Feeding of Neonate Born to HIV-Positive Mother

Cloherty's Manual of Neonatal Care (7th Edition) - Key Recommendations

Specific Guidance (Cloherty 7th Ed):

• Advise exclusive formula feeding from birth
• No breastfeeding; no mixed feeding
• Formula feeding eliminates postnatal HIV transmission risk via breast milk

• WHO 2010 recommendations (endorsed in Cloherty): HIV-seropositive women should be offered antenatal and intrapartum maternal ART or infant prophylaxis
• Each country decides whether HIV+ women should exclusively formula feed OR breastfeed with concomitant ART
• If breastfeeding is chosen: exclusive breastfeeding for the first 6 months, with complementary foods added thereafter, and rapid weaning at 12 months
• Do NOT mix-feed (breast milk + formula together) - mixed feeding carries higher HIV transmission risk than exclusive breastfeeding

• Combination ARV prophylaxis for the neonate should be given regardless of feeding mode
• Zidovudine (AZT) based regimen for 4-6 weeks (standard low-risk) OR triple-drug prophylaxis for high-risk infants (e.g., mother with no antenatal ART)
• Data from Thailand showed transmission rate of only 2% using ZDV + nevirapine + exclusive bottle feeding

"The Centers for Disease Control and Prevention recommends that women who test positive for HIV in the United States should avoid breastfeeding."

Indian (NACO) National Guidelines - Infant Feeding in HIV-Exposed Infants

• Safe water and sanitation may not be guaranteed
• Exclusive formula feeding increases risk of diarrhoea, pneumonia, malnutrition - negating the benefit of reduced HIV transmission
• Stigma of not breastfeeding may expose the mother's HIV status

NACO National Recommendation: Breastfeeding with Maternal ART

The 6 AFASS Criteria for Replacement Feeding (NACO Box 2):

1. Safe water and sanitation are assured at household and community level
2. Affordable - mother/caregiver can reliably provide sufficient replacement feeding to support normal growth
3. Feasible - milk can be prepared frequently enough in a clean manner (low risk of diarrhoea/malnutrition)
4. Sustainable - exclusive replacement feeding for the first 6 months can be maintained
5. Family is supportive of this practice
6. Access to health care offering comprehensive child health services

Breastfeeding Counselling by NACO (For Mothers Who Choose to Breastfeed):

• Initiate breastfeeding within the first hour of birth
• Practice exclusive breastfeeding for 6 months
• Introduce complementary foods at 6 months (180 days) while continuing breastfeeding
• Continue breastfeeding for at least 12 months, up to 24 months or beyond (same as general population) while on ART
• Stop breastfeeding only when a nutritionally adequate, safe diet without breast milk can be provided

Maternal ART Effect on Infant:

• Maternal ART decreases viral load in blood and breast milk
• ART in breast milk acts as pre-exposure prophylaxis (PrEP) for the infant
• Concomitant maternal ART + exclusive breastfeeding dramatically reduces postnatal transmission

Infant ARV Prophylaxis (Both Guidelines)

• NVP dose: 2 mg/kg/dose OD for term neonates
• Start within 6-12 hours of birth

Comparison: Cloherty vs. Indian (NACO) Guidelines

Red Book 2021 (AAP) Addendum

• All HIV-infected women should be counseled regarding breastfeeding
• HIV has been detected in human milk both as cell-free virus and cell-associated virus
• Neither maternal nor infant postpartum ART is sufficient to completely eliminate the risk of HIV transmission through breastfeeding
• HIV-infected women who choose to breastfeed should be informed of the residual risk

Key Take-Away

Steroidogenesis

The Complete Steroidogenesis Pathway

Step 1 - Cholesterol: The Universal Precursor

• Mostly derived from plasma LDL (majority)
• A small fraction synthesized in situ from acetyl-CoA via mevalonate and squalene
• Stored as cholesterol esters in cytoplasmic lipid droplets until needed

Step 2 - The Rate-Limiting Step: Cholesterol → Pregnenolone

• StAR protein (Steroidogenic Acute Regulatory protein) transports cholesterol from the outer to the inner mitochondrial membrane - this is the key rate-limiting event
• CYP11A1 (P450scc - side chain cleavage enzyme) then cleaves the side chain of cholesterol at C20-C22 via sequential hydroxylations:
  • First hydroxylation at C22
  • Second hydroxylation at C20
  • Side chain cleavage (removal of isocaproaldehyde, a 6-carbon fragment)
  • Product: Pregnenolone (a 21-carbon steroid)
• StAR expression is stimulated by ACTH (in adrenals) and LH/hCG (in gonads)

"An ACTH-dependent steroidogenic acute regulatory (StAR) protein is essential for the transport of cholesterol to P450scc in the inner mitochondrial membrane." - Harper's Biochemistry

Step 3 - Three Zone-Specific Pathways in the Adrenal Cortex

A. Zona Glomerulosa (Outer) - Mineralocorticoid Pathway → Aldosterone

• Note: Zona glomerulosa lacks 17α-hydroxylase (CYP17A1), so it cannot make cortisol
• Regulated by: Renin-Angiotensin-Aldosterone (RAA) system

B. Zona Fasciculata (Middle) - Glucocorticoid Pathway → Cortisol

• Regulated by: HPA axis (CRH → ACTH → Cortisol)
• C21 hydroxylation is necessary for both glucocorticoid and mineralocorticoid activity

C. Zona Reticularis (Inner) - Adrenal Androgen Pathway → DHEA/DHEAS

• CYP17A1 is a dual-function enzyme: 17α-hydroxylase activity + 17,20-lyase activity
• The lyase activity acts only on 17α-hydroxy-containing molecules
• DHEA is a prohormone - the weak androgen converted peripherally to more potent forms

Step 4 - Gonadal Steroidogenesis

Testicular (Leydig Cells) → Testosterone

• Stimulated by LH (not ACTH)
• Rate-limiting step is the same: StAR-mediated cholesterol transport → CYP11A1 → Pregnenolone
• Pregnenolone → Testosterone via two pathways:
  • Δ5 pathway (predominant in humans): Pregnenolone → DHEA → Androstenedione → Testosterone
  • Δ4 pathway: Pregnenolone → Progesterone → 17-OHP → Androstenedione → Testosterone
• Requires 5 enzyme activities in 3 proteins: 3β-HSD/Δ5,4-isomerase; 17α-hydroxylase/17,20-lyase (CYP17A1); 17β-HSD

Peripheral Conversion: Testosterone → DHT

• In skin, prostate, and external genitalia: 5α-reductase (SRD5A2) converts testosterone to 5-dihydrotestosterone (DHT), a more potent androgen
• Required for male external genitalia differentiation (weeks 8-14 of gestation)

Ovarian (Theca + Granulosa Cells) → Estrogens

• Two-cell, two-gonadotropin theory:
  • Theca cells (LH-driven): Cholesterol → Androstenedione/Testosterone
  • Granulosa cells (FSH-driven): Androstenedione/Testosterone → Estrone/Estradiol via aromatase (CYP19A1)
• Aromatization involves removal of the C19 methyl group and aromatization of the A ring

Key Enzymes Summary

Regulatory Control

• Adrenal cortisol secretion follows a circadian rhythm: peaks in the early morning (before awakening), lowest in the evening
• This is controlled by the hypothalamic suprachiasmatic nucleus (SCN) via pulsatile CRH release

Placental Steroidogenesis

• Has high steroid sulfatase activity: converts DHEAS (from fetal adrenal) back to DHEA
• DHEA → Estrogens (estrone, estradiol, and estriol) via 3β-HSD and aromatase
• Estriol (E3) is unique to pregnancy - requires fetal adrenal DHEAS as substrate

Clinical Significance - Enzyme Deficiency Disorders