seminar on maternal drugs

1. DR MOHTARAMA MOSTARI
DR AFROZA SHUMA
Resident ,year -3
Neonatology
BSMMU.

2. Effects of Maternal Medication on The
Fetus and The Newborn

3. objectives
Introduction
Pharmacokinetics and pharmaco-dynamics of during pregnancy
Drug therapy during pregnancy, childbirth and Lactation
 Physiological changes of drugs in pregnant women.
 Cross-placental transfer of drugs
 Excretion of drugs in breast milk
 Drug safety + FDA categories- ABCDX
Historical background
Commonly used drugs in pregnancy and their effects on neonates

4. Introduction
 Pregnancy, childbirth and lactation cause unique challenges in terms of
drug therapy.
 The pregnant mother and her unborn child are exceptionally vulnerable
from a physiological, clinical and ethical point of view.
 This warrants careful considerationof a number of important aspects,
which could influence the decision for drug therapy.

5. Why medication needed during pregnancy
Pharmacotherapy during pregnancy, childbirth and lactation may be necessary
for a number of reasons:
 Chronic illness or disability, e.g.- DM, HTN, HIV
 Acute illness or trauma during pregnancy.
 Pregnancy, labor related disorders and emergencies.
 In a few cases, the fetus may actually be the target of the drug therapy
administered to the mother, as part of a fetal therapy regimen.

6. +
Thefollowing aspects mustbe considered:
 Physiological changes during pregnancy that may affect drug
action and kinetics.
 Drug toxicity during pregnancy.
 Cross-placental transfer of drug molecules and their
metabolites.
 Excretion in breast milk.
 Drug safety during pregnancy and lactation

7. +
Physiological changes and drugtoxicity.

8. +
Physiological changes and drug toxicity
 Certain physiological changes during pregnancy have implications for
drug therapy and may affect any of the four basic pharmaco-kinetic
processes :
Absorptin
Progesterone slows gastric
emptying and gut motility
increase absorption
hepatic drug metabolizing enzymes
are induced due to progesterone
Metabolism and elimination
Increases CO, renal blood flow (100%)
and GFR by 70%
increase renal excretion
Excretion
Distribution
Increase plasma volume and Vd
low albumin increase free drugs

9. +
Cross-placental transfer of drug molecules and
their metabolites

10. +
Transport Across thePlacenta
gases
Facilitated
Diffusion
Active Transport
Pinocytosis.
Leakage.
glucose.
Amino acid, water
soluble vitamins,
digoxin
Complex protein,
antibodies, some
fat and viruses.
Fetal cells exfoliate
into the maternal
circulation.
Simple Diffusion
placenta

11. Drug Affinity for Specific Tissues
Tetracycline
 Warfarin
Aminoglycosides
Quinine
 Chlorpromazine
Diethylstilbestrol
Corticosteroids
Phenytoin
Iodides
Propylthiouracil
Teeth
Middle ear
Retina
Mullerianduct,Vagina
Adrenal Gland
Thyroid Gland

13. “The drugs which are lipid soluble, of low molecular
weight, low protein binding, less ionized can easily
cross the placenta & reach to the fetus”
Drugs Molecular weight< 1000
Daltons cross placenta (<500 D cross
easily)
Most drugs have a molecular weight
below 1000 daltons
Most drugs can cross placenta & reach to the fetus

15. +

16. “All Or None effect”
At pre-implantation stage that is before 20 days
after fertilization: teratogenicity
uncommon ……early embayonic death or
pregnancy will continue without residual effect

17. Window of susceptibility
A critical phase for the induction of structural malformations
(Teratogenicity)usually occurs during the period of
organogenesis. In humans, this critical period extends from
about 20–70 days after the first day of the last menstruation ,
or from 1 week before the missed menstruation until the
woman is 44 days late.

18. After Organogenesis( in 2nd & 3rd trimester)
Teratogenicity is unlikely , but
drugs may alter growth &
function of normally formed
fetal organs and tissues

19. +
Excretion of drugs in breast milk

20. +
Excretion of drugs in breast milk
During lactation, drugs may pass from the bloodstream to
the breast milk -
especially if they are lipid-soluble or basic drugs.
 and if they are water-soluble molecules with a relative
molecular mass of less than 100 Da.

21. WHO classification of drugs during breastfeeding
(2002)
1. Compatible withbreastfeeding.
2. Compatible with breastfeeding (occasional mild side effects) Monitor infant
for side effects
3. Avoid if possible (significant side effects).Monitor infant for side-effects
4. Avoid if possible. (May inhibit lactation). Monitor for amount of milk
5. Contraindicated (dangerous side effects)

23. +
Drug safety + ABCDX

24. +
FDA Categories of Drug Safety During Pregnancy
 The pregnancy risk classification used by the US Food and Drug Administration
(FDA) is often quoted and consists of five different categories, namely A, B, C, D
and X.
 Category A drugs are considered to be relatively safe during pregnancy
 Category X drugs are absolutely contraindicated.
 It is of great importance to consult suitable drug references when dispensing
medicines to pregnant or lactating mothers.
 Known teratogens should obviously be avoided during pregnancy.

25. FDA Pregnancy Category
(1979)

26. FDA pregnancy
Category: C/D
FDA category : X
Always consider the risk of the therapy against
the potential for not treating the disease
Risk-benefit
Ratio

27. Limitations of previous FDA
Pregnancy Category
oversimplification leads to a
Lack of data
doesn’t
imply safety
Lots of confusion
among category
B,C & D
It doesn’t provide
information following
inadvertent drug
exposure during an
unplanned pregnancy

28. An UpdateNEW FDA Pregnancy Drug labeling

29. DRUGS CATEGORY
Analgesics and antipyretics B and C
Acetaminophen B
Aspirin B
Phenacetin C
Antiemetics B and C
Antibiotics B,C and D
Penicillin,ampicillin,amoxicillin B
Cephalosporin B
Erythromycin B
Gentamycin C
Streptomycin ,Tetracycline D
Metronidazole B
Commonly used drugs and their categories

30. DRUGS CATEGORY
Antimalarial C
Antifungal C
Antitubercular B and C
Ethambutol B
Rifampicin C
Pyrizinamide C
Vitamin B,C,D,E and folic acid A

31. A study conducted in Canada by Wen et al.(2008) using a pharmacist database
to estimate the frequency of exposure to prescription FDA category C, D, and X
medicines in pregnant women showed that a total of 3604 (19.4%) of the
women were found to have used FDA category C, D and X medications at least
once during pregnancy.
 The pregnancy exposure rates were 15.8, 5.2and 3.9%, respectively, for
category C, D and X drugs, and
 In the first, second and third trimesters exposure rate were 11.2, 7.3 and 8.2%
respectively.
 The most common medicines were salbutamol, cotrimoxazole, ibuprofen,
naproxen and oral contraceptives.
Salbutamol and cotrimoxazole are category C medicines while ibuprofen and
naproxen are category D medicines and oral contraceptives are category X
medicine.

32. Teratogens
‘Teratos’means

33.  Term is derived from Greek “teratos=monster”
 Teratogen – An agent or factor which can cause
abnormalities of form &functions (birth defects) in an
exposed embryo or fetus

34. Examples of known teratogens

35. Vit-A Embroyopathy
Thymic
aplasia,
parathyroid
abnormality
Ear abnormality
High rate of
abortion,
cardiac
defects

36. Isotretinoin teratogenicity Prevention Programme

37. Fetal warfarin Syndrome
Fetal
haemorrhage
Optic atrophy
]First
Trimester
[
2nd
& 3rd
Trimester
Chondrodysplasia punctata
Midfacial hypoplasia
Category:X/D

38. Diethylstilbestrol(DES)
DES
-Mother
Breast
cancer
DES-Son
Infertility,
Testicular
cancer
DES-daughter
Adenocarcinoma
of vagina

39. Fetal alcohol syndrome (FAS) Category:X
“If you’repregnant,don’t drink,Ifyoudrink,don’t get pregnant”
Leading
cause Of
Mental
retardation

40. Fetal hydantoin syndrome CATEGORY: D
Cardiac
defect
(eg;VSD)
Urogenital
abnormality
eg; hypospadias
Cleft lip/palate Hypoplastic nails
PHENYTOIN

41. Fetal valproate syndrome
Cognitive
impairment,
autism
NTD
Cardiac
malformation
CATEGORY: D

42. Lithium induced teratogenicity
Fetal
Hypothyroidism
Fetal
diabetes
Insipidus
(reversible) Floppy-baby
syndrome
CATEGORY: D

43. The Thalidomide Tragedy
….Lessons for drug safety & regulation
Phocomelia
(seal limb)
Introdued in 1957 (Germany : sleeping pill→→pill for morning sickness)
More than 10,000 babies were affected around the world
Banned: 1962

45. Why Challenging ?????
Understanding the risk of drugs use in pregnancy has lagged behind
the advances in other areas of pharmacotherapy.
The ethical barriers to randomized clinical trials (RCT) with
pregnant women & lactating mothers is the main reason for
insufficient data.

46. But the fact is……..
About 90% of all pregnant women take at
least one medication & 70% take one or more
prescribed drugs at some point in their
pregnancy.
Large percentage of them also take OTC drugs
or herbal products of potential risk .
About 2-3% of all birth defects are due to
drugs used in pregnancy.

47. Use of drugs during pregnancy is common and it is increasing. It was observed
that approximately 64% of pregnant women were prescribed one or more
drugs during pregnancy, excluding vitamins and minerals, with an average of
2.9 drugs per prescription(Andrade et al, 2004).
About 8% of pregnant women need permanent treatment due to various
chronic diseases and pregnancy-induced complications (Kasaye and Mesfin,
2015).
 About 2% to 3% of all birth defects result from drugs that are taken during
pregnancy to treat a disorder or symptom (Sachdeva and Patel, 2009)
 Average number of drugs per prescription was 6.1±3.6. More drugs per
prescription were prescribed during 2nd trimester. <1% cause birth defect.
( department of pharmacology, DMC)

48. Anti-hypertensive drugs in pregnancy
20
weeks
Gestational HTN
Pre-existing HTN
Normally, during the second trimester, blood pressure decreases, and
then rises again in the last trimester – up to the level before pregnancy or
higher. During birth, cardiac output and blood pressure rise even further.
Generally, 1–3 days after birth hemodynamic levels are back to pre-
pregnancy levels, sometimes normalization may take 1 week.
Blood pressure targets : 120/80 mmHg

49. Recommended drugs
Labetalol (C )
Methyldopa (B)
Nifedipine (C)
Hydralazine (C)
Cautiously used:
β-blocker(C)
Diuretics(C)
Prazosin (C )
Contraindicated:
ACE-inhibitor
ARB
Spironolactone
Methyldopa: most studied drug;
preferred for long term Rx
Methyldopa avoided in post-partum
period as it causes depression
Labetalol now-a days Ist line(better
control with better safety profile)
Nifedipine-slow release formulation
ACE-inhibitor/ARB:
Ist trimester: class C
2nd & 3rd : Class D
 Renal Dysgenesis,
 Oligohydramnios,
 Pulmonary hypoplasia
 Reduce ossification
 IUGR, stillbirth
Atenolol should be avoided,
(risk of prematurity, SGA, IUGR)
Beta blocker during labour
→neonatal bradycardia &
hypoglycemia
Thiazide: preferred diuretic
( volume depletion
→oligohydramnios,
thrombocytopenia)

51. J of hypertension, Volume
35 Number 11 November
2017

52. Anti-diabetic drugs in pregnancy
24
weeks
Pre-existing DM Gestational DM
either
One-hour postprandial <7.8 mmol/L) or
Two-hour postprandial <6.7 mmol/L)
Target blood glucose
Fasting <5.3 mmol/L

53. Insulin is adrug of choice
Safe Insulins in pregnancy
• Soluble/regular insulin
• Intermediate acting
• Rapidly acting analogue(aspart,lispro)
• Among long acting analogue only
insulin detemir
Insulin which are
avoided
• Other long
acting : Glargine,
Degludeg
• Rapidly acting
analogue:
glulisine

54. All oral agents lack
long-term safety data
Metformin &
glyburide may be
used, both cross the
placenta to fetus,
with metformin likely
crossing to a greater
extent than glyburide.
Sulfonylurea causes
intractable
hypoglycemia
Recommendation
about metformin in
pregnancy
When used to Rx PCOS,
need not to be
continued once
pregnancy has been
confirmed.

56. Thyroid Disorders In Pregnancy

57. Hypothyroidism In Pregnancy
Levothyroxine : Category A
Target
TSH : <2.5 mU/L
(lower reference
range)
FT4: upper
limit of normal
TSH
monitoring:
4-6 weekly
Don’t give
FeSO4
simultaneously
with T4
–reduces its
efficacy.
At least 2
hour gap is
recommended

58. ↑dose of levothyroxine
by 30%
↑appx 25–50 µg daily
OR
Add two additional pills weekly
(eg; Monday & Friday) as soon
as pregnancy is diagnosed and
then adjust the dose by serial
measurements of TSH.
↑↑metabolism of
thyroxine by the
placenta
↑↑serum
thyroxine
binding globulin
Post-partum: may return to pre-pregnancy dose

59. Hyperthyroidism in pregnancy
Target :
FT4 level upper
third of reference
range
Propanolol 20-40
mg tds can be
used 2-3 weeks
while ATD take
effects
Hyperthyroidism is most difficult to control in the first
trimester of pregnancy & easiest to control in the third
trimester.
Antithyroid drugs(ATD) treatment of choice but cross placenta

60. Propylthiouracil (PTU)
drug of choice(Isttrimester),
carbimazole causes aplasia cutis
Hepatotoxicity
of PTU
Carbimazole(2nd &3rd trimester)
Breastfeeding
PTU drug of choice as less
excreted in milk
Safe at dose <150mg of PTU&
carbimazole <15mg
Check liver function
monthly
Check
TFT 4-6
weekly

61. Don’t use “Block &
replace regime”
As higher dose of ATD
required & there is
minimal transplacental
transfer of T4,thereby
risking fetal
hypothyroidism
Don’t use
“Radioiodine
therapy”
In pregnancy,
lactation & 4
months prior to
conception
DON’Ts…..
Risks of neonatal
hypothyroidism &
goiter are reduced if
woman on
carbimazole 20mg or
less (PTU 200mg or
less)in last few wks
of gestation

62. Asthma in Pregnancy

63. ICS is the preferred treatment of choice for long-term therapy in pregnancy
(Global Initiative for Asthma 2012). More thoroughly investigated substances such
asbudesonide areto be preferred.
Ipratropium bromide may be used for bronchodilatation during pregnancy
when drugs of choice (SABA, ICS, LABA) are not sufficiently effective.

64. Antibiotics in pregnancy
One of the safest antibiotics in pregnancy
Penicillin
Cephalosporin
Nitrofurantoin
Macrolids
One of the safest antibiotics in pregnancy ( ceftriaxone,
cefixime, cefotaxime are safer options)
Azithromycin & Erythromycin
Commonly used to Rx UTI but should avoid in late pregnancy
because of having potential risk of haemolytic disease of
newborn
FDA category: B

65. FDA Category : C/D
Fluoroquinolone
Cartilage
damage in
animals. safer
alternatives
usually exists
Trimethoprim Chloramphenicol
Sulfonamide
Folate antagonist
Better to avoid in
Ist
Trimester(NTD)
Gray-baby
syndrome
Hypotension
cyanosis
Hemolytic
anaemia
Methhemog-
lobinemia
Neonatal
Jaundice
–Kernicterus
(best to avoid in
3rd trimester)

66. FDA Category : D
Tetracycline Aminoglycosides
Gentamycin, Streptomycin
Permanent staining of teeth &
enamel hypoplasia(2nd &3rd
trimester)
Ototoxicity
Damage auditory and vestibular
nerve
Both are Compatible with breast-feeding

67. Anti-viral agents
[Lamivudine and zidovudine are medications that are preferred
in pregnancy because of extensive experience
acyclovir should be preferred as the best
evaluated antiviral drug( FDA category:B)
Nevirapine is the agent that should be preferred if a
NNRTI is required during pregnancy
Anti retroviral
therapy

68. ❑ Tenofovir →fetal bone changes and the paucity of other data
about its pregnancy-related risks (category:B)
❑ Zidovudine used in the perinatal period →transient anemia in
newborns & neutropenia
❑ Efavirenz→ teratogenic effects (EFV containing regimen must be
avoided)
❑ Nevirapine →be aware of hepatotoxicity.
❑ Combination of stavudine/didanosine →lactic acidosis with OR
without pancreatitis.

69. Anti-fungal agents
Clotrimazole and miconazole :local
antifungal medications of choice
Nystatin minimaly absorbed &
effective for vaginal therapy
life-threatening
deep fungal
infections
As griseofulvin has
teratogenitic potentiality
its application in pregnancy
should be avoided
ketoconazole is usually
avoided in systemic use
because it is poorly
tolerated and has many
suitable alternatives
liposomal Amphotericin B: Ist line
(no reports of teratogenesis)
fluconazole and itraconazole are to be
preferred as the better-tested
medications(start after the first trimester).
Fluconazole: exhibits
dose-dependent
teratogenic effects
(cranio-facial abnormality);
safe at lower doses(150
mg/day):

71. TB in Pregnancy
Active tuberculosis (TB) requires treatment in pregnancy, as the
disease endangers not only the mother, but also the fetus.
Pregnancy itself does not seem to affect the course of TB
First-line drugs : isoniazid (+pyridoxine), rifampicin,
ethambutol and pyrazinamide.
There is lack of sufficient data about 2nd line
drugs.It is challenging to Rx MDR or XDR TB

72. The use of Pyrazinamide (PZA)during pregnancy is
recommended in several guidelines (e.g. WHO 2010).
The American Thoracic Society recommends to hold
PZA as a reserve drug during pregnancy, as there are
currently insufficient data about its teratogenicity. If PZA
is not used, Rx may be prolonged ( 9 months :2HRE/7HR)
PNZ
phalacy
Streptomycin is contraindicated during pregnancy
because of its ototoxic properties.(Independent of
critical period of organogenesis; 1 in 6 is affected)

73. vitamin Kprophylaxis:
To prevent
Rifampicin induced
bleeding manifestation
Pyridoxine prophylaxis:
To prevent
INH induced neuropathy
Breast Feeding in not a contraindication when
a woman is on anti-TB drugs
Mother with open TB must
receive INH prophylaxis with
vit-B6 for 6 months.

74. quinine plus
clindamycin
first trimester with
uncomplicated malaria
tropica
second and third
trimester
artemisinin
derivatives
Although data from
prospective studies are
limited quinine, chloroquine,
proguanil, and clindamycin
are considered safe during
early pregnancy
Antimalarial agents
WHO recommendation
Halofantrine and primaquine should
be avoided

75. Analgesics agents
Acetaminophen (PCM) : choice of analgesic in all stages of pregnancy
Salicylates : aspirin in low dose used for prevention of pre eclampsia and IUGR
Therapeutic dose causes neonatal bleeding (deficiency of vitk dependent clotting factor)
Predispose to bilirubin encephalopathy (reduce bilirubin binding capacity of albumin)
Methemoglobinemia and platelet dysfunction in fetus.
NSAID : preferably be avoided.
 Causing miscarriage, fetal renal dysfunction. Oligohydomnios.
Closure of ductus arteriosus leading to PPHN in newborn

76. Data currently available suggest that
omeprazole is not teratogenic in humans.
While information on other PPIs is limited,
a systematic review of the evidence
suggests that they are also not teratogenic.
• Antacids
• H2-blocker(ranitidin
e preferred)
• Proton-pump
inhibitor (PPI)
Heartburn, GERD
PPI

77. Anti-epileptic drugs(AED) in Pregnancy
Update-2017
In a network meta-analysis involving 96 eligible studies, published in
BMJ in 2017, the newer generation AEDs, lamotrigine and levetiracetam,
were not associated with significant increased risks of CMs compared to
control, and were significantly less likely to be associated with children
experiencing cardiac malformations than control. However, this does not
mean that these agents are not harmful to infants/children exposed in
utero.
But, Gupta J et.al. reported a case of levetiracteam causing
facial dysmorphism.

78. Pre-pregnancy
counseling:
A woman suffering
from epilepsy needs
to know that risk for
major malformation
increases 2/3 folds
when using AED
higher risk of a recurrence
of birth-defect in a
subsequent pregnancy , if
the same AED is used.
So an alternative
antiepileptic regimen
should be considered
prior to the next
pregnancy.
Empirically this recurrence
risk has been estimated to
be about 15% for VPA
folate (1–4 mg/d),
Due to antifolate
effects of
anticonvulsant
Vit-K
prophylaxis
To prevent
neonatal
hemorrhage
Folic acid
prophylaxis: Breast feeding:
Encouraged
close
monitoring of
baby.
Drug conc in
breast milk
relative to
serum ranges
from ~5%
(valproic acid)
to 300%
(levetiracetam)

79. Immunosupressive Therapy in pregnancy

82. Safer Immunosupressives are…..
1. Low Dose Steroid
2. Sulfasalazine
3. Azathioprine
4. Hydroxychloroquine
5. Cyclosporine
Safer regimen for
Transplant in pregnancy
Prednisolone, <15/day
Azathioprine ,<2mg/kg/day or
Cyclosporine,2-4 mg/kg/day

83. Rx with high dose
steroid during wks
8–11 of pregnancy
may warrant an USG
evaluation of fetal
face for detection of
cleft lip & palate.
Safer
dose: <15
mg/day
For systemic, anti-allergic, anti-inflammatory or
immunosuppressive effect prednisolone is the drug of choice.
Category B in low dose
after Ist trimester
Fetal lung
maturation :
Dexamethasone/
betamethasone
Breast-feeding:
Safe but consider
delaying for 4
hours if dose > 20
mg/day
Steroid

84. Cyclophosphamide
Mycophenolate Mofetil
Tacrolimus
Biologics
Category : C/D

86. Use of Biologics in IBD with Pregnancy
A 2014 review of 105 articles on the use of anti-TNF therapy in patients
with IBD and pregnancy found that anti-TNF agents were safe during
pregnancy, and the authors even recommended maintained use and
initiation of therapy with anti-TNF agents for patients who were
refractory to azathioprine, steroids, and 5-aminosalicylate (Khan et al.,
2014). Clowse (2010) looked at the effect on pregnancy of infliximab,
adalimumab, and etanercept both combined and individually compared
with the general population and found no significant differences in the
number of live-born infants, miscarriages, elective terminations, or
congenital abnormalities.

87. Antineoplastic therapy
As a rule, neoplasms in pregnant women are treated in the same
way that they would be if the patient were not pregnant to give
her the best chance for survival .
following antineoplastic therapy, a waiting period of 2years for
the woman and 6 months for the man before conceiving is
recommended.
However, if a pregnancy occurs sooner, there is no
evidence that the risk to the fetus is measurably
increased by the previous treatment.
Busalfan and
chlorambucil induced
cleft palate

88. Vaccination in pregnancy
Live-attenuated vaccines
are contraindicated
MMR should be given at
least 3 months before
pregnancy or at
post-partum peroid Vaccination of women
who are or will be
pregnant during the flu
season is recommended.
Vaccination can occur in
any trimester.
Influenza vaccine(killed)

89. Anesthetic agents
Spinal anesthesia
Sudden maternal
hypotension may result in
fetal hypoxia
Jaundice (bupivacine)
General anesthesia
CNS and
 respiratory
depression
PNA
Local anesthesia
Apnea
Bradycardia
Hypotonia
Fixed and dilated pupil
Intractable seizure
soon after birth

91. Pre-pregnancy & Pregnancy counseling
“Patient-shared
approach”

92. Nursing Safety Options

94. As a general rule, no
drug is absolutely safe
in pregnancy

95. Always calculate
risk-benefit ratio

96. Try to choose an older
agent which has
long-term safety data

97. Consider lowest
possible dose for a
lowest possible period
of time

98. Consider all patients are at
risk of Pregnancy during
their reproductive age.

99. The Good Physician treat
the disease & the great
physician treats the
patient who has the
disease.
Willium Osler

100. Summery Of Resources:
Journal of hypertension, volume 35, number 11, November 2017
Oral anti-diabetic agents for women with established diabetes/impaired glucose tolerance or previous gestational diabetes planning pregnancy,
or pregnant women with pre-existing diabetes.Tieu J1, Coat S, Hague W, Middleton P, Shepherd E.
17 Oct 18;10:CD007724. doi: 10.1002/14651858.CD007724.pub3
 Veronikiet al. Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-
analysis of congenital malformations and prenatal outcomes. BMC Med. 2017 May 5;15(1):95.
Gupta J, Jain S, Rajaram S, Goel N, Gupta B. Facial Dysmorphism: An Unreported Teratogenicity with Levetiracetam. J Clin
Diagn Res JCDR. 2017 Jan;11(1):QD08-QD09.