, intrauterine growth retardation, fetal death and stillbirths

• Poorly controlled thyrotoxicosis may lead to a thyroid crisis (‘storm’) in the mother and heart failure, particularly at the time of delivery.

• The possibility of retrosternal extension of a goitre which can cause tracheal obstruction

Hyperthyroidism - Diagnosis

• A raised free T4 or free T3. Normal pregnant ranges for each trimester must be used

• TSH is suppressed, although this may be a feature of early pregnancy.

• Differentiation from hyperemesis gravidarum may be difficult

Hyperthyoidism - Management• Grave’s disease often improves, flares

postpartum

• CBZ (up to 15mg) & PTU (up to 150mg) cross placenta

-Blockers are safe

• Thyroidectomy is rarley necessary:-– Who fail to achieve euthyroidism– intolerant to drugs– with dysphagia or stridor related to a large goitre– with confirmed or suspected thyroid malignancy

Hypothyroidism

• Prevalence is in the order of 1%

• Commonest is autoimmune destructive thyroiditis

• Untreated - associated with infertility, miscarriage and fetal loss

Hypothyroidism - Clinical Features

• Features are common in normal pregnancy

• Discriminatory features in pregnancy are cold intolerance, slow pulse rate and delayed relaxation of the tendon (particularly the ankle) reflexes.

• It is associated with other autoimmune diseases, for example, pernicious anaemia, vitiligo and type-I diabetes mellitus

Hypothypidism - Diagnosis

• Low free T4.

• The TSH is raised, although this may be a feature of normal late pregnancy, or occasionally early pregnancy

• The finding of thyroid autoantibodies may help confirm the diagnosis, but these are present in 10-20% of the population and should not be used in isolation

Hypothypidism - Effect of Pregnancy

• Pregnancy itself probably has no effect on hypothyroidism

• If the dose does need to be increased in pregnancy, this is usually because of inadequate replacement prior to pregnancy

Hypothypidism - Effect on Pregnancy

• Severe and untreated - inhibition of ovulation and infertility.

• Those who do become pregnant and remain untreated have an rate of miscarriage, fetal loss, PET & LBW

• An association between untreated hypothyroidism in the mother and reduced IQin the offspring.

• With adequate replacement, the maternal and fetal outcome is usually good

Hypothyroidism - Management• Small amounts of thyroxine cross the placenta -

fetus is not at risk

• Most will be on maintenance doses of thyroxine of 100-150 ug/day

• Euthyroid women will not usually require any adjustment to dose

• TFT should be checked in all women, ideally pre-conceptually, or at least during the first trimester

• Replacement with thyroxine should begin immediately

• With adequate replacement, thyroid function should be checked once in each trimester

Epilepsy – Effect of Pregnancy

• About 1/3 of women experience an increased frequency of fits

• Poorly controlled epileptics are more likely to detriorate

• In most (54%) , the frequency of fits is not altered

Epilepsy – Effect on Pregnancy

• There is no increased risk of miscarriages

• The fetus is relatively resistant to short episodes of hypoxia

• The risk of the child developing epilepsy is increased (4%)

• Teratogenic effects of anticonvulsants

Epilepsy - Anticonvulsants

• All cross the placenta and are teratogenic• Not much difference in the risk of the four

principle AEDs• Background risk = 3% Untreated epileptic = 4% 1 drug = 7% 2 or more drugs = 15% Val + carb + phenytoin = 50%

• Assess need for treatment

• Optimize control – treat patient not drug level

• Monotherapy if possible

• Counsel re teratogenesis

• Give folate 5 mg / day

Epilepsy - Management

Migraine

• It can occur as a pregnancy-related phenomenon without any prior history

• Pre-existing migraine (50-80%) often improves in pregnancy

• Hemiplegic migraine may mimic TIA• Ergotamine, sumatriptan & pizotifen

should be avoided• Low-dose aspirin, beta-blockers, tricyclic

antidepressants & calcium antagonists may be used for prophylaxis

Asthma – Effect of Pregnancy

• May improve, deteriorate or remain unchanged

• Mild disease – unlikely problems

• Possible postnatal deterioration

• Deterioration of disease is commonly caused by reduction or cessation of medication

Asthma – Effect on Pregnancy

• Mostly no adverse effects

• Severe, poorly controlled asthma may adversely affect the fetus

• No association with PET, prem. labour, LBW, IUGR and neonatal morbidity

Asthma - Management

• Treatment differs little from Mx in non-pregnant patient

• Education and reassurance concerning the safety of asthma medications

• Inhaled, oral and intravenous steroids and inhaled, nebulized and intravenous beta-agonists are safe

• Do not withold a chest X-ray if necessary

Physiological changes of thrombotic/fibrinolytic system

• Increase in levels of factors VIII, IX, X and fibrinogen

• Decrease in fibrinolytic activity

• Decrease in antithrombin III and protein S

• Venodilation and decreased flow in lower limbs leads to venous stasis

Pulmonary Embolism (PE)

• PE is the major cause of maternal death

• 3% of direct deaths• 1.4 deaths per 100,000 maternities• 35 women died from TED in 1997-9

– 31 PE & 4 cerebral thrombosis– 13 antenatally (8 in 1st trimester)– 17 postnatally (7 after Caesarean, 10 after

vaginal delivery

Acute Episodes - PE

• Chest X-ray• Arterial blood gas analysis

pO2 - 13 kPa (100mmHg) standing, 11kPa (83mmHg) supine

pCO2 - 4 kPa (30mmHg) • SO2 drop by > 6mmHg• Electrocardiography• V/Q scan or spiral CT• D dimers not helpful• Thrombophilia screen

Estimated radiation to the fetus and excess risk of childhood cancer following common diagnostic procedures

Estimated radiation to the fetus (mGy) Probability of fatal cancer to

age 15y

Conventional X-rayChest 0.01 <1 in

1000,000Pelvis 1.1 1 in 300,000Skull 0.01 <1 in

1000,000Spine 1.7 1 in 20,000

Computerized TomographyChest (inc. spiral) 0.06 1 in 560,000Pelvimetry 0.2 1 in 170,000 Nuclear MedicineLung perfusion (Tc 99m) 0.2 1 in 170,000Lung ventilation (Tc 99m) 0.3 1 in 110,000Childhood fatal malignancy background risk is 1:650,000

V/Q scan Spiral CT

Pathological MRIspecimen

TED - Mx

• If DVT or PE is diagnosed [or strongly suspected], anticoagulation with heparin should be commenced

• Therapeutic-dose i.v. heparin or LMWH for ~ 12 weeks

• Then prophylactic LMWH for up to 6 weeks postpartum or longer (total of 6 months)

Drug transfer

• Most drugs have a molecular weight below 1000 daltons (D)

• Drugs 1000 D cross the placenta ( 600 D cross easily)

• Main determinant of the drug concentration in the embryo/fetus is the mother's blood concentration

• Other factors:-– lipid solubility & protein binding– degree of ionization at physiologic pH– placental blood flow & surface area available for transfer

– maternal serum concentration is the main determinant

– the milk pH is slightly acidic in comparison to serum pH; so weak bases could become trapped in milk (ion trapping)

The processes that govern the passage of a The processes that govern the passage of a drug into milk are similar to the placentadrug into milk are similar to the placenta

Type of Effects

• Teratogenicity (i.e. thalidomide) - readily detected at, or shortly after, birth

• Long term latency (i.e. DES - increased risk of vaginal adenocarcinoma after puberty, or abnormalities in testicular function and semen production)

• Impaired intellectual or social development (i.e. exposure to phenobarbitone- alters programming of brain)

• Predisposition to metabolic diseases (i.e. Barker hypothesis - low birthweight associated with increased risk of diabetes, hypertension, heart disease in adulthood)

Teratogenesis

• It is defined as structural or functional (e.g. renal failure) dysgenesis of the fetal organs

• Typical manifestations include– congenital malformations with varying severity– intrauterine growth restriction– carcinogenesis– fetal demise

• In humans, the critical time for drug-induced congenital malformations is in the first trimester

• Drug-induced toxicity can occur at any time during gestation

Malformations

• The overall incidence of– major congenital malformations is around 2-3%– minor malformations is 9%

• It has been estimated that– 25% are due to genetic or chromosomal

abnormalities– 10% due to environmental causes including

drugs– 65% of unknown aetiology

• The part played by drugs is probably small

Organogenesis

• The critical time for drug-induced congenital malformations is usually the period of organogenesis– about 20 to 55 days after conception– about 34 to 69 days after the first day of the LMP

• Interference in this process causes a teratogenic effect

• If a drug is given after this time it will not produce a major anatomical defect, but more of a functional one

1 2 3 4 5 6 7 8 9 10 3816

Central Nervous System

Face

Ear

Eye

Palate

Limb

Hand

Heart

Gut

Kidney

Genitourinay System

Timing of the development of major body structures in the embryo and fetus Hanretty KP et al. Identifying abnormalities. In: Rubin PC, ed. Prescribing in pregnancy, 2nd ed. London: BMJ Publishing; 1995; 8-21

Pregnancy risk categories - FDA• Category A: Controlled human studies have

demonstrated no fetal risk – levothyroxin

• Category B: Animal studies indicate no fetal risk, OR animal studies suggest a potential for harm, but no well-controlled human studies – paracetamol

• Category C: No adequate human or animal studies OR potential fetal effects in animal studies, but no available human data - theophyllin

• Category D: Evidence of fetal risk, but benefits outweigh risks - ACE inhibitors

• Category X: Evidence of fetal risk. Risks outweigh any benefits - statins, vitamin A analogues

Absolute Relative

CytotoxicBusulphan, Cyclophosphamide, MethotrexateVitamin A analoguesEtretinate, IsotretinoinThalidomideCardiovascular drugsAngiotensin-converting-enzyme inhibitors,

Losartan, AmiodaroneAntibioticsCiprofloxacin, Chloramphenicol (3rd trimester), Vancomycin, Trimethoprim (1st trimester)Antifungal drugsGriseofulvin, Ketoconazole, Fluconazole,

Itraconazole, TerbinafineAnti-inflammatory drugsNSAIDs (3rd trimester), COX-2 inhibitors,

ColchicineEndocrinological drugsDES, Chlorpropamide, SulphonylureasRadioactive iodine, Sex hormones, OctreotideAntihelminthic drugsMebendazole

CytotoxicAzathioprinePsychotropic drugsAntipsychotic drugs - LithiumAnticoagulantsWarfarinAnticonvulsantsCarbamazepine, Phenytoin, Sodium valproate, Lamotrigine, Felbamate, Gabapentin,

Oxcarbazepine, Tiagabine, Topiramate, VigabatrinEndocrinological drugsCarbimazole, PropylthiouracilCardiovascular drugsBeta-blockersAntibioticsAminoglycosides, Nitrofurantoin (3rd trimester)

Contraindicated drugs

Shehata HA, Nelson-Piercy C. Drugs in pregnancy. Drugs to avoid. Best Pract Res Clin Obstet Gynaecol. 2001; 15(6):971-86

Natural Remedies• Black Cohosh

– used for treating symptoms of PMS– can produce uterine contractions

• Chamomile– used in inflammation of the skin, mouth, throat &

colds– contains hydroxycoumarin, which is a relative of the

coumarin anticoagulants

• Ma Huang / Ephedra– used for treating sinus congestion, cold and "natural’ weight-

loss treatment– over 1000 reports of potential adverse occurrences have been

registered with the FDA regarding cardiovascular events– adverse events have included kidney stones and hepatic

injury

• Quinine– used for treating malaria, muscle cramps, fever, GIT

disturbances– has been used as a drug to promote abortion– should be avoided during pregnancy because of a risk for

causing miscarriage or stillbirth

• Iodides– can be purchased in some remedies for treating

symptoms of a cold or the flu– can cause fetal thyroid gland dysfunction when used

after 1st trimester

• St. John's Wort– a very weak antidepressant– not recommend during pregnancy due to its uterotonic

effects– no side effects were observed in infants during

breastfeeding

Natural Remedies

Elicit Drugs• amphetamines, and heroin, according to a 2003

study by the CDC and Prevention

• These and other illicit drugs may pose various risks for unborn babies and pregnant women

• Some of these drugs can cause a baby to be born too small or to have withdrawal symptoms, birth defects, or learning or behavioral problems

• However, because most pregnant women who use illicit drugs also use alcohol and tobacco (which also pose risks to unborn babies), it often is difficult to determine which health problems are caused by a specific illicit drug

Cocaine• Increase the risk of miscarriage

• preterm labour or IUGR

• Increased risk of lifelong disabilities such as mental retardation and cerebral palsy

• Cocaine-exposed babies also tend to have smaller heads, which generally reflect smaller brains

• Some studies suggest that cocaine-exposed babies are at increased risk of birth defects, including urinary-tract defects and, possibly, heart defects

• Cocaine also may cause an unborn baby to have a stroke, which can result in irreversible brain damage or a heart attack, and sometimes death.

• placental abruption

• Feeding difficulties and sleep disturbances, jittery and irritable.

• Greater chance of dying of sudden infant death syndrome (SIDS).

Marijuana• IUGR. These effects are seen mainly in women who use marijuana

regularly (6 or more times a week)

• Premature delivery

• After delivery, some babies undergo withdrawal-like symptoms including excessive crying and trembling

• Couples who are planning pregnancy also should keep in mind that marijuana can reduce fertility in both men and women, making it more difficult to conceive

• Some did not find any increased risk of learning or behavioral problems, however, others found children are more likely to have subtle problems that affect their ability to pay attention and to solve visual problems

• Exposed children do not appear to have a decrease in IQ

Ecstasy & amphetamines• The use of Ecstasy has increased dramatically in recent years. To

date there have been few studies on how the drug may affect pregnancy

• One small study did find a possible increase in congenital heart defects and, in females only, clubfoot

• Babies exposed to Ecstasy before birth also may face some of the same risks as babies exposed to other types of amphetamines

• Methylamphetamine, also known as speed, ice, crank and crystal meth may cause an increased risk of birth defects, including cleft palate, and heart and limb defects

• Contribute to maternal high blood pressure & IUGR, premature delivery, and PPH

• • After birth, babies who were exposed to amphetamines appear to

undergo withdrawal-like symptoms, including jitteriness, drowsiness and breathing problems.

Heroin• Common complications include miscarriage, placental

abruption, poor fetal growth, premature rupture of the membranes, premature delivery and stillbirth

• Low birthweight and serious prematurity-related health problems during the newborn period, including breathing problems and brain bleeds, sometimes leading to lifelong disabilities

• Most babies of heroin users suffer from withdrawal symptoms after birth, including fever, sneezing, trembling, irritability, diarrhea, vomiting, continual crying and, occasionally, seizures

• Babies exposed to heroin before birth also face a ten-fold increased risk of sudden infant death syndrome (SIDS)

Heroin• A pregnant woman who uses heroin should not attempt

to suddenly stop taking the drug as this can put her baby at increased risk of miscarriage or premature birth

• She should consult a doctor or drug treatment center about treatment with methadone

• Although infants born to mothers taking methadone also may show some signs of dependence on the drug, they can be safely treated in the nursery and generally do far better than babies born to women who continue to use heroin

• Some studies suggest that children exposed to heroin before birth are at increased risk of low IQ (in the mentally retarded range) and of serious behavioral problems

Teratogen Information Services

United Kingdom• National Teratology Information Service (NTIS)

– Newcastle (191) 232 1525

United States• Organization of Teratology Information Services

– Utah (801) 328-2229 (for referral to nearest service)– World Wide Web address: http://orpheus.uscd.edu/ctis/

Canada• Motherisk Program

– Toronto (416) 813-6780– World Wide Web address: http://www.motherisk.org

Thank you !